INTRODUCTION

Pyrethrins and their derivatives, pyrethroids, are insecticides frequently used in flea control products for dogs and cats. Pyrethrins, six distinct insecticidal constituents contained in the extract of the chrysanthemum flower, were structurally modified to increase their environmental stability.¹ The resultant derivatives, termed pyrethroids, have been used extensively in agricultural, house, and garden formulations over the last 3 decades and make up around one fourth of the world insecticide market.¹ The pyrethrins and pyrethroids have lower environmental contamination and vertebrate toxicity than other insecticides such as organophosphates and carbamates. The usefulness of an insecticide that is used clinically (i.e., topical flea products used in companion animals) is based on its differential toxic effect on the target versus the host organism: high potency against insects versus low toxicity for mammals. Selectivity ratios (mammalian oral lethal dose [LD₅₀]-to-insect topical LD₅₀) for pyrethroids are typically greater than 1000, but are less than 100 for other insecticides.² Flea products, particularly spot-ons containing high concentrations of pyrethroids, are the main source of toxicosis in small animals, especially in cats. Other formulations such as sprays, dips, powders, shampoos, gels, collars, pour-ons, and aerosol bombs are additional sources of toxicity. Substances contained in these products are pyrethrin I, allethrin, fenvalerate, resmethrin, sumethrin, and permethrin.

STRUCTURES OF PYRETHRINS AND PYRETHROIDS

The insecticide pyrethrum is a crude extract from chrysanthemum flowers (Chrysanthemum cinerariifolium and C. cineum). It exerts its insecticidal activity as a result of six distinct substances contained within: pyrethrin I and II, cinerin I and II, and jasmolin I and II. They are collectively termed pyrethrins, the most potent being pyrethrin I. Structurally they are very similar esters of a cyclopropane carboxylic acid (acid moiety) and a cyclopentenolone alcohol (alcohol moiety). Pyrethroids are synthetic derivatives of the natural pyrethrins and were generated primarily to achieve more photostability while retaining the desired insecticidal and toxicologic properties. The most important compounds are listed in Box 94-1.

Because pyrethroids contain two to three chiral carbons, four to eight stereoisomeric compounds exist for each substance. Not all stereoisomers of a given compound have insecticidal activity or cause mammalian neurotoxicity. The 1R,cis configuration of permethrin, for example, is toxic to both insects and mammalian species, although the trans configuration remains equally toxic to insects but is 100 times less toxic to mammals.¹ No specific molecular structure is identified that would be essential for the insecticidal activity, as reflected by the large number of synthetic compounds with good activity. Along with the stereospecificity, this indicates that the overall shape of the molecule is essential for binding to the site of action and exerting its effect in invertebrates and mammals.¹

Pyrethrins and pyrethroids have been classified further, based on the signs they induce in rat toxicity studies³ in which two distinct patterns occurred. The type I or T-syndrome (T is for tremor) is characterized by aggressive sparring, increased sensitivity to stimuli, fine tremors, prostration, and hyperthermia. The type II or CS-syndrome (CS is for choreoathetosis and salivation) is characterized by pawing and burrowing, salivation, coarse tremors progressing to choreoathetosis (e.g., jerky, uncontrolled, excessive movements), clonic seizures, abnormal hind limb locomotion, and hypothermia. The main structural difference between the two groups of pyrethroids is the presence of an α-cyano group in the alcohol moiety of type II compounds (see Box 94-1). The two groups have slightly differing mechanisms of toxicity that manifest as distinct syndromes (see following section). The presence of the cyano group generally enhances toxicity of the pyrethroids in both mammals and insects.¹

TOXICOKINETICS AND METABOLISM

Toxicokinetic data are scarce and are based largely on findings in rodents. This should be kept in mind when applying these results to dogs and cats. Furthermore, there are significant differences between compounds and isomers, altogether painting a heterogeneous toxicokinetic picture. Pyrethrins and pyrethroids are rapidly and extensively absorbed from the gastrointestinal (GI) tract after oral administration. Peak serum concentrations may be reached after 2 to 4 hours. A corn oil vehicle decreased the LD₅₀ for various substances (including permethrin) in acute toxicity trials in rats.¹ Dermal absorption is significantly lower, less than 2%, but is greatly enhanced if applied in an emulsion (as compared with a dust formulation).^1,4 Grooming, and thus oral ingestion of the toxin, may significantly increase the bioavailability. Inhaled pyrethroids are absorbed effectively from the respiratory tract. The lipophilicity of the pyrethroids allows for a large volume of distribution and easy penetration of the blood-brain barrier. Although preferential distribution to fat tissue was similar for all pyrethroids, its extent varied among various compounds and stereoisomers.¹ The oral or intravenous dose administered and brain tissue concentration reached correlate well with the degree of toxicity, but the same is not true for blood levels.¹ The plasma elimination half-life after a single oral or intravenous dose of permethrin has been determined to range from 8 to 17 hours in rats, but is significantly longer in neural tissue.⁵ Also, the maximum nervous tissue permethrin concentration was higher than that plasma, indicating accumulation in these tissues.⁵ Different isomers may have different elimination half-times; the trans isomer of permethrin was eliminated 10 times faster than the cis isomer in a person following intentional pyrethroid ingestion.⁶

Biotransformation of pyrethrins and pyrethroids consists of hydrolysis by tissue and plasma esterases at the central ester bond and oxidation by hepatic mixed function oxidases at various sites in the acid or alcohol moiety. The latter mechanism may be enhanced with long-term exposure by induction of microsomal enzymes,⁷ and their upregulation is also a mechanism of pyrethroid resistance in insects.⁸ All metabolites lack gross activity and are excreted renally after hydroxylation or conjugation to glycine, glucuronides, glucosides, or sulfates.¹ The ability for efficient metabolic inactivation is an important factor for limiting acute neurotoxicity. Synergists, substances that are commonly added to pyrethroids to enhance their insecticidal potency and duration of action, exert their effect by inhibiting esterases and P-450–dependent monooxygenases. These compounds, such as piperonyl butoxide, N-octyl bicycloheptene dicarboximide (MGK 264), sulfoxide, sesamin, and sesamolin, may increase mammalian neurotoxicity of pyrethroids, carbamates, and organophosphates.² Inefficient glucuronide conjugation in the feline liver leads to an accumulation of phase I metabolites. This, in turn, slows primary hydrolysis and oxidation of the parent compound, and thus decelerates detoxification. However, toxicokinetic data for the cat that would further substantiate and detail this assumption are lacking.