Environmental Health PerspectivesVol. 34, pp. 189-202, 1980

Pyrethrum Flowers and PyrethroidInsecticidesby John E. Casida*

The natural pyrethrins from the daisy-like flower, Tanacetum or Chrysanthemum cineraruifolium, arenonpersistent insecticides of low toxicity to mammals. Synthetic analogs or pyrethroids, evolved from theuntural compounds by successive isosteric modifications, are more potent and stable and are the newestinportant class of crop protection chemicals. They retain many of the favorable properties of the pyre-Uwns.

Most insect pests of crops, livestock, and manhave been easily controlled for the past 35 years byrelatively inexpensive organochlorine and organo-phosphorus compounds and methylcarbamates.Control ofpest insects is progressively more difficultand costly because of increasing restrictions on someof the major insecticides of these types. They areconsidered to have unfavorable persistence. en-vironmental impact and/or toxic effects on higheranimals including man. There is an urgent need foralternative chemical or biological control methodsfor pest control. Pyrethroids developed within thepast seven years are helping to meet this need. Theseinsecticides are structural modifications ofone oftheoldest insect control agents, the remarkably effec-tive but unstable pyrethrins from pyrethrum flowers.The newer pyrethroids have greatly improved po-tency and stability. It is appropriate as the use ofpyrethroids expands to examine their origin,properties and safety aspects as compared with thepyrethrins and their prospects for filling current andprojected gaps in insect control capabilities.

Pest insect control until the 1940's was moderatelysuccessful with the use of primarily compounds fromnatural sources either directly or after simple ex-tractions or other treatments. These "first genera-tion" insecticides were inorganic arsenic- or fluo-rine-containing toxicants or botanicals such asnicotine, rotenone, and pyrethrins. Except for the

*Pesticide Chemisiry and Toxicology Laboratory, Departmentof Entomological Sciences, University of California, Berkeley,California 94720.

pyrethrins, they were displaced in the 1940's and1950's by synthetic organic or "second generation"insecticides which provided nearly complete controlat reduced cost due to high potency or persistence orboth these properties. There are four principalclasses of second generation insecticides, i.e., or-ganophosphorus compounds, methylcarbamates,chlorinated hydrocarbons, and pyrethroids; all act asnerve poisons. The first two classes inhibit acetyl-cholinesterase and thereby disrupt synaptic trans-mission. The others probably act at nerve mem-branes principally by altering sodium conductancemechanisms. Several of the chlorinated hydro-carbons (e.g., DDT, aldrin, and dieldrin) have beenrestricted or banned because of unacceptable per-sistence, effects on wildlife, and evidence ofpossiblecarcinogenic activity. Some of the important or-ganophosphorus and methylcarbamate insecticidesare very hazardous to manufacture, formulate andapply due to their high acute toxicity when ingested,inhaled or absorbed through the skin. Most of thepyrethroids appear at present to have generallyfavorable persistence and toxicological characteris-tics.The first and second generation insecticides act on

systems important for survival in both pest and otherorganisms including mammals. They therefore lackthe selectivity which is theoretically possible withhormones or antihormones, agents that disrupt cuti-cle or chitin formation, or other types of insectgrowth regulators. These "third generation" insec-ticides have not yet been perfected for extensive use,and there are definite limitations in the types of pest

February 1980 189

infestations where such slow-acting compounds arelikely to prove acceptable. Chemical control of in-sects depends almost completely at present on firstand second generation insecticides including pyre-thrins and pyrethroids. The common names of im-portant compounds are given in Table 1.

Table 1. Common names of natural esters and synthetic analogsand origin or possible origin of names.

Name Origin

Natural materialsPyrethrins

Pyrethrins I

Pyrethrins II

Rethrins

CinerinsJasmolins

Pyrethrum cinerariifolium(old genus name)Derived from chrysanthemummonocarboxylic or chrysanthemic acidDerived from methyl ester of chrysanthe-mum dicarboxylic acid, i.e., pyrethric acidPyrethrins and related cyclopentenolone de-rivativesTanacetum cinerariifoliumSimilar structure tojasmone from Jasminiumgrandiflorium

Pyrethrin analogs with specific chemical groupsAllethrin Allyl analogPhenothrin Phenoxy analogTetramethrin Tetrahydrophthalimidomethyl analog

Pyrethrin analogs by Michael Elliott et al.Resmethrin Discovered at Rothamsted

Experimental StationPermethrin Enhanced persistenceCypermethrin Cyano analog of permethrinDecamethrin Deca (10)-fold more potent

Other originsKadethrinFenvalerate

Knockdown analog of pyrethrinA phenylisovalerate pyrethroid

Pyrethrum FlowersIn the early 1800's pyrethrum flowers were used

by Caucasian tribes and in Persia to control bodylice. The flowers were first produced commerciallyin Armenia in 1828. Production started in Dalmatia(Yugoslavia) about 1840 and was centered there untilthe first World War, in Japan until shortly before thesecond World War, and in East Africa since then.More than half of the world's current productioncomes from Kenya, with important amounts fromTanzania, Rwanda, and Ecuador. Insect powder wasfirst imported into the United States in about 1860,and several unsuccessful attempts were made overthe next 90 years to produce the flowers commer-cially in this country. Since about 60 years ago theflowers were extracted with kerosene or similar sol-vents to give liquid sprays more effective than thepowders.The pyrethrum plant of commerce is the daisy,

Tanacetum cinerariifolium (Trev.) Schultz Bip.

[Pyrethrum cinerariifolium Trev. and Chrysan-themum cinerariifolium (Trev.) Vis.], a herbaceousperennial of the family Compositae. The producingareas are near the equator, from 1800 to 4000 m inaltitude, and with rainfall of 50 to 200 cm spreadthroughout at least seven months of the year. Underthese growing conditions, flowering continues forseven to 11 months each year. In Kenya alone, morethan 85,000 families are engaged in growing pyre-thrum. Worldwide, perhaps 200,000 farmers are in-volved in pvrethrum culture. Pyrethrum productionis currently estimated at about 15,000 tons of driedflowers per year, about half the amount currentlyneeded for the world market. The dried flowerscontain 1-2% pyrethrins by weight, averaging about1.3%; so, the production of pyrethrins is about 150 to200 tons per year. Present annual production aver-ages about 560 kg dried flowers per hectare, althoughplant selection and improved propagation and culti-vation techniques make it possible to produce 900 kgof 1.8% or higher dried flowers annually in somegrowing areas.The pyrethrins are localized in the secretory ducts

of the achenes, where they are protected fromphotodecomposition and isolated so they are nottoxic to insects feeding on or visiting pyrethrumflowers. The flowers are hand picked when four orfive rows of disc florets are open, and each flowercontains about 3-4 mg pyrethrins. After drying in thesun or mechanically, the flowers are ground andextracted with hexane. Evaporating the hexaneyields a dark, viscous oleoresin concentrate con-taining about 30%o pyrethrins. The concentrate iseither diluted with plant or mineral oil to 25% pyre-thrins (oleoresin extract) or purified by methanolextraction and charcoal treatment to produce a de-waxed and decolorized refined extract. This purifi-cation removes components which earlier gave al-lergic responses evidenced as dermatitis in humanssensitive to ragweed pollen.Pyrethrum extract is important to control of pest

insects in the household, in barns, and in storedproducts, and for direct application to man andlivestock. Before the second World War, powderedpyrethrum flowers or pyrethrum extract were em-ployed for control of agricultural and horticulturalinsect pests, ause largely superseded in the 1940's bythe more effective and simpler chlorinated hydro-carbon and organophosphorus- insecticides. Com-pared with these synthetic organic insecticides, thepersistence of the pyrethrins, even with variousadditives to retard photooxidation, is not adequatefor crop protection or silviculture. The present usesfor pyrethrum are well established and dependablemethods of insect control, but for very specific pur-poses not likely to change in the foreseeable future.

Environmental Health Perspectives190

The selection of resistant strains, a problem withmost other insecticides, has had little impact on theuse pattern of the pyrethrins.The pyrethrins knock down houseflies, mos-

quitoes, and other flying insects rapidly and, at ap-propriate doses, the insects die a few minutes orhours later. Instructions for space sprays or aerosolapplications through the 1940's cautioned users to beneat and tidy, and to sweep the flies outside thehouse after knockdown; under these circumstancesthe user was oblivious to the recovery of the flies.The hyperexcited state preceding or associated withknockdown is also useful in other ways. It repels anddisorients biting flies and mosquitoes which there-fore bite less frequently. It flushes cockroaches fromtheir hiding places to contact lethal doses of theinsecticide. Three developments helped establishand maintain these uses for pyrethrum. The first wasan alternative method for delivering pyrethrins tocontrol mosquitoes by incorporating ground pyre-thrum flowers with other ingredients into mosquitocoils, which, burned throughout the night, generateda smoke that repelled, expelled, knocked down, orkilled mosquitoes in human habitats. The second in1941 was the aerosol can or "bomb" which, althoughnow used to disperse many types of household andindustrial agents, was originally perfected to deliverpyrethrum extract. It produces droplets below 30 ,umin diameter, essential for maximum effectivenessand economical use of the pyrethrins. The final de-velopment was an additive or synergist, piperonylbutoxide, which was discovered in 1949. Althoughessentially noninsecticidal, it increases the potencyof pyrethrum by more than fourfold when added attwo to ten parts of synergist per part of pyrethrins.The pyrethrins-synergist combination is much moreeconomical than the insecticide alone, since thesynergist costs less than 5% per unit weight of thepyrethrins. The synergist also increases the likeli-hood that insects knocked down will subsequentlydie rather than recover. In addition to piperonylbutoxide, another type of synergist, MGK 264, hasalso been important for many years.Pyrethrum is generally considered to be the safest

insecticide and was once labeled as "nontoxic tohumans and pets." This labeling is no longer al-lowed, so it is difficult for the user to differentiate therelative safety of various household insecticideproducts. After use for more than a century, thereare very few cases of human illness associated withexposure to pyrethrum, and most of these are earlyreports of dermatitis or allergic reactions due to im-purities no longer present in the purified extract.Pyrethrins were once used at three consecutive dailydoses of 10-20 mg per adult or 5 to 10 mg per child tocontrol intestinal worms without reported ill effects.

February 1980

However, it is known that accidental oral or dermalexposure to high doses of pyrethrins can cause atemporary numbness of the tongue and lips. Pyre-thrum extract has low acute toxicity to mammals andbirds despite a very high toxicity to insects, otherinvertebrates and fish (lethal concentrations of a fewparts per billion in water). Tests with laboratorymammals indicate that pyrethrum, even at highdoses or combined with piperonyl butoxide, does notproduce carcinogenic, mutagenic or teratogenic ef-fects. Any pathological changes observed at highdoses are in the liver.The pyrethrins are very unstable in light and air,

limiting the areas where they are effective but alsoproviding a safety factor against the accumulation ofhazardous residues. Uses of pyrethrum and itssynergists are regulated by restrictions under theEnvironmental Protection Agency and by tolerancesfor levels in food and feed under the Food and DrugAdministration. The tolerance values for post har-vest applications to various plant products are com-monly 1-3 ppm for pyrethrins and 8-20 ppm forpiperonyl butoxide. In several cases, these com-pounds are exempted from the requirement for toler-ances because their safety relative to the levels likelyto be present under normal conditions is acknowl-edged.

Chemistry of the PyrethrinsPyrethrum extract contains six closely related in-

secticidal esters, collectively referred to as thepyrethrins, which differ only in the terminal sub-stituents in the side chains of the acid and alcoholcomponents. The acid is a substituted cyclopropane-carboxylic acid and the alcohol a substitutedcyclopentenolone. Three alcohols are involved,pyrethrolone, cinerolone and jasmolone for thepyrethrins, cinerins, and jasmolins, respectively(Table 2). The two acids are chrysanthemic acid forthe I series and pyrethric acid for the II series. Themain structural features of these compounds wereelucidated between 1910 and 1916 but not reporteduntil 1924 by Hermann Staudinger and LeopoldRuzicka, two Swiss chemists each later awarded aNobel Prize for pioneering discoveries in severalfields of chemistry. Important contributions oncharacterization and synthesis in the period 1919to 1966 were also made by Masanao Matsui and RyoYamamoto in Japan, William Barthel, FrancesLaForge, Milton Schechter and coworkers in TheUnited States, and Leslie Crombie, Michael Elliott,Peter Godin and Stanley Harper and their associatesin England. The six individual esters are not avail-able commercially and are more economically pro-duced as botanicals than by chemical manufacture.

191

H\ HH>A2i/H

C10Hcyclopropane -carboxylic acid

trans-chrysanthemi

- H

OH

c acid 1R, trons- or bio-chrysanthemic acid

H

IO

H

cyclopentenolone

HO>cj,IH2 A

H H

R % Name

"I >chrysanthemotes' R CH=CH2 35 pyrethrin I

///,f"'tCH3 0 cinerin I

CH2CH3 5 jasmolin I

0d/° % pyrethrates

I R CH=CH2 32 pyrethrin IC8/,(°1>,,<f CH3 14 cinerin II

CH2CH3 4 jasmolin U

They could probably be obtained, if needed, by totalsynthesis, by reconstitution from the acids andalcohols derived from pyrethrum flowers, or byisolating the natural materials using various com-binations of column adsorption and partition chro-matography, gas-liquid chromatography and highpressure liquid chromatography.The pathways used by pyrethrum flowers in bio-

synthesis of the acid moieties of the pyrethrins frommevalonic acid are well established and of the al-cohol moieties are partially understood. The pyre-thrates originate biosynthetically from chrysan-themic acid or chrysanthemates by oxidation of thetrans-methyl group of the isobutenyl substituent,followed by biomethylation [Eq. (1)]. Oxidation ofan isobutenyl methyl substituent is involved inbiosynthesis ofpyrethrates in pyrethrum flowers andmetabolism of chrysanthemates in mammals and in-sects. The R' substituent may be hydrogen as in

192

chrysanthemic acid or an alcohol moiety as in thepyrethrins. The oxidases and dehydrogenases re-

quire pyridine nucleotide cofactors as indicated.Biomethylation utilizes S-adenosylmethionine as themethyl donor. Pyrethrate-hydrolyzing esterases re-quire no cofactors.The biological activities of the pyrethrum con-

stituents depend on the structures and stereochemi-cal characteristics of both the acid and alcohol com-ponents. Pyrethrins I and II are considerably more

potent than the cinerins and jasmolins. The chry-santhemates (I) are generally more potent for kill andthe pyrethrates (II) for knockdown. Thus, pyre-thrum contains a combination of an excellent knock-down agent (pyrethrin II) and a potent insecticidalcomponent (pyrethrin I). The pyrethrins have threechiral centers and therefore eight different opticallyactive forms are possible (Fig. 1). There is alsogeometrical isomerism (E or Z) in the side chain of

Environmental Health Perspectives

pyrethrolone

Table 2.

pyrethrin I

CH3\ /HC=C

CH \chrysanthemate

aldehydedehydrogenose

NAD

mixed-functionoxidaseNADPH

CH/ /Hc=c,

0

HOC\ /H

CH(

alcoholdehydro-genaseNAD

0II

HC\ /HC=C

CH/c\

0

biomethylation CH308\ /H-.

:1 C-Cesterose CH / \E

pyrethrate

FIouRE 1. Pyrethroid stereochemistry is illustrated with pyrethrin II. Asterisks designate chiral orasymmetric centers. TI indicatesthe remainder of the molecule beyond the bracketed portion. Partial structures give optical isomers in the bottom row andgeometrical isomers at the sides of the upper row. Arrows indicate names for the transformations and the chiral center or doublebond where inversion takes place. Two isomers are possible, the natural one in the pyrethrin II structure and the alternative onein the partial structure, in each of the five cases. This makes 25 or 32 possible isomers. Pyrethrin I lacks the methoxycarbonylgroup at the upper left so it has only 24 or 16 possible isomers.

the alcohol (chrysanthemates) or of the acid andalcohol (pyrethrates) increasing the number of pos-sible stereoisomers to 16 for the chrysanthematesand 32 for the pyrethrates. Although these isomershave not all been prepared and tested, the availableevidence strongly suggests that the naturally occur-ring configuration is likely to be the most potent one.

History of PyrethroidsSynthesis of naturally occurring compounds and

their bioactive analogs is a normal part of naturalproducts chemistry research. These investigationsare important in structural elucidation, often using

simplified compounds as models. Ifmodel chemicalsfor the pyrethrum constituents are insecticidal, theyare pyrethroid insecticides. The principles by whichsecond generation insecticides were later discoveredwere already recognized over 60 years ago, sinceStaudinger and Ruzicka prepared about 100 candi-date pyrethroids between 1910 and 1916, althoughnone was particularly insecticidal. After correctingsome details of the pyrethrins structures assigned byStaudinger and Ruzicka, LaForge, Barthel, andSchechter derived a simpler synthetic analog, inwhich an allyl group replaced the pentadienyl sidechain of the alcohol moiety. This compound, alle-thrin, the first commercial pyrethroid, culminated

February 1980

(I)

193

wartime research in both the United States and En-gland seeking pyrethrum substitutes to minimize de-pendence on the natural material produced in areaswhere shipping channels and therefore availablesupplies might be disrupted.Few new pyrethroids were discovered following

commercialization of allethrin until developmentsabout 15 years ago in the laboratories of theSumitomo Chemical Company (Osaka andTakarazuka, Japan) and of Michael Elliott, NormanJanes and their co-workers at Rothamsted Ex-perimental Station (Harpenden, England). The acidmoiety was standardized as the now commercially-

ROe>,t

pyrethrins ISa

available chrysanthemic acid and new alcoholmoieties were examined. Pyrethroids developed atthis time served essentially as pyrethrum substituteswithout expanding the general scope of use. Varia-tions of the acid moiety were then made, using thebest alcohol moieties available. At present, dozensof laboratories in many countries are examiningthousands of potential pyrethroids each year. Thereare four primary optimization goals at present: higheffectiveness as knockdown agents for flies andmosquitoes (i.e., pyrethrum substitutes); maximumpotency as broad spectrum insecticides; adequatestability for plant protection; reasonable cost rela-

allethrin resmethrinkadethrin

4IRO 0

0

tetramethrin cypermethrindecamethrinfenvalerate

phenothrinpermethrin

(2)

c11 IR OR

pyrethrin Iallethrintetramethrinphenothrinresmethrin

kadethrin fenvalerate

-iCi O<OR

0

permethrincypermethrin

decamethrin

Environmental Health Perspectives

pyrethrin II(pyrethricacid, R=H)

(3)

194

tive to the use levels for adequate pest control.It is sometimes difficult to decide whether or not a

synthetic insecticide is a pyrethroid. Generally, newcompounds may be considered pyrethroids if theirbiological properties depend on stereochemical fea-tures similar to those of the pyrethrins. The mostactive compounds are carboxylic acid esters with thecarbons adjacent to the carboxyl group bearing ap-propriate substituents positioned, if they are at chiralcenters, in a configuration corresponding to pyre-thrin I. Structural optimization is normally achievedby sequential isosteric replacements of critical sub-stituent groups, as illustrated in Eq. (2) for the alco-hol moiety and Eq. (3) for the acid moiety. Selectingappropriate replacement groups is not as easy orobvious as it might appear. Each novel moiety wasdiscovered in tests ofmany hundreds or thousands ofesters, most of which proved to be essentially non-insecticidal. Some of the acid and alcohol moietiesare closely related to those of the natural esters,while others seem far removed, e.g., chlorophenyl-containing acid moieties and cyano-containing al-cohol moieties. One test for a pyrethroid acid moietyis to determine if it is most potent with the normalpyrethroid alcohol moieties; the same argumentapplies for pairing candidate alcohol with acidmoieties. The acid moieties ofsome pyrethroids beara close structural resemblance to a portion of

molecules of the DDT type, raising the question ofwhether pyrethroids and DDT might act in part atsimilar or the same neuroreceptors. Although thereare many similarities of action between pyrethroidsand DDT, the relevant neuroreceptors are not ade-quately defined so specific neurophysiological testscannot be used to differentiate unequivocally pyre-throids from nonpyrethroids.

Pyrethroids as PyrethrumSubstitutes

Five pyrethroids are used in much the same man-ner as pyrethrum extract (Fig. 2). They are highlyinsecticidal but not persistent enough for agriculturaluse. Three are primarily knockdown agents and theother two are very potent for kill. Household spraysare usually a mixture to mimic the action of pyre-thrum. They contain a knockdown agent, a moreinsecticidal component, and a synergist, normallypiperonyl butoxide. With the exception ofkadethrin,these compounds are chrysanthemates.The knockdown property requires rapid penetra-

tion conferred by the polarity of either the acid oralcohol component. Instability results from suscep-tibility to photooxidation at allyl, isobutenyl, furanand thiolactone substituents. For example, the

R =/

J

allethrin (1949)knockdown

>=+h,lOR

0

chrysanthematesor

biochrysanthemates

resmethrin (1967)kill

0R = \,f, R= \

tetramethrin (1964) phenothrin (1971)knockdown kill

J kadethrin (1976)knockdown

FIGURE 2. Pyrethrum substitutes used or proposed for use toknock down household insects or to kill household, garden,and stored products pests.

February 1980 195

isobutenyl group of chrysanthemates undergoesepoxidation and methyl oxidation and the furan ringdegrades via an unstable peroxide intermediate. Theyears for discovery or first reports in the literatureare given. Commercialization usually followed a fewyears later. Allethrin is employed as the isomershown (S-bioallethrin) or as a mixture of two (4RS orbioallethrin) or eight isomers. Tetramethrin, resme-thrin and phenothrin are available as mixtures offourisomers (IRS, cis, trans) and potentially as variousmixtures of two isomers (IRS, trans; IRS, cis; IR,cis, trans or forte mixtures). Kadethrin is used as theindividual isomer shown.

S-Bioallethrin, the most potent isomer of allethrin,has the same optical configuration as pyrethrinl. It isgenerally less active than the pyrethrins but morestable due to the less easily-oxidized alcohol moietyside chain. The other two knockdown pyrethroids, incontrast to the pyrethrins and allethrin, contain ele-ments in addition to carbon, hydrogen and oxygen,i.e., nitrogen in tetramethrin of Sumitomo ChemicalCompany and sulfur in Kadethrin of Roussel-Uclaf(Paris). Kadethrin is the most potent knockdownagent, even more active than pyrethrin II, but is verylabile due to the photoinstability of both the furanring and the thiolactone moiety.1{esmethrin has insecticidal potency equal or

superior to the pyrethrins on a wide variety of pests.The cyclopentenolone nucleus of the pyrethrins isreplaced by the sterically equivalent furylmethyl unitand the pentadienyl side chain by a benzyl group.

C I / IO

Phenothrin is derived from resmethrin by replacingthe furan ring by a phenyl group and the methylenebridge by oxygen, resulting in a more stable butusually less active compound. Both insecticides lacksignificant knockdown properties and the IR, transisomers (i.e., bioresmethrin and biophenothrin) aremore potent with some species and the IR, cis iso-mers with others. Synergists are of little or no valuewith resmethrin and phenothrin at normal ratios ofsynergist to insecticide. Resmethrin was discoveredin Rothamsted and offered for commercialization bythe National Research Development Corporation(NRDC) based in London. Phenothrin was discov-ered independently in England and Japan.

Pyrethroids for Crop ProtectionFour pyrethroids are currently used for crop pro-

tection: permethrin, cypermethrin, decamethrin,and fenvalerate, compounds obtained by replacingphotolabile centers in earlier esters with alternativeand more stable structural units (Fig. 3). Thesepyrethroids are derived from phenoxybenzyl alcoholfirst synthesized for other purposes in 1935 or froma-cyanophenoxybenzyl alcohol known since 1973.The acid moiety of permethrin was first investigatedby Jihri Farka's in Prague in 1958. He prepared theallethrin analog with enhanced insecticidal activitycompared to the chrysanthemate. It took 15 years forthis dichlorovinyl acid to appear once again in theliterature, when Elliott showed its importance as a

permethrin (1973) cypermethrin (1975)

decamethrin (1974) fenvalerate (1976)

FIGURE 3. Pyrethroids used for crop protection or public healthpest control. The years for discovery or first reports in theliterature are given. Commercialization usually followed a fewyears later. The compounds are shown as the isomer composi-tion normally employed for crop protection. The most potentof the eight isomers of cypermethrin is equivalent in insectici-dal activity to decamethrin, in which bromine replaceschlorine.

Environmental Health Perspectives196

pyrethroid acid having derived it by isosteric modifi-cations. Permethrin, containing this photostablecomponent, was the first pyrethroid with propertiesappropriate for crop protection. The a-cyano de-rivatives, cypermethrin and decamethrin, also firstprepared at Rothamsted, are extremely active insec-ticides. The cyano substituent in the S-configurationincreases the potency by about 3- to 6-fold. TheR-configuration is essentially inactive. Decamethrinand the equivalent IR, cis, aS isomer of cyper-methrin are the most potent pyrethroids at present.The research of Sumitomo Chemical Company cul-minating in fenvalerate involved a series of discov-eries, i.e. the useful properties of phenoxybenzylalcohol, of its a-cyano analog, and of the indicatednon-cyclopropanecarboxylic acid as an excellentsubstitute for chrysanthemic acid analogs. Fenval-erate is generally in the range of 0.3 to 2 times thepotency of permethrin, depending on the pestspecies.

Pyrethroid Metabolism andEnvironmental DegradationTwo ways have been used to enhance the stability

and therefore the potency of pyrethroids such aspyrethrin I. The first involves adding a synergist orantioxidant to retard metabolic or photochemicaloxidative reactions. The second and much more ef-fective procedure replaces substituents susceptibleto photochemical or metabolic degradation with al-temative groupings that confer greater overall sta-bility to the molecule. Much of the safety of thepyrethrins is attributed to their instability. Thus, thestabilizing process could potentially generate com-pounds persisting in mammals and acting as en-vironmental contaminants. The pyrethroid should beprotected from abiotic (mainly photochemical) deg-radation and insect metabolism but susceptible tometabolism in mammals and environmental sys-

al lethrin

4'-~~~~~~~~O.

piperonyl butoxide

tems. The author and his colleagues at Berkeley haveemphasized research on metabolism and environ-mental degradation, as have Miyamoto, Ohkawa,and co-workers of Sumitomo.Metabolic detoxification is a major factor limiting

the insecticidal activity of the pyrethrins and otherchrysanthemates. Houseflies metabolize pyrethrinI, S-bioallethrin, and biotetramethrin by oxidation ofa methyl group in the isobutenyl substituent to thecorresponding carboxylic acid, a pathway paral-leling the first steps in the biosynthetic conversion ofchrysanthemic acid or its esters to pyrethric acid orpyrethrates in pyrethrum flowers [Eq. (1)]. House-flies also oxidize allethrin in the alcohol component,probably at the double bond and the methylenegroup of the allyl moiety. These reactions areeffected by the housefly microsomal mixed-func-tion oxidase system when fortified with reducednicotinamide-adenine dinucleotide phosphate(NADPH), the critical cofactor.

Synergist action involves inhibition of pyrethroiddetoxification resulting in greater persistence in in-sects and higher potency. The microsomal mixed-function oxidase system metabolizes both the pyre-throid and the synergist, e.g., allethrin and piperonylbutoxide. Sites of oxidation are indicated by arrowsin Eq. (4). Piperonyl butoxide, both in vivo and invitro, inhibits housefly metabolism of allethrin andother chrysanthemates, the synergist in the processundergoing metabolism at methylene substituentsadjacent to oxygen atoms. The synergist is usually abetter metabolic inhibitor in insects than in mam-mals.

Metabolic considerations played an important rolein designing pyrethroid acid and alcohol moieties forenhanced insecticidal activity. Oxidation at anisobutenyl methyl group was circumvented by thedihalovinyl replacement or by shifting to the fenval-erate acid moiety. Pyrethroids are also detoxified byhydrolytic processes. Insect esterases generally

microsomalmixed

functionoxidase

detoxificationproducts

oxidaseinhibition

(4)

February 1980 197

hydrolyze trans-chrysanthemates faster than cis-chrysanthemates, providing a partial explanation forthe greater toxicity of the cis-isomer in some cases.Suitable esterase inhibitors synergize the insectici-dal activity of several pyrethroids but such combi-nations are not commonly used. The a-cyano sub-stituent also retards esterase hydrolysis and possiblyoxidative detoxification as well. Thus, the structuralfeatures used in optimizing the insecticidal activityof decamethrin are those designed to resistmetabolism, i.e. a dihalovinyl group, the cis-isomerabout the cyclopropane ring, and the cyano sub-stituent. Even these modifications have not com-pletely overcome the limiting effect of decamethrindetoxification in houseflies, since it can be syner-gized at least tenfold by a very high level ofpiperonylbutoxide or related synergist.Mammals also metabolize pyrethroids by oxida-

tion and ester cleavage. The same detoxificationreactions account for the low toxicity of pyrethrin Iand allethrin to mammals and the need to use asynergist for increasing their toxicity to insects.Fortunately, piperonyl butoxide as normally usedgives little if any increase in toxicity ofthese rethrinsto mammals. However, high synergist levels to blockmammalian detoxification by oxidases (piperonylbutoxide) or esterases (organophosphorus com-pounds) generally increase pyrethroid toxicity.Caution must be exercised in using synergists be-cause of such potential hazards. Structural modifi-cations to stabilize the pyrethrins to insect metabo-lism could produce very hazardous compounds ifthey stabilized them in a parallel fashion to mam-malian metabolism. Fortunately this is not the casefor pyrethroids studied so far, e.g. decamethrin).Although the dibromovinyl group is not oxidized inmammals, there are still five sites of oxidation atmethyl and aryl groups, the 4'-position being major,and ester hydrolysis is also important [Eq. (5)].Decamethrin metabolism in rats and mice involves

hydroxylation at either methyl group or any one ofthree aromatic positions. Ester cleavage by esteraseaction or possibly oxidative processes yields the acidand alcohol fragments. The cis-hydroxymethyl de-rivative is detected only after ester cleavage. Thecyanohydrin breaks down to hydrogen cyanide andthe aldehyde which is then oxidized to the acid. Thetwo carboxylic acids are excreted with or withoutconjugation with glucuronic acid or amino acids suchas glycine and taurine. The hydroxymethyl andphenolic derivatives are conjugated in part as sulfateesters. The liberated cyanide is quickly detoxified byconversion to thiocyanate which is excreted or tem-porarily bound in the stomach and hair prior to ex-cretion. In soil a portion of the cyano moiety ofrelated compounds is hydrated to the amide.

198

trans-

conjugates

HO>}-

HO

N

y\

Q."f

2'-HO

-OH

NH2

HCN > HSCN(5)

Metabolism studies of this type made on pyre-thrins I and II and all the synthetic analogs discussedabove clearly show that structural modifications canbe made for enhanced insecticidal activity andphotostability while maintaining rapid biodegrada-tion in mammals. There are structure-dependentdifferences in the persistence of pyrethroid residuesin mammals and birds; for example, although theresidues are low, the more metabolically-stable cis-permethrin persists longer than trans-permethrin infat, milk and eggs.Environmental movement and fate were of little

concern with the unstable pyrethrins and earlychrysanthemates but are of considerable importancewith the more stable pyrethroids used for crop pro-tection. As with DDT, the newer halogen-containingpyrethroids are;highly liposoluble, almost insolublein water and persist on surfaces due to low vaporpressure (the pyrethrins and permethrin are viscousliquids and decamethrin a crystalline solid). Airmovements are not likely to disperse these pyre-throids except during application or shortly thereaf-ter. They are quite persistent on plants due to acombination of retention in leaf cuticular waxes (sothat they are not washed off by rain), low volatility,and resistance to photochemical degradation.Studies at Berkeley show that photodecompositionof the pyrethroids shown in Figure 3 involvesisomerization at the cyclopropane ring [Eq. (6)],ester cleavage, decarboxylation, diphenyl ethercleavage, oxidation to benzoic acid derivatives, anddehalogenation. These occur slowly enough that ifonly abiotic factors were involved these pyrethroidswould be some of the most persistent organic insec-ticides.

Environmental Health Perspectives

H 1

X9gIR

0ORtwo IR

insecticidalisomers

X 'iXsORfrans

0

two 1 Snoninsecticidal

isomershvz/

(6)

The photoisomerization shown in Eq. (6) involvesa breaking and re-forming of the cyclopropane ringvia a diradical intermediate. The final equilibriumbalance favors the trans isomers (upper structures)about 2:1 over the cis isomers (lower structures).Only the IR isomers at the left are insecticidal. Xrefers to methyl, halogen or other substituents. Thisis one of many processes involved in pyrethroidphotodecomposition, usually yielding less activeproducts.

It is fortunate that environmental cleansing in-volves biotic as well as abiotic processes since thedegradation rate of agricultural pyrethroids is greatlyincreased once they enter biological systems. Plantsmetabolize these pyrethroids, on partitioning out ofcuticular waxes, by ester cleavage (trans isomermore rapid than cis), methyl and aryl oxidation andconjugation reactions as in mammals (except thatglucoside rather than glucuronide conjugates areformed in plants). Although there is no evidence forplant metabolites that are hazardous, the residueanalyses often consider several metabolites andphotoproducts in addition to the parent compounds.Pyrethroids are not expected to undergo a high levelof biological magnification on passing through foodchains. They are nearly immobile in soils due to theirlow water solubility, rapid adsorption and minimalvapor diffusion. Although contamination of aquaticsystems is a serious potential problem from directapplication or erosion oftreated soil, it is not likely tooccur by diffusion or leaching. Thus, under fieldconditions the pyrethroids are rapidly absorbed intostream banks, pond sediments and organic matter todecrease their concentration in water. Soils high inmicrobial activity extensively metabolize pyre-throids within a few weeks by ester and diphenylether cleavage, hydration of the cyano moiety andother reactions ultimately leading to carbon dioxide.Pyrethroids do not seem to affect soil microorga-nisms adversely.

Pyrethroid ToxicologyPyrethroids are generally broad-spectrum insec-

ticides. They control a large variety of insects, al-though the effective dose may vary greatly betweenthe most and least sensitive species. In stored prod-ucts protection a synergist is commonly added. Infood and fiber production the pyrethroid is oftenused in the same fields as one or more other insec-ticides, miticides or ovicides. To protect susceptiblehoneybees, pyrethroids must be applied at times andin amounts to minimize pollinator and hive damage.Predator and parasite kills may lead to resurgencesof pests no longer controlled by their naturalenemies. Pyrethroids are not effective in controllingsoil insects possibly due to soil binding and metab-olism of the compounds. Crustaceans and beneficialaquatic insects are potential non-target victims ofpyrethroid uses to control mosquito larvae and otherdipterous larvae of medical importance.

Resistance has previously curtailed the use of al-most every type of insecticide and poses a seriousthreat to the future of pyrethroids. Cross resistancedoes not appear to be a problem between pyrethroidsand organophosphates or methylcarbamates. How-ever, previous selection of houseflies with DDT for arecessive factor conferring knockdown resistance(kdr) carries with it a cross-resistance to pyrethroids.Houseflies on Danish farms developed pyrethroidresistance when pyrethrins and pyrethroids replacedchlorinated hydrocarbon and organophosphorus in-secticides. One pyrethroid-resistant field strain wassubsequently selected in the laboratory with biores-methrin to a resistance factor of 1400-fold. Despiteno previous exposure, this strain was more than60,000-fold resistant to decamethrin. Thus, the mostpotent of all insecticides on a normal strain has al-most no effect on this resistant strain. This is themost dramatic example available of pyrethroid re-sistance. Some of the housefly resistance mecha-

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I I ar, hy

X')

199

FIGURE 4. Housefly resistance mechanisms of three distinct typesare recognized from studies involving crosses of resistant un-marked fly strains with susceptible flies carrying markers onappropriate chromosomes. Bioassays and the visible markersare used to associate resistance factors with individualchromosomes. Recessive factors on chromosome 3 conferreduced penetration to many insecticides and knockdown re-sistance (kdr) to pyrethroids and DDT. The detoxifyingmixed-function oxidases or incompletely dominant mfo ofchromosome 2 are also associated with resistance to manyother types of insecticides. Pyrethroid resistance is greatlyenhanced by recessive modifier characters conferred bychromosome 2 and to a lesser degree by 1 and 5.

nisms are considered in Figure 4. Low levels of fieldresistance are also known in local areas with mos-quitoes, Australian cattle ticks, some lepidopterouspests on cotton, and a few other pest species. It maybe possible to forestall pyrethroid resistance by re-stricting their use to minimal doses and numbers ofapplications and by more fully utilizing integratedpest management systems. Routine application ofpyrethroids at high doses, as done in the past withother insecticides, practically guarantees that resis-tance will reach levels where economic use of pyre-throids is no longer possible.

Fish are sensitive to pyrethroids at part per billionlevels, so great care must be taken in treating agri-cultural crops and forests to avoid contaminatinglakes and streams and commercial fish-producingareas. The high sensitivity of fish is possibly relatedto the ability of their gills to concentrate pyrethroidswhich then disrupt nerve-controlled respiratorymechanisms. Birds seem to be unusually tolerantand have survived high oral doses of several syn-thetic pyrethroids. Although the mechanism of avianinsusceptibility is not known, chickens rapidlymetabolize and excrete orally-administered perme-thrin.

Mammals appear to be relatively tolerant to pyre-throids, so in this respect these synthetic insecticidesare welcome alternatives to some ofthe other secondgeneration insect control agents. Selectivity is oftenexpressed as a ratio for the amount of insecticide pergram of body weight to kill 50% of a group of orallytreated rats divided by the comparable value forvarious topically-treated insects. This selectivityratio averages about 4000 for many pyrethroids but isless than 100 for various chlorinated hydrocarbon,organophosphorus and methylcarbamate insec-ticides. A few compounds (pyrethrin II and kade-thrin) administered intravenously are toxic to rats atlevels equivalent to their potency on susceptible in-sects. The relatively low toxicity to mammals fol-lowing oral, dermal or inhalation exposure thereforeresults largely from factors preventing entry into thenervous system, such as metabolic detoxification.Excessive exposure to certain pyrethroids may re-sult in skin irritation in sensitive individuals.

Lifetime feeding studies with mammals are at leastas important as acute toxicity observations inevaluating the safety of pyrethroids. Some of thesestudies have been completed and others are still inprogress on each pyrethroid proposed or in use forcrop protection. Tolerance values or the maximumallowable residues in food and feed will be based onthe dietary levels found to have no effect, the amountof residues normally present when the compoundsare used in accordance with good agricultural prac-tice, and a safety factor to correct for possible differ-ences in sensitivity of humans and the laboratorymammals.

Pyrethroids are nerve poisons, but their mode ofaction at the molecular level remains obscure. Theycause repetitive discharges in arthropod nerve due tointerference with axonal sodium and potassiumchannels. The repetitive firing is attributed primarilyto prolongation of the turning off of the increase insodium conductance and secondarily to the suppres-sion of the increase in potassium current. It is notclear which symptoms in insects or other animals-aredue to effects on the central or the peripheral ner-vous system or both. Pyrethroids are more toxic toinsects at low than high temperatures, as is also thecase with DDT. Many types of isolated nerve prepa-rations from insects and other arthropods are highlysensitive to pyrethroids, but none ofthe investigatedsystems so far is an adequate model of the effects onorganisms. In pyrethroid poisoning of various insectspecies, fish and mammals, there is probably no needto invoke a fundamentally different primary mode ofaction. Poisoning of rats and mice is related to butnot necessarily dependent on the levels of somepyrethroids in the brain.

Structure-activity studies, particularly with sy-

Environmental Health Perspectives200

nergist-treated insects, help to define the configura-tion of the physiologically-important nerve receptor.The flexible pyrethroid molecule with its highstereospecificity must adopt a conformation inwhich all structural features essential for potency areappropriately oriented with respect to each other andto a complementary chiral receptor. The most sensi-tive and relevant receptor must be isolated and de-fined pharmacologically as a prelude to understand-ing pyrethroid mode ofaction at the molecular level.

SummaryPyrethroids are the most potent lipophilic insec-

ticides. They are also the most expensive per unitweight. The cost is increased by producing thesingle, most potent optical isomer using advancedtechniques of synthesis and resolution. Less activeisomers and byproducts can often be converted to auseful isomer or intermediate in a recycling process.The pyrethroids may potentially provide an ex-cellent cost/benefit ratio in agricultural pest insectcontrol, in part because they persist sufficiently torequire relatively few applications. This economicsituation would change drastically if resistancephenomena required increases in pyrethroid doses oftwo- to ten-times. The potency of pyrethroids alsomeans a smaller environmental burden of the parentcompound and its photoproducts and metabolites,with their possible undesired effects. Thus with de-camethrin, a single compound of high chemical andisomeric purity, application at 10 g/hectare for pestcontrol gives an initial deposit of 1 mg/M2. Mostother types of pesticides, because of lower potency,require deposits of 50 to 200 times as high. Insec-ticides as active as some pyrethroids are knownamong the chlorinated hydrocarbons, organophos-phates, and methylcarbamates, but with the lattercompounds this remarkably high insecticidal activityis usually accompanied by unacceptable mammaliantoxicity.

Pyrethroids do not provide new or unique ap-proaches to insect control. They are strictly alterna-tives to or replacements for current compounds.Synthetic analogs have been used for 30 years aspyrethrum substitutes without diminishing the de-mand for the natural product. However, the pyre-thrum industry in various countries must becomebetter organized and more efficient in productionand distribution continually to compete with theever-increasing number of synthetic alternatives,although these take time to develop such a provensafety record. The more stable pyrethroids are beingincreasingly used to replace DDT and other chlori-nated hydrocarbons. Both classes include long re-sidual contact insecticides effective on many of the

same pest complexes. The current pyrethroids arenot phytotoxic, so their use results in higher yieldsthan are obtained with other equally-effective butphytotoxic insecticides. Pyrethroids are not suitablereplacements for organophosphates and methylcar-bamates as plant systemics because of low watersolubility or as soil insecticides due to soil binding,metabolism, and low vapor pressure. The future ofpyrethroids as contact insecticides and stomachpoisons will depend on what further restrictions areplaced on the present insecticides, the comparativeseasonal cost for pest control with pyrethroids andwith other compounds, and the final risk assess-ments based on the toxicological findings.Advances in the past seven years establish pyre-

throid insecticides as one of the major classes ofpesticide chemicals. They also indicate that theo-retically additional structural modifications can in-crease their potency more than 10-fold further and/orreduce the seasonal pest control cost by a similarfactor. Alternative pyrethroids are available for in-troduction if there are toxicological problems withthe current compounds. Structure optimization isnow focusing on new properties in addition to po-tency, low mammalian toxicity, competitive priceand suitable persistence. These goals are: dimin-ished toxicity to fish or to honeybees, predators andparasites; broader spectrum of activity includingmites and aphids to reduce the need for pesticidemixtures; effective on strains resistant or cross re-sistant to current pyrethroids; potent as ovicides forinsect and mite eggs; effective as nematocides andanthelmintics. How many new pyrethroids can bejustified and might it be practical to develop? Atcurrent or anticipated costs probably no more thanfour to eight additional pyrethroids could be de-veloped for agricultural use over the next ten yearson a worldwide basis. It is therefore important to usethe current pyrethroids at doses and in a manner tominimize the selection of resistant strains andthereby conserve this valuable resource for controlof pest insects in the years and hopefully decadesahead.

The author is indebted to the Rockefeller Foundation for ap-pointment as a Scholar-in-Residence at the Bellagio Study andConference Center at Lake Como, Italy where this article wasprepared. It is similar to a lecture presented on receiving the 1978Kenneth A. Spencer Award of the American Chemical Society.Helpful comments were provided by Michael Elliott and co-work-ers at Rothamsted Experimental Station, Tom Bogaard of Mc-Laughlin Gormley King Co., Derek Gammon of the PesticideChemistry and Toxicology Laboratory, and Ruth Patrick of theAcademy of Natural Sciences in Philadelphia. Portions of thisreview are based on studies supported by NIEHS Program Project5 P01 ES00049 and EPA Grant R805999.

February 1980 201

REFERENCES

1. Casida, J. E., Ed. Pyrethrum. The Natural Insecticide.Academic Press, New York, 1973.

2. Elliott, M., Ed. Synthetic Pyrethroids. ACS SymposiumSeries, No. 42, American Chemical Society, Washington,D.C., 1977.

3. Elliott, M., and Janes, N. F. Synthetic pyrethroids - a newclass of insecticides. Chem. Soc. Revs. (London) 7: 473(1978).

4. Elliott, M., Janes, N. F., and Potter, C. The future of pyre-throids in insect control. Ann. Rev. Entomol. 23: 443 (1978).

5. International Trade Center. Pyrethrum: A Natural InsecticideWith Growth Potential. UNCTAD/GATT, Geneva, Switzer-land, 1976.

6. Nelson, R. H., Ed. Pyrethrum Flowers, 3rd ed., 1945-1972.McLaughlin Gormley King Co., Minneapolis, 1975.

202 Environmental Health Perspectives