UKPID MONOGRAPH PYRETHROIDS SA Cage MSc M Inst Inf Sci SM Bradberry BSc MB MRCP JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Birmingham B18 7QH This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. PYRETHROIDS Toxbase summary Type of product Insecticides Toxicity Dermal and inhalational exposures are associated usually with no or only mild adverse effects. Following substantial ingestion, patients may develop coma, convulsions and severe muscle fasciculations and may take several days, occasionally weeks, to recover. Fatalities have occurred rarely, usually following ingestion (He et al, 1989). Ingestion of deltamethrin 2 mg/kg caused coma in a four year-old child. Recovery was uneventful (O'Malley, 1997). Features Dermal exposure - Tingling and pruritus with blotchy erythema on the face or other exposed areas, exacerbated by sweating or touching. Systemic toxicity may ensue following substantial exposure (see below). Ocular exposure - Lacrimation and transient conjunctivitis may occur. Inhalation Brief exposure: - Respiratory tract irritation with cough, mild dyspnoea, sneezing and rhinorrhea. Substantial and prolonged exposure: - Systemic toxicity may ensue - see below. Ingestion - May cause nausea, vomiting and abdominal pain. Systemic toxicity may ensue following substantial ingestion (see below). Systemic toxicity - Systemic symptoms may develop after widespread dermal exposure, prolonged inhalation or ingestion. Features include headache, dizziness, anorexia and hypersalivation. - Severe poisoning is uncommon. It usually follows substantial ingestion and causes impaired consciousness, muscle fasciculations, convulsions and, rarely, non-cardiogenic pulmonary oedema. Chronic exposure - Long-term exposure is no more hazardous than short-term exposure. Management Dermal 1. Remove soiled clothing and wash contaminated skin with soap and water. 2. Institute symptomatic and supportive measures as required. 3. Topical vitamin E (tocopherol acetate) has been shown to reduce skin irritation if applied soon after exposure (Flannigan et al, 1985), but it is not available as a pharmaceutical product in the UK. 4. Symptoms usually resolve within 24 hours without specific treatment. Ocular 1. Irrigate with lukewarm water or 0.9 per cent saline for at least ten minutes. 2. A topical anaesthetic may be required for pain relief or to overcome blepharospasm. 3. Ensure no particles remain in the conjunctival recesses. 4. Use fluorescein stain if corneal damage is suspected. 5. If symptoms do not resolve following decontamination or if a significant abnormality is detected during examination, seek an ophthalmological opinion. Inhalation 1. Remove to fresh air. 2. Institute symptomatic and supportive measures as required. Ingestion 1. Do not undertake gastric lavage because solvents are present in some formulations and lavage may increase risk of aspiration pneumonia. 2. Institute symptomatic and supportive measures as required. 3. Atropine may be of value if hypersalivation is troublesome, 0.6-1.2 mg for an adult, 0.02 mg/kg for a child. 4. Mechanical ventilation should be instituted if non-cardiogenic pulmonary oedema develops. 5. Isolated brief convulsions do not require treatment but intravenous diazepam should be given if seizures are prolonged or recur frequently. Rarely, it may be necessary to give intravenous phenytoin or to paralyze and ventilate the patient. References Box SA, Lee MR. A systemic reaction following exposure to a pyrethroid insecticide. Hum Exp Toxicol 1996; 15: 389-90. Flannigan SA, Tucker SB, Key MM, Ross CE, Fairchild EJ, Grimes BA, Harrist RB. Synthetic pyrethroid insecticides: a dermatological evaluation. Br J Ind Med 1985; 42: 363-72. He F, Wang S, Liu L, Chen S, Zhang Z, Sun J. Clinical manifestations and diagnosis of acute pyrethroid poisoning. Arch Toxicol 1989; 63: 54-8. Lessenger JE. Five office workers inadvertently exposed to cypermethrin. J Toxicol Environ Health 1992; 35: 261-7. O'Malley M. Clinical evaluation of pesticide exposure and poisonings. Lancet 1997; 349: 1161-6. INTRODUCTION Pyrethrins were developed as pesticides from extracts of dried and powdered flower heads of Chrysanthemum cinerariaefolium. The active principles of these (see Fig. 1) are esters of chrysanthemumic acid (R1 = CH3) or pyrethric acid (R1 = CH3O2C) (both cyclopropane (three membered ring) carboxylic acids), with one of three cyclopentanone alcohols (cinerolone, R2 = CH3; jasomolone, R2 = CH2CH3; or pyrethrolone, R2 = CHCH2), giving six possible structures. These natural pyrethrins have the disadvantage that they are rapidly decomposed by light. Once the basic structure of the pyrethrins had been discovered, synthetic analogues, pyrethroids, were developed and tested. Initially esters were produced using the same cyclopropane carboxylic acids, with variations in the alcohol portion of the compounds. The first commercial synthetic pyrethroid, allethrin (Fig. 2), was produced in 1949, followed in the 1960s by dimethrin, tetramethrin, resmethrin (Fig. 2), prothrin, and proparthrin. 3-Phenoxybenzyl esters were also found to be active as pesticides (phenothrin, permethrin) (Fig. 3). Synthetic pyrethroids with this basic cyclopropane carboxylic ester structure (and no cyano group substitution) are known as type I pyrethroids. In animal studies type I pyrethroids have been shown generally to produce a typical toxic syndrome (see page 10). The insecticidal activity of synthetic pyrethroids was enhanced further by the addition of a cyano group at the benzylic carbon atom to give alpha-cyano (type II) pyrethroids. Examples of type II pyrethroids include cyphenothrin and cypermethrin (Fig. 4). In animal studies type II pyrethroids have been shown generally to produce a typical toxic syndrome (see page 10). Similar insecticidal activity was found in a group of phenylacetic 3-phenoxybenzyl esters, despite the lack of the cyclopropane ring. This led to the development of fenvalerate, an alpha-cyano-3-phenoxy-benzyl ester, and other related compounds (Fig. 5). These all contain the alpha-cyano group and hence are type II pyrethroids. Some common type I and type II pyrethroids are shown in Table 1. Table 1. Type I and type II pyrethroids Type I Type II Allethrin Cyfluthrin Bioallethrin Cyhalothrin Bifenthrin Lambda-cyhalothrin Permethrin Cypermethrin d-Phenothrin Alpha-cypermethrin Prallethrin Deltamethrin Resmethrin Fenpropathrin Bioresmethrin Fenvalerate Tefluthrin Esfenvalerate Tetramethrin Flucythrinate Flumethrin Tau-fluvalinate Animal studies suggest that the two structural types of pyrethroids give rise generally to distinct patterns of systemic toxic effects. Type I pyrethroids produce the so-called "T (tremor) syndrome", characterized by tremor, prostration and altered "startle" reflexes. Type II (alpha-cyano) pyrethroids produce the so-called "CS (choreoathetosis/salivation) syndrome" with ataxia, convulsions, hyperactivity, choreoathetosis and profuse salivation. These observations are consistent with some differences in the mechanisms of toxicity between type I and type II pyrethroids (see below) but the division of reactions by chemical structure is not exclusive. Some compounds produce a combination of the two syndromes, and different stereoisomeric forms can produce different syndromes (Dorman and Beasley, 1991). The classification into "T" and "CS" syndromes is not used clinically. All pyrethroids have at least four stereoisomers, with different orientation of the substituents on the cyclopropane ring (or the equivalent part of the phenylacetate). The isomers have different biological activities, as discussed below (see Mechanisms of toxicity). Different isomers may have separate common names (Table 2), reflecting their commercial importance (Aldridge et al, 1978). In general, only the cyclopropane carboxylic acid esters with the R absolute configuration at the cyclopropane C1 atom, and alpha-cyano-3-phenoxy benzyl esters with the S absolute configuration at C-alpha (see Fig. 6) are toxic to man or insects (R and S refer to variations in the three dimensional structure of the molecule). Table 2. Pyrethroids with commercially available isomers Pyrethroid Isomers Resmethrin bioresmethrin, cisresmethrin Allethrin d-allethrin, bioallethrin, esbiothrin, s-bioallethrin Fenvalerate esfenvalerate Cyhalothrin lambda-cyhalothrin Phenothrin d-phenothrin Cypermethrin alpha-cypermethrin EPIDEMIOLOGY In 1989-1990, world-wide annual production of pyrethroids included approximately 1000 tonnes of fenvalerate (IPCS, 1990c), 600 tonnes of permethrin (IPCS, 1990b), several hundred tonnes of allethrin and its isomers (IPCS, 1989a), 340 tonnes of cypermethrin (IPCS, 1989c), about 250 tonnes of deltamethrin (IPCS, 1990d), a few hundred tonnes of tetramethrin (IPCS, 1990e), 70-80 tonnes of d-phenothrin (IPCS, 1990f) and 20-30 tonnes of resmethrin (IPCS, 1989b). No data on cyhalothrin and lambda-cyhalothrin production were available in 1990 (IPCS, 1990a). In spite of their long history of use, there are relatively few reports of pyrethroid toxicity. Less than ten deaths have been reported from ingestion of or occupational (primarily dermal/inhalational) exposure to fenvalerate and deltamethrin (He et al, 1989; Peter et al 1996). MECHANISMS OF TOXICITY In neuronal cells the generation of an action potential by membrane depolarization involves the opening of cell membrane sodium channels and a rapid increase in sodium influx. The closure of sodium channels begins the process of action potential inactivation. Delayed sodium channel closure thus increases cell membrane excitability. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels in mammalian and invertebrate neuronal membranes (Eells et al, 1992; Narahashi, 1989) to delay their closure. They are dissolved in the lipid phase of the membrane (Narahashi, 1996) and bind to a receptor site on the alpha sub-unit of the sodium channel (Trainer et al, 1997). This binding is to a different site from local anaesthetics, batrachotoxin, grayanotoxin, and tetrodotoxin (Narahashi, 1996). The interaction of pyrethroids with sodium channels is highly stereospecific (Soderlund and Bloomquist, 1989), with the 1R and 1S cis isomers binding competitively to one site and the 1R and 1S trans isomers binding non-competitively to another. The 1S forms do not modify channel function but do block the effect of the 1R isomers (Ray, 1991). The prolonged opening of sodium channels by the neurotoxic isomers of pyrethroids produces a protracted sodium influx which is referred to as a sodium "tail current" (Miyamoto et al, 1995; Soderlund and Bloomquist, 1989; Vijverberg and van den Bercken, 1982). This lowers the threshold of sensory nerve fibres for the activation of further action potentials, leading to repetitive firing of sensory nerve endings (Vijverberg and van den Bercken, 1990) which may progress to hyperexcitation of the entire nervous system (Narahashi et al, 1995). At high pyrethroid concentrations, the sodium "tail current" may be sufficiently great to depolarize the nerve membrane completely, generating more open sodium channels (Eells et al, 1992) and eventually causing conduction block. The depolarizing activity is specific for the neurotoxic isomers (Eells et al, 1992), and parallels mammalian toxicity: deltamethrin > cypermethrin > fenvalerate >> permethrin (Clark and Marion, 1989; Eells et al, 1992). Only low pyrethroid concentrations are necessary to modify sensory neurone function. For example, when tetramethrin was added to a preparation of rat cerebellar Purkinje neurons, only about 0.6-1 per cent of sodium channels needed to be modified to produce: (i) Repetitive discharges in nerve fibres and nerve terminals; An increase in discharges from sensory neurons (due to membrane depolarization); and (ii) Severe disturbances of synaptic transmission (Narahashi, 1989; Narahashi et al, 1995; Song and Narahashi, 1996). Although both type I and type II pyrethroids primarily affect sodium channels, experimental studies have identified some specific differences in their effects. These are summarized below and may, in part, account for the differences in clinical manifestations observed following experimental intoxication with type I and type II pyrethroids. Type I pyrethroids (without the alpha-cyano group) Type I compounds: (i) Keep sodium channels open (Narahashi, 1989); (ii) Produce repetitive firing of sensory nerve endings (Soderlund and Bloomquist, 1989; Vijverberg and van den Bercken, 1982); (iii) Modify sodium channels in the resting or closed state so that they subsequently open more slowly (Dorman and Beasley, 1991); (iv) Show a more pronounced positive temperature-dependent capacity for developing repetitive discharges (more likely to occur at higher temperatures) and negative temperature dependence for nerve-blocking action (more likely to occur at lower temperatures) (Clark and Marion, 1989; Dorman and Beasley, 1991; Narahashi, 1989); and (v) Produce effects on cultured neurons that are easily reversed by washing with a pyrethroid-free solution (Song et al, 1996). Type II pyrethroids (mainly alpha-cyano-3-phenoxybenzyl esters) Type II compounds: (i) Cause depolarization of myelinated nerve membranes without repetitive discharges (Dorman and Beasley, 1991; Vijverberg and van den Bercken, 1982); (ii) Are associated with a decrease in action potential amplitude (Dorman and Beasley, 1991); (iii) Stabilize a variety of sodium channel states by reducing transition rates between them (Dorman and Beasley, 1991; Eells et al, 1992; Narahashi, 1989), causing a greatly prolonged open time (Vijverberg and van den Bercken, 1982), and producing stimulus-dependent nerve depolarization and block (Soderlund and Bloomquist, 1989); (iv) May act post-synaptically by interacting with nicotinic acetylcholine and GABA receptors (Dorman and Beasley, 1991; Eells et al, 1992); and (v) Produce effects on cultured neurons that are largely irreversible after washing cells with a pyrethroid-free solution (Song et al, 1996). In addition, type II pyrethroids, such as deltamethrin, enhance noradrenaline (norepinephrine) release (Clark and Brooks, 1989). Tetramethrin (Clark and Marion, 1989), but not deltamethrin or fenvalerate (Narahashi, 1989), also blocks voltage-dependent calcium channels. Oral deltamethrin increases monoamine oxidase activity selectively in different parts of rat brains, and produces morphological changes in Purkinje neurons in the cerebellum (Husain et al, 1996). In human investigations, maximal conduction velocity in sensory nerve fibres of the sural nerve showed some increase in subjects exposed to pyrethroids, but there were no abnormal neurological signs, and other electrophysiological studies were normal in the arms and legs (Le Quesne et al, 1980). He et al (1991) assessed nerve excitability using an electromyograph and pairs of stimuli at variable intervals. They showed a prolongation of the "supernormal period" in the median nerve in individuals who had been exposed to pyrethroids occupationally for three days. The "supernormal period" was even more prolonged two days after cessation of exposure. (Note: the "supernormal period" is the period for which the action potential induced by a second stimulus is greater than the action potential produced by an initial stimulus). Pyrethroids are some 2250 times more toxic to insects than mammals. This can be explained in terms of differences in their potency as neuronal toxins and differences in rates of detoxification between invertebrates and vertebrates (Narahashi, 1996; Narahashi et al, 1995; Song and Narahashi, 1996). The sensitivity of invertebrate neuronal sodium channels to pyrethroids is ten times greater than in mammals (Song and Narahashi, 1996). Furthermore, invertebrates typically have body temperatures some 10°C lower than mammals and in vitro studies show tetramethrin to be more potent at evoking repetitive neuronal discharges at lower temperatures (Song and Narahashi, 1996). In these experiments it was noted that the recovery of sodium channels from tetramethrin intoxication after washing was some five times faster in mammals than invertebrates. In addition pyrethroid hepatic metabolism (detoxification) is faster in mammals. Finally small insect size increases the likelihood of end-organ (neuronal) toxicity prior to detoxification (Song and Narahashi, 1996). TOXICOKINETICS In addition to the important differences between invertebrates and vertebrates outlined above, the low toxicity of pyrethroid insecticides in mammals is due to poor dermal absorption (the main route of exposure) and metabolism to non-toxic metabolites (Bradbury and Coats, 1989). Absorption Dermal Based on excretion studies, dermal absorption of pyrethroids is low, reaching a maximum of 1.5 per cent (Nassif et al, 1980). After application of 25 mg cypermethrin in a hydrocarbon solvent to human volunteers, the mean dermal absorption as assessed by excretion studies was 0.1 per cent (Eadsforth et al, 1988). The mean dermal absorption of cypermethrin was estimated to be 1.2 per cent after application of a spray formulation containing 31 mg cypermethrin to volunteers (Woollen et al, 1991; Woollen et al, 1992). Excretion of cypermethrin and its metabolites in most urine samples was below the limit of detection in workers exposed, by spraying, to cypermethrin 1.5-46.1 mg/h, implying limited absorption (IPCS, 1989c). Dermal exposure of three mixer/loaders to cypermethrin 0.25-5.27 mg/8h resulted in urinary excretion of 12-23 µg cypermethrin equivalents on the day of exposure (Chester et al, 1987); these data also suggest that pyrethroid absorption is limited. Only about 0.0001 per cent (54 µg) of lambda-cyhalothrin handled and sprayed each day by spraymen was absorbed, based on estimation of metabolites in urine and serum (Chester et al, 1992). Some 0.5 per cent of the total dose of permethrin cream (5 per cent) applied to the skin of patients with scabies was excreted (as metabolites) in the first 48 hours after application, implying limited absorption (van der Rhee et al, 1989). When permethrin was applied in a powder formulation to patients with bodylice, less than one per cent of a 125 mg dose and some 1.5 per cent of a 250 mg dose was retrieved as metabolites in urine (Nassif et al, 1980). d-Phenothrin applied to head and pudendal hair of volunteers (0.44-0.67 mg/kg body weight) gave blood metabolite concentrations below the limit of detection (IPCS, 1990f), suggesting very limited absorption. When protective clothing was used the concentrations of cypermethrin and permethrin metabolites in urine at the end of a working day were at the limit of detection (Desi et al, 1986). Similar results were found for deltamethrin (IPCS, 1990d) and alpha-cypermethrin (IPCS, 1992). Oral Between 19 and 57 per cent of orally administered cypermethrin was absorbed in human studies (Woollen et al, 1991; Woollen et al, 1992). Metabolism Pyrethroids are hydrolyzed rapidly in the liver to their inactive acid and alcohol components (Hutson, 1979; Ray, 1991), probably by microsomal carboxylesterase (Hutson, 1979). Further degradation and hydroxylation of the alcohol at the 4' position then occurs, and oxidation produces a wide range of metabolites (Hutson, 1979; Leahey, 1985). There is some stereospecificity in metabolism, with trans-isomers being hydrolyzed more rapidly than the cis-isomers, for which oxidation is the more important metabolic pathway (Soderlund and Casida, 1977). Although the alpha-cyano group reduces the susceptibility of the molecule to hydrolytic and oxidative metabolism (Hutson, 1979; Soderlund and Casida, 1977), the cyano group is converted to the corresponding aldehyde (with release of the cyanide ion), followed by oxidation to the carboxylic acid, sufficiently rapidly for efficient excretion by mammals (Leahey, 1985). Other differences in the chemical structure of pyrethroids have less effect on rates of metabolism (Soderlund and Casida, 1977). The pattern of metabolites varies between oral and dermal dosing in humans (Wilkes et al, 1993). For example, following dermal dosing with cypermethrin the ratio of trans/cis cyclopropane acids excreted was approximately 1:1, compared to 2:1 after oral administration. Such measurements might be useful in determining the route of exposure (Woollen, 1993; Woollen et al, 1991; Woollen et al, 1992). Animal studies have shown that pyrethroid hydrolysis is inhibited by dialkylphosphorylating agents such as organophosphorus insecticides (Abou-Donia et al, 1996; He et al, 1990; Hutson, 1979), and urinary excretion of unchanged pyrethroid was higher in sprayers using a methamidophos/ deltamethrin or methamidophos/fenvalerate mixture than from those using the pyrethroid alone (Zhang et al, 1991). Experiments with chickens (Abou-Donia et al, 1996) showed that permethrin toxicity was also enhanced by pyridostigmine bromide and by the insect repellent N,N-diethyl-m-toluamide (DEET). The authors hypothesized that competition for hepatic and plasma esterases by these compounds led to decreased pyrethroid breakdown and increased transport of the pyrethroid to neural tissues. Elimination Pyrethroids are excreted mainly as metabolites in urine but a proportion is excreted unchanged in faeces. When permethrin was used in a five per cent cream to treat scabies, about 0.5 per cent of the total dose was excreted as metabolites in 48 hours, but metabolites were still detectable in urine collected on day seven in three of ten patients, and on day 14 in one patient (van der Rhee et al, 1989). No detectable metabolites were found 30 or 60 days after patients had been treated with a powder formulation of permethrin for body lice (Nassif et al, 1980). After oral administration of cypermethrin to volunteers, peak excretion rates in urine were seen between eight and 24 hours, and about 24 per cent of the administered dose was excreted as metabolites (Woollen et al, 1991; Woollen et al, 1992). In human volunteer studies the oral administration of cypermethrin 1:1 cis/trans mixture in corn oil in gelatine capsules resulted in the mean excretion of 78 per cent of the trans isomer and 49 per cent of the cis isomer dose as free or conjugated cyclopropane carboxylic acid (Eadsforth and Baldwin, 1983). Alpha-cypermethrin showed similar results, with 43 per cent excreted as the free cyclopropane carboxylic acid in 24 hours (Eadsforth et al, 1988). After occupational exposure, deltamethrin and fenvalerate metabolites were detectable in urine: deltamethrin was detectable for up to 12 hours, whereas fenvalerate was still detectable after 24 hours (Zhang et al, 1991). Fenvalerate metabolites were still present in the urine of workers five days after packaging the pyrethroid (He et al, 1988). In another study, deltamethrin and metabolites were detectable in urine early on the first day of spraying, and persisted for up to two days (He et al, 1991). In two field studies, urinary excretion of cypermethrin metabolites increased with time during five days of exposure (IPCS, 1989c), but decreased 24 hours after spraying had ceased. In another field study, urinary excretion of permethrin metabolites peaked in the first 24 hours after exposure, but persisted for at least 40 hours (Asakawa et al, 1996). Pyrethroid metabolites could be detected in 24 hour urine samples of 9/12 pest control operators, and metabolites remained detectable for up to 3.5 days after spraying cyfluthrin (Leng et al, 1996). CLINICAL FEATURES: ACUTE EXPOSURE Occupationally, the main route of pyrethroid absorption is through the skin; inhalation is much less important (Adamis et al, 1985; Chen et al, 1991; Zhang et al, 1991). Inhalation is more likely when pyrethroids are used in confined spaces (Llewellyn et al, 1996). The use of protective clothing can reduce dermal exposure (Chester et al, 1987). The physical formulation also affects exposure, with inhalation being more important for dust and powder formulations, and dermal exposure more important for liquids (Llewellyn et al, 1996). Dermal exposure This is the most common route of pyrethroid exposure. Adverse effects manifest primarily as peripheral neurotoxicity with reversible hyperactivity of sensory nerve fibres (paraesthesiae), though erythema and pruritus are also described (see below). Peripheral neurotoxicity Paraesthesiae have been reported frequently (Table 3) particularly after the inappropriate handling of pyrethroids. Paraesthesiae occur most commonly on the face (He et al, 1991). It seems probable that paraesthesiae are related to the repetitive firing of sensory nerve endings in contaminated skin (Aldridge, 1990) and not to inflammation as there is little effect on neurogenic vasodilatation (Flannigan and Tucker, 1985b). The symptoms are exacerbated by sensory stimulation (heat, sun, scratching) (Aldridge, 1990), sweating or application of water (Tucker and Flannigan, 1983). In two studies, paraesthesiae were reportedly more severe after deltamethrin and flucythrinate exposure, less after cypermethrin and fenvalerate, and least after permethrin exposure (Aldridge, 1990; Flannigan and Tucker, 1985a). The cutaneous symptoms following exposure to fenvalerate may be severe enough to prevent sleeping (Tucker and Flannigan, 1983). Ten of 52 workers handling fenvalerate developed paraesthesiae compared to none handling permethrin (Kolmodin-Hedman et al, 1982). Twenty-two of 44 farmers exposed to airborne deltamethrin 2.5 per cent (by inhalation and skin contact) complained of "itching and burning sensations" on their faces, but deltamethrin in the urine was below 0.2 µg/L, the limit of detection (Wang et al, 1988). Table 3. Reports of paraesthesiae after pyrethroid exposure Pyrethroid Studies Alpha-cypermethrin Chester et al, 1987 Bifenthrin Advisory Committee on Pesticides, 1989a Cyfluthrin Advisory Committee on Pesticides, 1988a Cyhalothrin IPCS, 1990g; IPCS, 1990a Cypermethrin Chen et al, 1991; Flannigan and Tucker, 1985a; He et al, 1988; IPCS, 1989c; Le Quesne et al, 1980 Deltamethrin Chen et al, 1991; He et al, 1988; He et al, 1989; IPCS, 1990d; Le Quesne et al, 1980; Wang et al, 1988; Zhang et al, 1991 Fenpropathrin Boshard, 1993; Le Quesne et al, 1980 Fenvalerate Advisory Committee on Pesticides, 1992; Chen et al, 1991; Flannigan and Tucker, 1985a; He et al, 1988; He et al, 1989; Knox and Tucker, 1982; Knox et al, 1984; Kolmodin-Hedman et al, 1982; Kolmodin-Hedman et al, 1995; Le Quesne et al, 1980; Tucker and Flannigan, 1983; Zhang et al, 1991 Flucythrinate Flannigan and Tucker, 1985a; Flannigan and Tucker, 1985b Lambda-cyhalothrin Advisory Committee on Pesticides, 1988b; Chester et al, 1992; IPCS, 1990g; Moretto, 1991, Advisory Committee on Pesticides, 1993 Permethrin Flannigan and Tucker, 1985a; IPCS, 1990b; Kolmodin-Hedman et al, 1982; Le Quesne et al, 1980 Tau-fluvalinate Advisory Committee on Pesticides, 1997 Tefluthrin Advisory Committee on Pesticides, 1991 After treating an area with a combination of cypermethrin and cyfluthrin, several pesticide sprayers complained of paraesthesiae (Wagner, 1994). Contamination of face, hands and feet with large quantities of 2.5 per cent deltamethrin resulted in severe pain and numbness in the extremities with muscle tremor; these symptoms disappeared within seven days (Wang et al, 1988). One drop of 2.5 per cent deltamethrin dripped into an open foot wound caused local pain but no inflammation (He et al, 1989). Paraesthesiae generally start 30 minutes to two hours after exposure and peak after about six hours. Recovery is usually complete within 24 hours (Aldridge, 1990; He et al, 1989; Knox and Tucker, 1982; Knox et al, 1984; Tucker and Flannigan, 1983). Dermal toxicity When used at recommended doses in the treatment of scabies and lice, pyrethroids only rarely produce adverse effects. Pruritus is the side-effect reported most frequently (Brandenburg et al, 1986; DiNapoli et al, 1988), although this may also be caused by the skin infestation being treated. Skin irritation during occupational pyrethroid exposure may occur in up to ten per cent of workers (Kolmodin-Hedman et al, 1982) and may be influenced by the ratio of stereoisomers used in the pyrethroid formulation, being more prevalent with a higher proportion of the trans isomer. In addition to pruritus, erythema, burning and blisters have been reported (Brandenburg et al, 1986; Kalter et al, 1987; IPCS, 1990b; Kolmodin-Hedman et al, 1995). In one clinical trial of permethrin scabies treatment, none of the ten patients treated with 21-32 g five per cent permethrin cream reported any side effects (van der Rhee et al, 1989). In a second trial, 1/28 patients treated with one per cent permethrin, developed mild testicular erythema and irritation 12 hours after application (Kalter et al, 1987). In trials of head lice treatments, only three of ten patients treated with 15-40 mL one per cent permethrin solution reported mild erythema (IPCS, 1990b). In a further study (Brandenburg et al, 1986) involving 287 patients given a single application of one per cent permethrin, pruritus was the side-effect reported most frequently occurring in 5.6 per cent of patients. A burning sensation occurred in the affected area in 3.1 per cent of cases; erythema was present in 1.4 per cent, and tingling occurred in 1.0 per cent of patients (Brandenburg et al, 1986). Ten volunteers who wore permethrin-treated clothes, giving an average exposure of 3.8 mg/day, reported no irritation (IPCS, 1990b). A powder formulation of phenothrin or d-phenothrin applied to the head and pudendal hair of eight volunteers resulted in no significant effects (IPCS, 1990f). In a double-blind study of occupational exposure, skin symptoms could not be related to the degree of dermal permethrin exposure (Kolmodin-Hedman et al, 1995). Fenvalerate (a type II pyrethroid) produced more symptoms than permethrin in planters handling treated conifer seedlings (Kolmodin-Hedman et al, 1982). Symptoms were more severe from permethrin formulations containing a higher proportion of the trans isomer. The most common symptoms were: itching (ten per cent of 52 workers exposed to fenvalerate, two per cent of 45 workers exposed to permethrin with a trans/cis ratio 60/40, none of 42 workers exposed to permethrin with a trans/cis ratio 75/25); burning (ten per cent, none, 12 per cent respectively); blisters (eight per cent, none, ten per cent respectively) and a "dry feeling in the face" (12 per cent, after 75/25 trans/cis permethrin exposure only). Five of nine employees exposed to airborne cypermethrin via an air conditioning system complained of pruritus (Lessenger, 1992). Allergic reactions to pyrethroids are uncommon. Lisi (1992) assessed 230 volunteers for irritant or delayed contact sensitivity reactions to a range of pyrethroids. Two (non-atopic) patients had irritant reactions to five per cent resmethrin and a further two had positive patch tests to one per cent fenvalerate. There were no positive reactions to allethrin, deltamethrin, fenothrin or permethrin. In other patch test studies tetramethrin was neither a primary irritant nor skin sensitizer (IPCS, 1990e). In a double blind study of occupational permethrin exposure, two of 18 workers who developed mucosal blisters, and one who had eczematous changes on the leg, gave negative skin tests to permethrin (Kolmodin-Hedman et al, 1995). Dermatitis with blisters and miliary papules have been reported in those occupationally exposed to deltamethrin (Wang et al, 1988; He et al, 1989). Possible exposure to spilt cypermethrin resulted in a general urticarial eruption the following day, which progressed to involve the eyelids (Wagner, 1994). Ocular exposure Symptoms of mild eye irritation have been reported following occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS, 1990d; Lessenger, 1992). Transient conjunctivitis was reported among workers employed in the production of a deltamethrin aerosol (IPCS, 1990d). Eye contact with tefluthrin gave a "cold sensation" which lasted for about six hours (Advisory Committee on Pesticides, 1991). Eye irritation was also reported after permethrin was splashed in the eye (Kolmodin-Hedman et al, 1982). Employees exposed to cypermethrin via an air conditioning system complained of burning eyes (Lessenger, 1992). Inhalation Inhalational pyrethroid exposure typically is occupational and produces symptoms and signs of pulmonary tract irritation; systemic effects may occur following more substantial exposure (He et al, 1989) and are described below. Nineteen per cent of 52 workers handling fenvalerate-treated seedlings and 13 per cent of 42 workers handling permethrin ( trans/cis 75/25)- treated seedlings but only two per cent of 45 workers handling permethrin ( trans/cis 60/40)-treated seedlings complained of increased nasal secretions during a six hour exposure (Kolmodin-Hedman et al, 1982). "A slight nose tickle" has been reported after fenpropathrin exposure (Advisory Committee on Pesticides, 1989b; Boshard, 1993). Irritation of the respiratory tract was reported among workers producing an aerosol of deltamethrin (IPCS, 1990d). Cypermethrin, introduced inadvertently to the air conditioning ducts of an office building, produced wheezing and shortness of breath which persisted seven months after exposure in three smokers and one non-smoker, all with no previous pulmonary problems (Lessenger, 1992). One of these patients (a smoker) showed a mild restrictive pulmonary function defect. Cough and dyspnoea were also reported in six and four per cent of those exposed to fenvalerate and eight and two per cent of those exposed to permethrin (Kolmodin-Hedman et al, 1982). A respiratory challenge test with a formulation containing tetramethrin and pyrethrins produced chest tightness with severe non-productive cough, sneezing, rhinorrhea and lacrimation in six of seven patients but only one had a significant fall in FEV1 (Newton and Breslin, 1983). Ingestion Pyrethroid ingestion typically gives rise to nausea, vomiting and abdominal pain within minutes. In one series (He et al, 1989) involving some 344 cases, vomiting was a prominent feature in 56.8 per cent. The Chinese literature includes a case of erosive gastritis with haematemesis following ingestion of 900 mL deltamethrin solution (concentration not given) (Poisindex, 1996). In another case, permethrin/pyrethrins accidentally sprayed directly into the mouth resulted in a burning sensation which commenced several hours after exposure, and only gradually improved over five months, with persistent disordered taste sensation (Grant, 1993). Substantial pyrethroid ingestion may give rise to neurological features and other systemic effects as discussed below. Systemic effects Systemic effects generally have occurred after inappropriate occupational handling of pyrethroids. This may involve using too concentrated solutions, prolonged exposure, spraying against the wind or using unprotected hands or mouth to unblock congested sprayers (He et al, 1989). Most reported cases have involved dermal, inhalational and sometimes also oral exposure to fenveralate, deltamethrin or cypermethrin with systemic features occurring between four and 48 hours after spraying (He et al, 1989). Intentional ingestion may also produce systemic effects (He et al, 1989; Peter et al, 1996). Most patients recover over two to four days with only seven fatalities among 573 cases in one review (He et al, 1989). Four of the seven fatalities developed convulsions, one patient died from non-cardiogenic pulmonary oedema, one from "atropine intoxication" and one death followed exposure to a pyrethroid/organophosphorus pesticide combination. A further death has been reported recently in a patient who became comatose within ten hours of 30 mL deltamethrin ingestion and died from aspiration pneumonia complicated by renal failure (Peter et al, 1996). Gastrointestinal toxicity As discussed above gastrointestinal irritation is common following pyrethroid ingestion. Vomiting was a prominent symptom also in 16 per cent of occupational cases (He et al, 1989) in whom ingestion was not suspected, but where exposure involved deltamethrin, cypermethrin or fenvalerate. In this review, which included occupational exposures, anorexia occurred in 45 per cent of 573 cases of acute pyrethroid poisoning (He et al, 1989). Neurotoxicity He et al (1989) described dizziness in 60.6 per cent, headache in 44.5 per cent, fatigue in 26 per cent, increased salivation in 20 per cent and blurred vision in seven per cent of 573 cases of acute pyrethroid poisoning (229 occupational and 344 accidental exposures). Cypermethrin introduced inadvertently to the air conditioning ducts of an office building produced dizziness, headache and vertigo (Lessenger, 1992). Limb muscle fasciculations, coma and convulsions may complicate severe acute pyrethroid poisoning, and have occurred as soon as 20 minutes after ingestion (He et al, 1989). "Convulsions" was the stated cause of death in four of seven fatalities among 573 cases of acute pyrethroid poisoning (He et al, 1989) but further details were not given. An electromyelogram (EMG) in one case of acute pyrethroid poisoning (not specified) showed repetitive muscle discharges without denervation potentials (He et al, 1989). Transient slow and sharp waves with high amplitude were seen on electroencephalogram in a 23 year-old female following three days "heavy dermal exposure" to deltamethrin. She did not have a seizure but complained of headache, nausea, dizziness, anorexia and fatigue with clinical evidence of muscle fasciculations (He et al, 1989). She recovered over several weeks with symptomatic and supportive care. O'Malley (1997) described a four year-old who was found unconscious less than 20 minutes after ingesting approximately 2 mg/kg deltamethrin (as a chalk containing 0.98 per cent pyrethroid). She recovered uneventfully within a few hours. A 21 year-old female developed headache and muscle fasciculations some five hours after ingesting 30 mL 2.5 per cent deltamethrin with suicidal intent (He et al, 1989). Eight hours later she developed convulsions which persisted for two weeks and were treated with diazepam and baclofen. An electromyelogram, electrocardiogram and electroencephalogram were normal. She was discharged in good health 21 days after exposure. A 25 year-old female sprayed cotton fields for three days using a 1:9000 dilution of 2.5 per cent deltamethrin:water, without a protective mask and clothing such that her clothes became "heavily soaked with deltamethrin" (He et al, 1989). She developed a burning, tingling sensation in her cheeks in association with headache, vomiting, limb-muscle fasciculations and convulsions (He et al, 1989). The initial diagnosis was acute organophosphorus insecticide poisoning but there was no improvement with oxime therapy. She recovered over four weeks with symptomatic and supportive care. There is animal evidence that the neurotoxicity of permethrin is increased by pyridostigmine and by DEET (Abou-Donia et al, 1996; McCain et al, 1997). Cardiovascular toxicity Palpitation was reported in 13.1 per cent of 573 cases of acute pyrethroid poisoning involving oral, inhalational and/or dermal exposure (He et al, 1989). An electrocardiogram (ECG) showed ST and T wave changes in eight of 71 patients. Other ECG abnormalities included sinus tachycardia, ventricular ectopics and (rarely) sinus bradycardia (He et al, 1989). All ECG changes resolved over 2-14 days. Pulmonary toxicity Chest tightness has been described following accidental or deliberate ingestion of deltamethrin, fenvalerate or cypermethrin (He et al, 1989). Non-cardiogenic pulmonary oedema has been reported rarely following substantial pyrethroid ingestion, usually in association with severe neurological complications and may contribute to a fatal outcome (He et al, 1989). Musculoskeletal toxicity A case of acute polyarthralgia after skin exposure to flumethrin has been reported recently (Box and Lee, 1996). Haemotoxicity Among 235 cases of occupational or accidental acute pyrethroid poisoning in whom a full blood count was performed, 15 per cent showed a leucocytosis (He et al, 1989); this was probably a non-specific response. Nephrotoxicity Urinalysis among 124 patients with acute pyrethroid poisoning (involving oral, dermal and/or inhalational exposure) showed three patients with haematuria (He et al, 1989). CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Few long-term adverse effects from pyrethroids have been reported (IPCS, 1990d; Chen et al, 1991, He, 1994). There is no confirmed evidence that repeated exposure to pyrethroids leads to permanent damage to sensory nerve endings (Vijverberg and van den Bercken, 1990). In plant workers dermally exposed to deltamethrin, slight desquamation occurred (which could be due to the hydrocarbon solvent). The desquamation was restricted to the area contaminated with deltamethrin, and was sometimes accompanied by pruritus (IPCS, 1990d). One hundred and ninety-nine workers employed in a pyrethroid packaging plant over four to five months on two occasions (winter and summer sessions) were observed for cutaneous effects (He et al, 1988). Work involved transferring pyrethroid emulsions (deltamethrin 2.5 per cent, fenvalerate 20 per cent and (to a lesser extent) cypermethrin ten per cent) in xylene, from large containers to fill some 50,000 100 mL bottles daily. Gloves (and gauze masks) were used in winter only with no protective measures in summer. One hundred and forty of 199 (70 per cent) workers complained of "abnormal facial sensation" with burning, tingling, itching, tightness or numbness. Symptoms were more prevalent (p<0.05) in summer, occurring in 92 per cent of summer workers (n=87) compared to only 54 per cent of winter workers (n=112). Red miliary, mildly pruritic papules were found in 14 per cent of all workers, mainly on the face and chest and again were more prevalent (p<0.05) in summer. This was probably due to increased sweating during summer months (which tends to exacerbate cutaneous symptoms), but may also have been contributed to by the absence of protective measures during summer (He et al, 1988). The symptoms described in this study are identical to those following acute pyrethroid exposure and did not last more than 24 hours once subjects were away from the work environment. This suggests there are no true chronic effects from repeated pyrethroid exposure. Inhalation The 199 workers described above were exposed to estimated fenvalerate and deltamethrin ambient air concentrations of 0.012-0.055 mg/m3 and 0.005-0.012 mg/m3 respectively. Sixty-four (32 per cent) complained of sneezing and increased nasal secretions but these symptoms were only present at work, again suggesting no difference in effect between chronic or acute pyrethroid exposure. Systemic symptoms of dizziness, fatigue and nausea were mild and reported by only 14, nine and ten per cent of workers respectively. MANAGEMENT Dermal exposure Decontamination Clothes contaminated with pyrethroids should be removed, and contaminated skin washed with soap and water (He, 1994). Specific measures Topical alpha tocopherol (vitamin E) to treat paraesthesiae As paraesthesiae usually resolve in 12-24 hours, specific treatment is not generally administered or required. However, the topical application of dl-alpha tocopherol acetate (vitamin E) has been shown to reduce the severity of skin reactions to fenvalerate (IPCS, 1990c; Tucker et al, 1984; Tucker et al, 1983), flucythrinate, permethrin and cypermethrin (Flannigan and Tucker, 1985a). The reaction to cypermethrin was completely inhibited by vitamin E (Flannigan et al, 1985). Vitamin E appears to be useful both prophylactically and therapeutically (Flannigan and Tucker, 1985a). In a controlled human volunteer study, a commercial vitamin E oil preparation produced 98 per cent inhibition of the cutaneous symptoms from fenvalerate when applied immediately (Flannigan et al, 1985). At four hours the inhibition was only 50 per cent (Advisory Committee on Pesticides, 1992). The mechanism of the effect of topical vitamin E has not been clarified, although some in vitro studies suggest vitamin E may block the pyrethroid-induced sodium "tail current" in neuronal membranes (Song and Narahashi, 1995). Vitamin E is not included in the British National Formulary but is available from health food or alternative medicine sources. Other agents to treat paraesthesiae Various other topical therapies have been tested for treatment of pyrethroid-induced paraesthesiae: in human trials mineral oil, corn oil and "A&D ointment" (Tucker et al, 1984; Tucker et al, 1983) were almost as effective as Vitamin E cream (but the oils may lead to defatting of skin). Butylated hydroxyanisole and an industrial barrier cream (Tucker et al, 1984) and topical indomethacin (Flannigan and Tucker, 1984) were of little therapeutic benefit and in two studies zinc oxide paste exacerbated paraesthesiae (Tucker et al, 1984; Tucker et al, 1983). Ocular exposure Irrigate the affected eye with lukewarm water or 0.9 per cent saline for at least ten minutes. A topical anaesthetic may be required for pain relief or to overcome blepharospasm. Ensure no particles remain in the conjunctival recesses. Use fluorescein if corneal damage is suspected. If symptoms do not resolve following decontamination or if a significant abnormality is detected during examination, seek an ophthalmological opinion. Inhalation Removal from exposure is the priority. Mild symptoms of rhinitis respond to oral antihistamines. Other symptomatic and supportive measures should be dictated by the patient's condition. Ingestion Gut decontamination Gastric lavage should be avoided since solvents present in many formulations may increase the risk of aspiration pneumonia. Systemic toxicity Most patients exposed to pyrethroids require only simple supportive care. Systemic toxicity is rare but in such patients the presence of excess salivation, muscle fasciculations and pulmonary oedema may present diagnostic difficulty since similar features are typical also of severe organophosphorus pesticide poisoning. Measurement of the red cell cholinesterase activity (which is reduced in acute organophosphorus poisoning but not in pyrethroid intoxication) allows clarification but may not be available rapidly. Isolated brief convulsions do not require treatment but intravenous diazepam 5-10 mg should be given if seizures are prolonged. Rarely it may be necessary to give intravenous phenytoin, or to paralyze and ventilate the patient. Diazepam is useful also in the treatment of muscle fasciculations. The role of atropine is discussed below. Several experimental studies have investigated the role of pharmaceuticals in the management of the neurological complications of severe pyrethroid poisoning. However, these should be interpreted with caution, not only because they usually have involved high-dose parenteral pyrethroid administration, but also because there is considerable interspecies variation with regard to therapeutic efficacy (Casida et al, 1983; Vijverberg and van den Bercken, 1990). Atropine for hypersalivation and pulmonary oedema In experimental studies atropine sulphate (25 mg/kg subcutaneously) reduced hypersalivation produced by oral fenvalerate or cypermethrin (each at a dose exceeding the LD50), but did not increase survival (Hiromori et al, 1986). Intravenous atropine (0.6-1.2 mg in an adult) may be useful to control excess salivation but care should be taken to avoid excess administration. In a review of pyrethroid poisoning cases reported from China (He et al, 1989), 189 of 573 patients were treated with atropine which led to an improvement in salivation and pulmonary oedema in a few severe cases, but eight patients developed atropine intoxication following intravenous administration of 12-75 mg. One patient, probably misdiagnosed as having acute organophosphorus insecticide poisoning, died of atropine intoxication after a total dose of 510 mg, and one patient acutely intoxicated with a fenvalerate/dimethoate mixture could not be revived despite a total atropine dose of 170 mg. Atropine and ethylcarbamate In a French study a combination of intravenous atropine 3 mg/kg and ethylcarbamate 1000 mg/kg effectively protected rodents against the lethal effects of intravenous deltamethrin, increasing the LD50 by a factor of 3.48 (Leclercq et al, 1986). Diazepam and phenobarbital for convulsions In mice (n=10) pre-treatment with intraperitoneal diazepam (1 mg/kg), but not phenobarbital (10-30 mg/kg), significantly increased the time to onset of convulsions caused by the intracerebroventricular administration of deltamethrin (p<0.005) and fenvalerate (p<0.05) (Gammon et al, 1982). Under the same conditions diazepam was not effective in preventing permethrin- or allethrin-induced seizures. Propranolol and procainamide for tremor Pre-treatment with intravenous propranolol or procainamide (each 15 µmol/kg) reduced the severity of tremor or writhing induced in rats by the intravenous administration of deltamethrin (10 µmol/kg) (Bradbury et al, 1983). Ivermectin and pentobarbital for choreoathetosis In rodents administered 2 mg/kg intravenous deltamethrin, pre-treatment with 4 mg/kg intravenous ivermectin reduced choreoathetosis from 3.9 to 3.2 (as graded on a scale of 1-4) (p = 0.023), and reduced salivation by 72 per cent. Pentobarbital (15 mg/kg i.p.) reduced choreoathetosis produced by 1.5 mg/kg intravenous deltamethrin from 3.0 to 1.3 (p = 0.004). An equi-sedative dose of phenobarbital produced a non-significant fall to 2.4 (p = 0.11) (Forshaw and Ray, 1997). Mephenesin and methocarbamol The skeletal muscle relaxant mephenesin 22 µmol/kg prevented all motor symptoms induced in rats by the intravenous administration of deltamethrin (10 µmol/kg) (n=4-20 in different treatment groups) (Bradbury et al, 1983). Mephenesin has a short half-life in vivo, but intraperitoneal methocarbamol (a mephenesin derivative) (400 mg/kg intraperitoneally followed by 200 mg/kg whenever tremor was observed) significantly (p<0.01) reduced mortality in rats administered more than the oral LD50 of fenvalerate, fenpropathrin, cypermethrin or permethrin (n=10 in each treatment group) (Hiromori et al, 1986). There are insufficient data to advocate a clinical role for methocarbamol in systemic pyrethroid toxicity. Sodium-channel blockers (local anaesthetics) In vitro studies suggest local anaesthetics may be useful as antagonists of the effect of deltamethrin on sodium channels (Oortgiesen et al, 1990). The relevance to human poisoning is not known. MEDICAL SURVEILLANCE Although blood and urine pyrethroid/pyrethroid metabolite concentrations are useful as biological exposure indicators for research purposes, avoiding dermal and inhalational exposure via adequate self-protection and sensible use is the most important requirement to reduce adverse effects from occupational pyrethroid use. OCCUPATIONAL DATA Maximum exposure limit International Standards Organization (ISO) limits for natural pyrethrins: long-term exposure limit (8 hour TWA reference period) 5 mg/m3, short term exposure (15 min ref period) 10 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Endocrine toxicity In vitro studies show that several pyrethroids interact competitively with human skin fibroblast androgen receptors and with sex hormone binding globulin (with the relative potency being bioallethrin > fenvalerate > fenothrin > fluvalinate > permethrin > resmethrin) (Eil and Nisula, 1990). A possible anti-androgenic effect of pyrethroids in humans was suggested following an outbreak of gynaecomastia in refugees exposed to fenothrin, but there was insufficient evidence to confirm this (Eil and Nisula, 1990). Animal studies regarding other endocrine effects of pyrethroids have produced conflicting results. For example oral bifenthrin 0.5 mg daily or lambda-cyhalothrin 0.2 mg daily for 21 days suppressed serum tri-iodothyronine and thyroxine concentrations with concomitant stimulation of thyrotrophin in rats (Akhtar et al, 1996), whereas intraperitoneal fenvalerate 100-200 mg/kg body weight daily for 45 days increased circulating tri-iodothyronine and thyroxine concentrations (Kaul et al, 1996). Immunotoxicity In oral dosing studies in rodents, supercypermethrin at 1/14 LD50 for 28 days suppressed the cellular immune response (Tulinská et al, 1995) as did permethrin at one per cent LD50 for ten days (Blaylock et al, 1995). Oral deltamethrin 5-10 mg/kg body weight daily for 28 days produced thymus atrophy in rodents (Madsen et al, 1996) and a single intraperitoneal dose of deltamethrin 6-50 mg/kg also caused a reduction in thymus weight, which was dose- and time-dependant (maximum effect two weeks after dosing) (Enan et al, 1996). The significance of these immunological studies to man are not known. Carcinogenicity The International Agency for Research on Cancer has concluded there is inadequate evidence to assess the carcinogenicity of deltamethrin (IARC, 1991b), fenvalerate (IARC, 1991a) or permethrin (IARC, 1991c). In a variety of animal studies there was no evidence for carcinogenicity for the following pyrethroids: allethrin and its isomers (IPCS, 1989a), cyhalothrin or lambda-cyhalothrin (IPCS, 1990a), cypermethrin (IPCS, 1989c), deltamethrin (IPCS, 1990d), prallethrin (Advisory Committee on Pesticides, 1995), resmethrin and its isomers (IPCS, 1989b). Reprotoxicity In a variety of animal studies, there were no indications of teratogenicity, embryotoxicity or fetotoxicity for the following pyrethroids: allethrin (and isomers) (IPCS, 1989a), bifenthrin (Advisory Committee on Pesticides, 1989a), cyfluthrin (Advisory Committee on Pesticides, 1988a), cyhalothrin (IPCS, 1990a) cypermethrin (IPCS, 1989c), deltamethrin (IPCS, 1990d), fenopropathrin (Advisory Committee on Pesticides, 1989b), fenvalerate (Advisory Committee on Pesticides, 1992, IPCS, 1990c), tau-fluvalinate (Advisory Committee on Pesticides, 1997) permethrin (IPCS, 1990b), d-phenothrin (IPCS, 1990f), prallethrin (Advisory Committee on Pesticides, 1995), resmethrin (and isomers) (IPCS, 1989b), tefluthrin (Advisory Committee on Pesticides, 1991) or tetramethrin (IPCS, 1990e). Genotoxicity Data regarding the potential genotoxicity of pyrethroids provide conflicting results (Puig et al, 1989; Barrueco et al, 1992; Herrera et al, 1992; Dolara et al, 1992; Barrueco et al, 1994; Surrallés et al, 1995), though toxicity reviews of in vitro and in vivo data for most compounds conclude there is insufficient evidence for them to be considered genotoxic or mutagenic. Pyrethroids for which this is the case include allethrin (IPCS, 1989a), bifenthrin (Advisory Committee on Pesticides, 1989a), cyfluthrin (Advisory Committee on Pesticides, 1988a), cyhalothrin (IPCS, 1990a) or lambda-cyhalothrin (Advisory Committee on Pesticides, 1988b, 1993), deltamethrin (IPCS, 1990d), fenpropathrin (Advisory Committee on Pesticides, 1989b), fenvalerate (IPCS, 1990c) or esfenvalerate (Advisory Committee on Pesticides, 1992), tau-fluvalinate (Advisory Committee on Pesticides, 1997), permethrin (IPCS, 1990b), d-phenothrin (IPCS, 1990f), prallethrin (Advisory Committee on Pesticides, 1995) resmethrin (IPCS, 1989b), tefluthrin (Advisory Committee on Pesticides, 1997), tetramethrin (IPCS, 1990e). Cypermethrin showed some mutagenicity in vivo in mouse and Chinese hamster bone marrow, although it showed no evidence of mutagenicity in in vitro studies (IPCS, 1989c). Fish toxicity Pyrethroids are more toxic at cooler temperatures, and thus more toxic to cold than warm water fish, but toxicity is little affected by pH or water hardness (Mauck et al, 1976). Some examples of specific fish toxicity data for commonly encountered pyrethroids are given here. See individual pyrethroid monographs for other specific data. Cypermethrin: LC50 (96 hr) for brown trout is 2-2.8 µg/L. LC50 (96 hr) for Atlantic salmon is 2-2.4 µg/L (DOSE, 1997). Deltamethrin: LC50 (96 hr) for minor carp, rainbow trout, cichlid, pumpkinseed sunfish range from 0.5-1.8 µg/L (DOSE, 1997). Fenvalerate: LC50 (24 hr) for rainbow trout and carp are between 20 and 76 µg/L. Exposure to fenvalerate 10µg/L for 6-48 hours inhibited magnesium and sodium-potassium ATPases in the gill, brain, liver and muscle of carp (DOSE, 1997). Permethrin: LC50 (48 hr) for rainbow trout and bluegill sunfish are 5.4 and 1.8 µg/L respectively. LC50 (96 hr) for channel catfish, largemouth bass, brook trout and desert pupfish are 1.1, 8.5, 3.2 and 5.0 µg/L respectively. Permethrin in a concentration of 1.25, 2.5, 5.0, 10, 20 and 40 µg/L had no effect on sheepshead minnow embryo survival. Fry were unaffected by permethrin 10 µg/L but only 19 per cent survived at 20 µg/L (DOSE, 1997). EC Directive on Drinking Water Quality 80/778/EEC Maximum admissible concentration (any pesticide) 0.1 µg/L (EC Directive, 1980). AUTHORS SA Cage MSc M Inst Inf Sci SM Bradberry BSc MB MRCP JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH UK This monograph was produced by the staff of the Birmingham Centre of the National Poisons Information Service in the United Kingdom. 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