synthetic pyrethroid insecticides: dermatological evaluation · the synthetic pyrethroids in...

British Journal of Industrial Medicine 1985;42: 363-372

Synthetic pyrethroid insecticides: a dermatologicalevaluationS A FLANNIGAN,' S B TUCKER,' M M KEY,' C E ROSS,2 E J FAIRCHILD II,'B A GRIMES,' AND R B HARRIST'

From the University of Texas' Health Science at Houston, Schools of Medicine and Public Health, Houston,Texas, and Corporate Medical Department,2 Shell Oil Company, Houston, Texas, USA

ABSTRACT Synthetic pyrethroids are lipophilic insecticides whose biological activity seems to bedirectly related to their chemical structure. In this investigation differences in cutaneous sensa-tion were detected by human participants between synthetic pyrethroids with a cyano group inthe (S)-configuration of the 3-phenoxybenzyl alcohol of their molecular structure (fenvalerate)and those that do not (permethrin). A strong relation was noted between insecticidal potency anddegree of induced cutaneous sensation for the alpha-cyano and non-cyano pyrethroids, with aprominent difference between the two. No sensation was observed by any of the same particip-ants on topical exposure to the inert ingredients of these agents. A linear correlation betweenconcentration and degree of induced dysaesthesia was observed for both pyrethroids. Regressingthe cutaneous sensation on the common logarithm of concentration resulted in a regressionequation of Y = 84-0 + 310X, for fenvalerate and Y = 27-5 + 15 8X, for permethrin. A highlyefficacious therapeutic agent for pyrethroid exposure was noted to be dl-alpha tocopherol ace-tate. An impressive degree of inhibition of paraesthesia resulted from the topical application ofvitamin E acetate, with a therapeutic index of almost 100%.

Synthetic pyrethroid insecticides have evolvedthrough a classic sequence of events: activity wasfirst noticed in a natural extract from the flowers ofChrysanthemum cinerariaefolium; reactive agentswere isolated and identified; and finally, increasinglyactive analogues were synthesised. Few insecticidesare as biologically active or possess such a greatpotential for structural variation with total reten-tion, or even possibly enhancement, of potency asthe synthetic pyrethroids. They incorporate a highinsecticidal activity (knockdown) for a wide varietyof insects with a relatively low toxicity for mammals.Numerous derivatives of the original pyrethroids arenow among the most potent pesticides known toman and are being evaluated for many differentapplications, as well as for possible replacements ofthe organophosphate, carbamate, and organo-chlorine insecticides.' Well over 1000 pyrethroidshave been synthesised to date.The natural pyrethrins have long been used

against a wide variety of garden and horticulturalpests, but their poor residual capability, combined

Received 21 May 1984Accepted 2 July 1984

with a high cost, restricted their agricultural applica-tion.2 The more recently synthesised pyrethroids,however, combine this high insecticidal activity witha persistence necessary to control a broad range ofpests. A better knowledge of the field behaviour ofthe synthetic pyrethroids in relation to the pest/predator complex of each agricultural region hasshown how judicious applications can actuallyminimise harm to beneficial insects. Physical proper-ties, such as involatility, lipophilicity, and suscepti-bility to degradation by micro-organisms, haveseverely restricted the efficaciousness of theseagents against various soil insects.The biological activity of the synthetic pyrethroid

insecticides seems to be directly related to theirchemical structure.34 Almost all active pyrethroidsare esters of cyclopropane carboxylic acids withalkenylmethyl cyclopentenolone alcohols. Theirconstituent acids and alcohols, and simple deriva-tives, are practically inactive. Properties such aselectron density and polarisability are of littleimportance. The alpha-cyano derivatives, with acyano group in the S-configuration of the3-phenoxybenzyl alcohol of the molecular structure,have an increased potency of approximately four-

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Flannigan, Tucker, Key, Ross, Fairchild II, Grimes, and Harrist

fold with insects.3 A higher toxicity for cis-isomers,as compared with their corresponding trans-isomers,has also been observed for numerous pyrethroids inthe rat. The highly lipophilic nature of the syntheticpyrethroids has made them practically insoluble inwater, a property that promotes rapid penetrationthrough an insect's cuticle.

Synthetic pyrethroids are considered broad rangeinsecticides that are nerve toxins. They act directlyon the axon through interference with the sodiumchannel gating mechanism that underlies the genera-tion and conduction of each nerve impulse.56 Thepyrethroids induce the sodium channels to closeslower than normal, resulting in a gradually decay-ing inward sodium current after termination ofmembrane depolarisation. This slow influx ofsodium ions on termination of depolarisation isreferred to as a sodium tail current. Non-cyanopyrethroids induce tail currents with time constantsof decay in the order of milliseconds, whereasalpha-cyano pyrethroids result in time constants ofdecay in the hundreds of milliseconds to more thanone second.

Recent clinical studies with isolated preparationsof the peripheral nervous system of the clawed frog,Xenopus laevis, have augmented the distinctionbetween two main classes of these synthetic insecti-cides:

(1) Pyrethroids which do not have an alpha-cyanogroup attached to their molecular structure (al-lethrin, permethrin, cismethrin, and bioresmethrin).These particular insecticides result in relatively shorttrains of nerve impulses in the lateral line senseorgan. In the peripheral nerves they induce adepolarising after potential with repetitive firing.

v c,C1l=C%",CCH3 7 CO-O-Cll2- 10jJ

Cli 3 Perniethrin

(2) Pyrethroids with an alpha-cyano groupattached to the 3-phenoxybenzyl alcohol of themolecular structure (deltamethrin, cypermethrin,fenvalerate, and fenpropathrin). These pyrethroidsinduce long trains of nerve impulses in the lateralline sense organ and do not invoke repetitive activityin the peripheral nerves. Instead, they cause aquickly reversible, stimulus frequency dependentsuppression of the nerve action potential, resultingin a long lasting depolarising after potential.78

CH3 H 3

CI_ _L"< i-LO-0-CH(CN )Fte

Fenvelerate

People are capable of tolerating greater exposuresto synthetic pyrethroids than other insecticides,making them a welcome option. Toxicity from inha-lation or oral or dermal contact with these agents areall minimal. They are not teratogenic in rats, mice,or rabbits nor mutagenic with select bacterialstrains. Subacute and chronic feeding of greaterquantities of these agents to rats has invariablycaused some histopathological changes in the liver;however, these studies are neither indicative norsuggestive of tumorigenicity.9 The relatively lowinherent toxicity witnessed in mammals may beattributed to various factors preventing directinteraction with the nervous system. Unlike otherinsecticides, they have numerous sites for metabolicdegradation.'" One route involves ester cleavage,often controlled by the degree of stearic hindranceabout the linkage. Numerous sites on the moleculesare also susceptible to attack by mixed functionoxidase systems. Therefore, their lipophilic charac-teristic enhances rapid penetration to the arth-ropod's nervous system, whereas in mammals theyare biodegraded both oxidatively and hydrolytically,depending on the chemical composition of thepyrethroid. Rapid metabolic degradation, togetherwith incomplete absorption from the gastrointestinaltract, accounts for the low acute toxicity of theseinsecticides. This has been substantiated by theirincreased toxic nature when administered to mam-mals intravenously rather than orally.'" Evenmyelinated nerves of vertebrates are thought tosequester the pyrethroid molecules, known to belipid soluble in the myelin sheath, thereby prevent-ing a portion of their chemical effect on the nerveaxon.'2 The accumulation of the pyrethroids, how-ever, and their degradation products in various tis-sues over time has not been fully evaluated. Conse-quently, further chronic toxicity studies are war-ranted to ascertain the final destination of thesemolecules after exposure.At present, there is little information in the occu-

pational medical journals concerning the biologicalramifications of human cutaneous exposure to thesynthetic pyrethroids. Kolmodin-Hedman et alnoted that forestry workers displayed symptoms thatwere mainly irritative, such as itching and burning ofthe skin.'3 Some individuals reported cough anddyspnoea when using fenvalerate and permethrin asa wettable powder. The authors indicated thatwhether the burning and tingling skin sensationreported by some of the subjects was an irritativeone, or a sign of peripheral sensory nerve involve-ment, could not be discerned. LeQuesne et al foundthat among 23 research workers exposed to synthe-tic pyrethroids at the Shell Research Laboratories atSittingbourne, 19 experienced one or more episodes

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Synthetic pyrethroid insecticides: a dermatological evaluation

of abnormal facial sensation, developing with alatent period of 30 minutes to three hours and per-sisting for about 30 minutes to eight hours.4 Theynoted that the delay in the onset of symptoms afterexposure was unlike that after cutaneous contactwith any other irritant solution. There were noabnormal neurological signs, and electrophysiologi-cal studies were normal in the arms and legs of eachworker. Tucker and Flannigan noted a difference inthe degree of paraesthesia among agriculturalapplicators of fenvalerate.'5 The susceptibility of theworkers did not appear to be based on race, per-sonal history of atopy, or the number of exposures.Virtually all exposed individuals were affected. Thecutaneous sensation described was a stinging orburning that progressed to numbness in about onethird of the exposed workers. The sensation typi-cally began several hours after contact, peaked inthe evening, and was rarely present the next morn-ing. The intensity of the sensation varied accordingto the type and extent of exposure. Clinical signs ofinflammation, such as oedema or vesiculation, werenot apparent. The response did not increase withcontinued exposure in a given season or even overseveral seasons, and did not appear to decrease insensitivity, as one might expect in a tachyphylacticresponse when using a compound on a daily basis.As early as 1941, workers with the plant extract,

pyrethrum, noted a paraesthesia similar to, but lessintense than, that described by present day workerswith the more potent synthetic agents.'6 The univer-sal aspect of this cutaneous reaction is emphasisedby reports from diverse parts of the world, as well asfrom varying occupational settings, indicating thatparaesthesia from the pyrethroids is a widespreadproblem.'3 -16 The sensation can be quite uncom-fortable, and may result in the substitution of moretoxic insecticides by sensitive workers in order toavoid the annoying paraesthesia. Even mild sensa-tions may lead to pronounced anxiety. To summarise,the occurrence of paraesthesia is widespread andmay result in discomfort and anxiety leading to adecrease in the usefulness of this class of insecticide,despite several advantages over other insecticideswhich cause no apparent cutaneous sensation.

Materials and methods

The following studies were conducted to test thehypothesis that possible differences between twowidely used synthetic pyrethroids exist in producingcutaneous sensation or irritation or both. One of thetwo agents evaluated was fenvalerate, an alpha-cyano pyrethroid, the other being permethrin, anon-cyano pyrethroid. The chemical name for fen-valerate is cyano (3-phenoxyphenyl) methyl

4-chloro-alpha-( 1-methylethyl) benzeneacetate,with an empirical formula of C25H22C1NO3. Tradenames for fenvalerate are Sumicidin, Belmark, andPydrin. Permethrin's chemical name is (3-phenoxyphenyl) methyl (±+) cis-trans 3-(2-2-dichloroethenyl)-2-, 2-dimethyl-cyclopropane-carboxylate and has an empirical formula ofC2,H20C1203. Trade names for permethrin areAdion, Ambush, Ectiban, Kafil, Matadan, Perth-rine, Pounce, and Talcord. Two chemical grades ofboth insecticides were evaluated in this investiga-tion. The technical grade of either pyrethroid wascomposed of approximately 94-96% active ingre-dient, whereas the formulated grade consisted of32-36% active ingredient. The remainder of eithergrade, of both pyrethroids, entailed similar inertingredients (organic solvents and surfactants).

All portions of this investigation have beenreviewed and approved by the University of Texasat Houston Committee for the Protection of HumanSubjects. The animal study was also reviewed anddeemed acceptable by the Health Science CenterAnimal Shelter Committee. Therefore, based onnumerous earlier investigations and the high dermalLD50, the following studies were conducted.

STUDY 1: COMPARISON OF INDUCEDPARAESTHESIA FROM FENVALERATE,PERMETHRIN, OR THE INERT INGREDIENTSClinically, a comparison was made of the capabilityof human participants to discriminate between thedysaesthesia induced by a technical or formulatedalpha-cyano pyrethroid (Fenvalerate), a technical orformulated non-cyano pyrethroid (permethrin), andthe inert ingredients that comprise a major portionof both formulated compounds. Both technicalpyrethroids were diluted with absolute ethanolwhereas the formulated compounds were diluted indistilled water. The evaluation used a previouslydeveloped assay.'7 18 The participants were exposedto the cutaneous sensation before the onset of thestudy. Preparation consisted of two separate topicalapplications, one with a field strength alpha-cyanopyrethroid (0-13 mg/cm2) and the other with a fieldstrength non-cyano pyrethroid (0-13 mg/cm2), witha review and discussion of the paraesthesia felt byeach subject. The same technique was used for allparticipants in each portion of this research. Con-centrations were prepared and recorded throughoutthe investigation in mg/cm2 which pertains to thenumber of milligrams of synthetic pyrethroid topi-cally applied per unit area of skin.

Application of 0*05 cc of field strength formulatedor technical fenvalerate (0-13 mg/cm2), fieldstrength formulated or technical permethrin

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(0-13 mg/cm2), or the inert ingredients were deli-vered to a 4 cm2 area on the lower margin of oneearlobe of each participant via a tuberculin syringe(accuracy + 0-002 cc) on five separate occasions.The opposite earlobe received 0-05 cc of distilledwater when opposing a formulated pyrethroid andabsolute ethanol as the control for a technical pyre-throid. Participant evaluation after each applicationcontinued for 48 hours and involved grading anddescribing any unusual cutaneous sensations. Thegrading scale was on a basis of 0 to 4, with 0 = nosensation; 1 = mildly felt sensation; 2 = definitesensation, no discomfort; 3 = moderate sensation,little or no discomfort; and 4 = intense sensationwith discomfort. All applications were made in adouble blind fashion from numbered vials. Eachparticipant was therefore treated with only one ofthe five possible agents on each test date, with thevehicle always applied to the opposite ear. About 48hours after each application, the same participantwas treated with one of the remaining compoundson the opposite earlobe from the preceding applica-tion. Earlier investigations showed that there wereno significant carry over effects-that is, prior appli-cations of a pyrethroid to an earlobe did notinfluence later applications to the same earlobe.'8This procedure was followed until each participanthad evaluated both formulated and technical pyre-throids, and the inert ingredients. All treatmentsand sites were randomly assigned beforeapplication.When comparing the overall cutaneous sensation

from the various compounds, the aggregate of thereaction scores contained the same number of sub-jects, applications, and days applied. Since the uni-que characteristics of each individual remained con-stant under the different treatments, observations byeach person tended to be correlated. The data over48 hours for each participant were summarised,averaged, and tabulated. The results were analysedusing an analysis of variance (ANOVA) with arepeated measure design, incorporating three cells(treatment levels) with six observations (subjects)per cell.'9 20To rank the three treatments, composed of either

the inert ingredients, formulated fenvalerate andformulated permethrin, or the inert ingredients,technical fenvalerate and technical permethrin, aleast significant difference (LSD) multiple compari-son test was used if the overall F test of the treat-ment differences was significant. The LSD test waschosen since it has good control of type I errors(rejecting the null hypotheses when the nullhypotheses is correct) and more power than themethods of Newman-Keuls, Tukey, and Scheffe.2'

Variations within each pyrethroid classification

were evaluated by using an ANOVA with a re-peated measure design, incorporating two cells withsix observations per cell. Comparisons were madebetween either formulated and technical fenvalerateor formulated and technical permethrin.

STUDY 2: DIFFERENCES IN THE DOSE-RESPONSECURVES FOR FENVALERATE AND PERMETHRINThe dose-response curves for a formulated alpha-cyano pyrethroid (fenvalerate) and for a formulatednon-cyano pyrethroid (permethrin), using the aboveassay on people, was assessed. For each participant,0-05 cc of a given dilution of a synthetic pyrethroidwas applied to a 4 cm2 area on the lower margin ofan earlobe through a tuberculin syringe (accuracy +

0-002 cc). The opposite earlobe was treated withdistilled water (vehicle) and acted as the control.Evaluation by any participant continued for 48hours and included grading and describing anyunusual cutaneous sensation. All treatments weremade in a double blind fashion from numbered vialsthat were randomly assigned before application.Dilutions of each formulated pyrethroid consisted of2.69, 1P00, 0-36, 0-13, and 0.01 mg/cm2. Each suc-cessive application was applied about 48 hours afterthe prior treatment on the opposite earlobe from thepreceding application. Each participant's data for agiven concentration of a pyrethroid were summedand tabulated. Columns were constructed proceedingfrom the lowest to the highest concentration of eachpyrethroid for each participant. Columns of corres-ponding concentrations for each pyrethroid per par-ticipant were joined and normalised. The columnswere then divided into separate pyrethroids, aver-aged over all participants and graphed on linear,semilog, and log paper to find the most appropriatelinear fit for cutaneous sensation v concentration. Aregression analysis was calculated for both formu-lated fenvalerate and formulated permethrin byregressing the cutaneous sensation on the concentra-tion of pyrethroid. A final plot consisted of bothregression equations and their corresponding 95%confidence bands as calculated using the predictedmean values for either synthetic pyrethroid.

STUDY 3: THERAPEUTIC BENEFIT OF VITAMIN EACETATE FOR SYNTHETIC PYRETHROIDEXPOSUREThe therapeutic capability of topical vitamin E ace-tate (dl-alpha tocopheryl acetate) to ameliorate theparaesthesia that accompanies cutaneous exposureto a technical or formulated alpha-cyano pyrethroid(fenvalerate) and to a technical or formulated non-cyano pyrethroid (permethrin) was evaluated. Theinvestigation used the aforementioned ear assay,with the same grading scale of 0 to 4.

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Six volunteers were randomly treated with 0-05 ccof either field strength technical or formulated fen-valerate (0-13 mg/cm2) or with technical or formu-lated permethrin (0.13 mg/cm2), applying each on aseparate occasion to both the right and left earlobes.Approximately 0-05 cc of vitamin E acetate (1 mg =1 IU) was then randomly applied to either the rightor left earlobe of each participant, allowing eachsubject to act as his own control. Evaluation con-tinued for 48 hours and consisted of grading anddescribing any unusual cutaneous sensations. One ofthe remaining synthetic pyrethroids was then evalu-ated through the same format outlined above about48 hours later. This procedure was followed until allparticipants had evaluated both formulated andtechnical fenvalerate, as well as formulated andtechnical permethrin. All applications were in adouble blind fashion from numbered vials whereastreatments and sites were randomly assigned to par-ticipants before application.The data acquired during the four evaluation

periods, for each participant, were then summed,averaged, and tabulated. A therapeutic index wascalculated for each synthetic pyrethroid using theequation:

averagescore of therapeutic

Therapeutic index = 100 - pyrethroid + agent x 100average score ofpyrethroid alone

An ANOVA with a repeated measure design,incorporating two cells with six observations percell, was calculated on the averaged data to deter-mine if a significant difference (p s 0.05) actuallyexisted between sites topically treated with or with-out dl-alpha tocopheryl acetate to ameliorate thecutaneous sensation of a synthetic pyrethroid.

Results

Figures 1 and 2 give the results of study 1 comparingthe induced paraesthesia occurring from the topicalapplication of fenvalerate, permethrin, or the inertingredients. Figure 1 displays a prominent increasein paraesthesia between formulated fenvalerate(0-13 mg/cm2) and formulated permethrin(0.13 mg/cm2). No cutaneous sensation was notedby any of the participants to the inert ingredients(organic solvents and surfactants) when appliedseparately. The sensation developed with a latentperiod of about 30 minutes, peaked by eight hoursand deteriorated as early as 24 hours. Comparisonof the area under each curve shows an approximatefourfold difference in paraesthesia between the twosynthetic pyrethroids. There was no statisticallysignificant difference (p - 0.05) in sensation be-

tween the inert ingredients and formulated perme-thin (table 1). Nevertheless, there was a significantdifference between formulated fenvalerate and for-mulated permethrin, and between formulated fen-valerate and the inert ingredients.The degree of induced paraesthesia for technical

fenvalerate (0.13 mg/cm2), technical permethrinl(0-13 mg/cm2), and the inert ingredients is displayedin fig 2. Again, an approximate fourfold increase canbe noted between technical permethrin and techni-cal fenvalerate, with the inert ingredients not beingdetected. The time course for cutaneous sensation

26-214.

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o Fenvalerate (0-13 mg/cm2)/X Permethrin (0-13 mg/cm2)

o: Inert ingredients (surfactantsand organic solvents)

0 L 8 12 16 20 2 28 32 36 0 LLL8Time (hours)

Fig 1 Paraesthesia resulting from formulated fenvalerate,formulated permethrin, and the inert ingredients on people.

26.24-

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Fenvalerate (0-13 mg/cm2)l Permethrin (013 mg/cm2)

o Inert ingredients (surfactantscand organic solvents)

0 1. 8 12 16 20 21 28 32 36 .0 41 18Time (hours)

Fig 2 Paraesthesia resulting from technical fenvalerate,technical permethrin, and the inert ingredients on people.

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was similar to that for the formulated syntheticpyrethroids. There was a statistically significant dif-ference between technical fenvalerate and technicalpermethrin, and between technical fenvalerate andthe inert ingredients (table 1). As noted with theformulated compounds, there was little differencebetween technical permethrin and the inert ingre-dients. Interestingly, a significant difference did notexist between formulated and technical fenvalerate,nor between formulated and technical permethrin,when evaluated at the same concentration of0413 mg/cm2.

Study 2 compared differences in the dose-response curves for fenvalerate and permethrinusing formulated fenvalerate and formulated per-methrin at successive concentrations of 2-69, 1-00,0-36, 0-13, and 0-01 mg/cm2. The most appropriatelinear fit for both pyrethroid insecticides was on

semilog paper with cutaneous sensation on the ordi-nate axis (Y) and the common logarithm of concen-tration on the abscissa (X).The correlation coefficient (R) of the average

cutaneous sensation noted by all participants forformulated fenvalerate and the common logarithmof concentration was 99 0%. Regressing cutaneoussensation on the common logarithm of concentra-tion resulted in a regression equation of Y = 84-0 +310X1, with a square of the correlation coefficient(R2) of 84-9%. The R value for the average cutane-ous sensation felt by all participants for formulatedpermethrin and the common logarithm of concen-

tration was 94-0%. Regressing the cutaneous sensa-

tion on the common logarithm of concentrationresulted in a regression equation of Y = 27-5 +15-8X1, with an R2 value of 75 6%. Figure 3 pre-sents the regression equations for formulated fen-valerate and formulated permethrin with 95%confidence bands appended to both. Comparing theequations, the y-intercept for fenvalerate is approx-imately threefold greater than for permethrin,whereas the slope (m) is roughly twice as large.

Study 3 entailed the evaluation of the therapeuticbenefit of dl-alpha tocopheryl acetate (1 mg = 1 IU)for the dysaesthesia that results from topical expos-

Table 1 Comparison oftreatmnent means for paraesthesiathe inert ingredients on people

c0

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Common logarithm of concentration

Fig 3 Regression equations for formulated fenvalerate andformulated permethrin with 95% confidence bands.

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o[ Formulated fenvalerate withvitomin E acetate applied immediately

+: Formulated fenvalerate alone

8 12 16 20 2. 28 32 36 40 14 48Time (hours)

Fig 4 Therapeutic inhibition offormulated fenvalerate(0-13 mglcm2) with vitamin E acetate (I mg = I IU) on

people.resulting from topical exposure to fenvalerate, permethrin, and

Composition Cell means

Inert ingredients Permethrin (0.13 mglcm2) Fenvalerate (013 mglcm2)

Formulated 0-0000 0-1467 + 0-5867 ++---------------------+

(LSD = 0-1709)Technical 0 0000 0-1600 0-6067

+ ...+ + +(LSD = 0-1609)

+ ---- +: Not statistically significant at p S 0 05.

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ure to a synthetic pyrethroid insecticide. Technicaland formulated fenvalerate (0.13 mg/cm2) andtechnical and formulated permethrin (0-13 mg/cm2)were used in this study. An extensive degree ofinhibition accompanied the topical application ofvitamin E acetate for formulated fenvalerate (fig 4).By comparing the digitised area under each curve,there was an approximate 40-fold inhibition ofcutaneous sensation. Figure 5 presents the therapeu-tic treatment of technical fenvalerate, with a corres-ponding 20-fold inhibition of paraesthesia. A statis-tically significant (p s 0-05) inhibition of sensationfor both purities of fenvalerate is shown by the datain table 2. The therapeutic index for formulated fen-valerate was substantial at 98% inhibition, whereastechnical fenvalerate reached 100%. Similar resultswere noted with the cutaneous inhibition of formu-lated and technical permethrin (figs 6 and 7). Inboth cases total inhibition of the cutaneous sensa-tion resulted from the topical application of dl-alphatocopheryl acetate; the vitamin E acetate yielded a

therapeutic index of 100% and a significant differ-ence from either form of permethrin applied sepa-rately.

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t: Technical fenvalerate alone

Discussion

All synthetic pyrethroids are lipophilic compoundsthat are recognised as nerve toxins. They are viscousliquids with relatively high boiling points and lowvapour pressures. Since their initial introduction in1973, they have attained over 30% of the commer-cial market for insecticides by providing an excellentcost/benefit ratio for agricultural and domestic pestcontrol.22 Well over 1000 pyrethroids have beensynthesised to date.The biological activity of the synthetic pyrethroids

appears to be directly associated with their chemical

1-6 -

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5 1.0-c

06

02O-2

c Formulated permethrin withvitamin E acetate applied immediately

+ Formuloted permethrin alone

tt---

0 4 8 12 16 20 2. 28 32 36 .0 U 48Time (hours)

Fig 6 Therapeutic inhibition offormulated permethrin(0-13 mg/cm2) with vitamin E acetate (1 mg = I IU) onpeople.

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Time (hours)Fig 5 Therapeutic inhibition of technical fenvalerate(0-13 mg/cm2) with vitamin E acetate (I mg = I IU) onpeople.

a Technical permethrin withvitamin E acetate applied immediately

4 Technical permethrin alone

0 8 12 16 20 21 28 32 36 .0 LL 48Time (hours)

Fig 7 Therapeutic inhibition oftechnical permethrin(0-13 mg/cm2) with vitamin E acetate (1 mg = 1 IU) on

people.

Table 2 Comparison oftreatment means for inhibition ofparaesthesia by vitamin E acetate (I mg = 1 JU) on people

Synthetic pyrethroid Cell mean without vitamin E Cell mean with vitamin E p value Therapeuticacetate acetate index (%o)

Formulated fenvalerate(0-13 mg/cm2) 0-6436 0-0233 0000 98

Technical fenvalerate(0-13 mg/cm2) 0 5763 0 0000 0 000 100

Formulated permethrin(0-13 mg/cm2) 0-1236 0-0000 0039 100

Technical permethrin(0-13 mg/cm2) 0-1600 00000 0047 100

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Flannigan, Tucker, Key, Ross, Fairchild 11, Grimes, and Harrist

structure. Almost all active pyrethroids are esters,whose constituent acids and alcohols are basicallyinert. Electron density and polarisability are of littleimportance to their reactivity.23 The cyano substi-tute, located in the S-configuration of the3-phenoxybenzyl alcohol of alpha-cyano syntheticpyrethroids, tends to increase the potency of themolecule by approximately three to sixfold. Fenval-erate has been listed in a range of 0*6 to four timesthe insecticidal potency of permethrin, dependingon the pest species evaluated.'2 In studies 1 and 2 ofthis investigation a close correlation was noted be-tween the insecticidal potency (knockdown) forboth fenvalerate and permethrin and the degree ofinduced cutaneous paraesthesia on people.The human assay, incorporated into studies 1, 2,

and 3, necessitated the topical application of milli-gram quantities of a field strength synthetic pyre-throid to the lobule of a patient's ear. Numerousprior investigations have attested to the safety andefficaciousness of this assay, and the documentedlow inherent mammalian toxicity of the syntheticpyrethroids. Rapid penetration was enhanced sincethe pyrethroids are extremely lipophilic and weredirectly applied to an extremity composed of bothareolar and adipose tissue. The auriculotemporalnerve, branching from the inferior maxillary of thetrigeminal (fifth cranial) innervates most of thelobule. LeQuesne et al observed in electrophysiolog-ical studies that the disturbances produced by thesynthetic pyrethroid insecticides occurred more fre-quently in sensory than in motor nerves and that thesymptoms resulting in man from occupationalexposures were solely due to sensory nerveinvolvement.'4 Based on this rationale, it seemedappropriate for the human assay to use a source oftissue where rapid penetration would be enhancedwith prominent sensory nerve involvement.The cutaneous sensation, often referred to as

paraesthesia or dysaesthesia, is the most prominenthealth symptom that accompanies topical contactwith these potent insecticides.'3 -'5 It appears to beunique in quality, time of onset, and duration. Pre-vious stinging sensations of the skin have been notedafter topical application of certain agents, but gen-erally occurred either immediately or within severalminutes after contact and only in a very sensitivesubset of the population, usually fair skinnedwomen.2425 This is not the case with the syntheticpyrethroid cutaneous sensation, which seems to bealmost universal and possess a latent period of oneto two hours after application.'8

Participants in study 1 of this investigation noted aprominent increase in paraesthesia between formu-lated fenvalerate and formulated permethrin, andbetween technical fenvalerate and technical per-

methrin. Nevertheless, no cutaneous sensation wasrecorded by any of the same participants on topicalexposure to the inert ingredients of these pyre-throids. It would seem that the inert ingredients,organic solvents and surfactants, are not the offend-ing agents causing the paraesthesia. Narahashi,using a voltage clamp assay in combination with var-ious toxins, drugs, and enzymes showed that thenerve impulse, thought to be responsible for thisparticular sensation, arises from a rapid transientchange in the semipermeability of the nerve mem-brane to sodium and potassium ions. This transitionin permeability is governed by molecular pores inthe axon membrane referred to as sodium andpotassium channels. An extended sodium current,after termination of the nerve membrane depolar-isation, is the mechanism thought to be responsiblefor the occurrence of this repetitive activity. Vijver-berg et al have shown that after topical treatmentwith alpha-cyano pyrethroids, this sodium tail cur-rent deteriorates much more gradually than afternon-cyano pyrethroids, and that the difference intime restraints is at least one-fold greater.26 Theyalso noticed considerably smaller variations in themagnitude of the sodium tail current among agentsthat belong to the same synthetic pyrethroidcategory-non-cyano or alpha-cyano. This corres-ponds closely with the results of study 1, which didnot substantiate a statistically significant difference(p 3 0.05) between the fenvalerate pyrethroids orbetween the permethrin pyrethroids evaluated atsimilar concentrations. These results also coincidewith an earlier investigation which established thatthere was no difference between heavy ends andtechnical fenvalerate, at the same concentration,when evaluated by 36 participants.'8

In a more recent investigation Vijverberg and vanden Bercken concluded that the non-cyano pyre-throids produce sodium tail currents with a timeconstant of decay in the order of approximately 10milliseconds,22 whereas the alpha-cyano pyrethroidsrange from hundreds of milliseconds to more thanone second. These results were indicative of the factthat the actual rate of relaxation of the activationgate (m-gate) in pyrethroid affected sodium chan-nels is a characteristic of each particular category ofsynthetic pyrethroid, and that the rate of relaxationis substantially slower after treatment with alpha-cyano pyrethroids. Therefore, the rate of relaxationof the sodium channel influx helps to explain the40-fold difference noted between formulated fen-valerate and formulated permethrin, and betweentechnical fenvalerate and technical permethrin inthis investigation.

Study 2 denoted a linear correlation between con-centration of a formulated synthetic pyrethroid and

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the degree of induced paraesthesia. Fenvalerateresulted in a substantially steeper slope (m = 31-0)than permethrin (m = 15-8). This could be consi-dered connotative of an enhanced cutaneous sensa-tion from only minor increases in concentration of aformulated alpha-cyano pyrethroid, whereas anon-cyano pyrethroid merely fluctuated to a minordegree over a similar range of concentrations. Poss-ibly, these regression curves are indicative of the factthat, as the concentration of a pyrethroid isincreased, so will be the number of sodium channelsaffected during membrane depolarisation. Thiswould result in a direct influence on the correspond-ing amplitude of the pyrethroid induced sodium tailcurrent and coincide with the fact that the amplitudeof a pyrethroid induced sodium tail current is alwaysproportional to the number of sodium channels thatopen during nerve membrane depolarisation.222627

In study 3 vitamin E acetate (C31H5203) wasfound to be a highly efficacious therapeutic agent forsynthetic pyrethroid exposure. Vitamin E acetate (1mg = 1 IU) was chosen because it is a well knownbiological antioxidant that inhibits peroxides fromaccumulating and protects cells from the scavengingeffects of free radicals. It also ensures the stabilityand integrity of biological membranes.2829 One ofthe two possible routes of absorption through theepidermis consists of a direct transition through thestratum corneum, granulosum, spinosum, andbasalis to the dermis; this is possible since dl-alphatocopheryl acetate is a highly lipophilic compound.Access is also secured through the pilosebaceousunit and connective tissue sheaths. Dl-alphatocopheryl acetate also has a high affinity for smallblood vessels and possesses an anti-inflammatorycapability. Kamimura and Matsuzawa indicate thatit will suppress inflammation with either topical orsystemic administration, and with prophylactic ortherapeutic treatment.20 Its anti-inflammatoryaction is thought to be related to its ability to stabil-ise lyosomal membranes, histamine liberation fromgranules of mast cells, and serotonin liberation fromtissue cells. Further, vitamin E acetate is non-irritating and non-sensitising when evaluated byitself.

Vitamin E acetate is stable to the oxidisinginfluences of air or light, including ultraviolet light.It is also relatively stable to acids and heat. It maytherefore be used practically in the field for occupa-tional exposure with little concern as to handlingprecautions. To date, no cases of hypervitaminosis Ehave been documented from topical application ofdl-alpha tocopheryl acetate.

This research was made possible through a grantfrom the Shell Oil Company.

References'Elliott M, Janes NF. Synthetic pyrethroids-a new class of insec-

ticide. Chemical Society Reviews 1978; 7:473-505.2 Oetting RD, Morishita FS. Potential of pyrethroid insecticides

for greenhouse whitefly, Trialeurodes vaporariorum, control.Journal of the Georgia Entomological Society 1980; IS:272-80.

Elliott M. Synthetic pyrethroids. In: Elliott M, ed. Syntheticpyrethroids. Washington DC: American Chemical Society,1977:1-28. (American Chemical Society symposium series No42.)

Elliott M, Farnham W, Janes F, Needham PH, Pulman DA.Insecticidally active conformations of pyrethroids. In: KohnGK, ed. Mechanism ofpesticide action. Washington: AmericanChemical Society, 1974:80-91. (American Chemical Societysymposium series No 2.)

5 Narahashi T. Nerve membrane as a target for pyrethroids. Pesti-cide Science 1976;7:267-72.

6 Vijverberg HP, van den Bercken J. Frequency-dependent effectsof the pyrethroid insecticide decamethrin in frog myelinatednerve fibers. Eur J Pharmacol 1979;58:501-4.

7Harris GG, Miline DB. Input-output characteristics of thelateral-line sense organ of Xenopus laevis. J Acoust Soc Am1966;40:32-41.

8 van den Bercken J, Akkermans LMS, van der Zalm JM. DDT-like action of allethrin in the sensory nervous system ofXenopus laevis. Eur J Pharmacol 1973;21: 195-206.

9 Miyamoto J. Degradation, metabolism and toxicity of syntheticpyrethroids. Environ Health Perspec 1976; 14:15-28.

'0 Hutson DH. The metabolic fate of pyrethroid insecticides inmammals. Progress in Drug Metabolism 1979;3:215-52.

" Elliott M. The future for insecticides. In: Locke M, Smith DS,eds. Insect biology in the future. New York: Academic Press,1980:879-903.

12 Casida JE. Pyrethrum flowers and pyrethroid insecticides. Envi-ron Health Perspec 1980;34: 189-202.

3 Kolmodin-Hedman B, Swensson A, Akerblom M. Occupationalexposure to some synthetic pyrethroids (permethrin and fen-valerate). Arch Toxicol 1982;50:27-33.

41 LeQuesne PM, Maxwell UC, Butterworth ST. Transient facialsensory symptoms following exposure to synthetic pyrethroids:a clinical and electrophysiological assessment. Neurotoxicol1980;2: 1-11.

'5 Tucker SB, Flannigan SA. Cutaneous effects from occupationalexposure to fenvalerate. Arch Toxicol 1983;54: 195-202.

16 Martin TJ, Hester KH. Dermatitis caused by insecticidal pyre-thrum flowers (Chrysanthemum cinerariaelfolium). Br J Der-matol Syph 1941;53: 127-42.

7 Knox JM, Tucker SB. A new cutaneous sensation caused bysynthetic pyrethroids. Clin Res 1982;30:915A.

18 Knox JM, Tucker SB, Flannigan SA. Paresthesia from cutaneousexposure to a synthetic pyrethroid insecticide. Arch Dermatol1984; 120:744-6.

Winer BJ. Single-factor experiments having repeated measureson the same elements. In: Winer BJ, ed. Statistical principles inexperimental design. New York: McGraw-Hill, 1962:105-40.

20 Engelman L. One-way analysis of variance and covariance. In:Dixon WJ, ed. BMDP statistical software. Berkeley: Universityof California Press, 1981:345-436.

21 Snedecor GW, Cochran WG. One-way classifications; analysis ofvariance. In: Snedecor GW, Cochran WG, eds. Statisticalmethods. Ames, Iowa: Iowa State University Press,1980:215-39.

22 Vijverberg HP, van den Bercken J. Action of pyrethroid insecti-cides on the vertebrate nervous system. Neuropathol ApplNeurobiol 1982;8:421-40.

23 Elliott M, Janes NF, Potter C. The future of pyrethroids in insectcontrol. Ann Rev Entomol 1978; 23:443-69.

24 Laden K. Studies on irritancy and stinging potential. Joumal of

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the Society of Cosmetic Chemists 1973;24:385-93.25 Frosch PH, Kligman AM. A method for appraising the stinging.

capacity of topically applied substances. Journal ofthe Societyof Cosmetic Chemists 1977;28:197-209.

26 Vijverberg HP, van der Zalm JM, van Kleef RG, van den Berc-ken J. Temperature and structure dependent interaction ofpyrethroids with the sodium channels in frog node of Ranvier.Biochimica et Biophysica Acta 1983;728:73-82.

27 Beeman RW. Recent advances in mode of action of insecticides.

Ann Rev Entomol 1982;27:253-81.28 de Duve C, Wattiaux R, Wibo M. Effects of fat-soluble com-

pounds on lysosomes in vitro. Biochem Pharmacol1962;9:97-116.

29 Ehrlich HP, Taver H, Hunt TK. Inhibitory effects of vitamin Eon collagen synthesis and wound repair. Ann Surg1972; 175:235-40.

30 Kamimura M, Matsuzawa T. Percutaneous absorption of alphatocopheryl acetate. J Vitaminol 1968; 14: 150-9.

The May 1985 issue

THE MAY 1985 ISSUE CONTAINS THE FOLLOWING PAPERS

Editorial

"One simple set of regulations"

Neurobehavioural effects of repeated occupationalexposure to toluene and paint solvents NICOLACHERRY, HELEN HUTCHINS, T PACE, AND HA WAL-DRON

No acute behavioural effects of exposure to styrene:a safe level of exposure? C EDLING AND KERSTINEKBERG

Dechlorination of halocarbons by microsomes andvesicular reconstituted cytochrome P-450 systemsunder reductive conditions A G SALMON, J A NASH,C M WALKLIN, AND R B FREEDMAN

Clinical and immunological reactions to Aspergillusniger among workers at a biotechnology plant M DTOPPING, D A SCARISBRICK, C M LUCZYNSKA, E CCLARKE, AND A SEATON

A study of dose-response relationships for asbestosassociated disease M M FINKELSTEIN

Rates of sickness absenteeism among employees ofa modern hospital: the role of demographic andoccupational factors A PINES, K SKULKEO, E POL-LAK, E PERITZ, AND J STEIF

Accident liability J B KUNE

Risk factors for radiogenic cancer: a comparison offactors derived from the Hanford survey with thoserecommended by the ICRP K F BAVERSTOCK ANDD G PAPWORTH

Some factors influencing interobserver variation inclassifying simple pneumoconiosis D C MUSCH, I T THIGGINS, AND J R LANDIS

Short reports

Asymmetric rapidly progressive lung fibrosis: acause of pseudotumour in asbestosis w o c MCOOKSON, J J GLANCY, AND F A FROST

Reticulocyte haem synthesis in occupational expos-ure to trinitrotoluene H SAVOLAINEN, R TENHU-NEN, AND HA HARKONEN

Book reviews

Correction: Health of workers exposed to electricfields (February 1985)

Information section

Copies are still available and may be obtained from the PUBLISHING MANAGER, BRITISH MEDICALASSOCIATION, TAVISTOCK SQUARE, LONDON WC1H 9JR, price £4-25 (USA $9.20), includingpostage.

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