UKPID MONOGRAPH PERMETHRIN SA Cage MSc M Inst Inf Sci SM Bradberry BSc MB MRCP S Meacham BSc 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 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. PERMETHRIN Toxbase summary Type of product Insecticide 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 after pyrethroid exposure, usually following ingestion (He et al, 1989). No known fatalities have been reported after permethrin exposure. 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. 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. 3. 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. Substance name Permethrin Origin of substance Permethrin was first synthesized as one of the new photostable pyrethroids in 1973, and was first marketed in 1977. It contains four stereoisomers (IPCS, 1990b). Synonyms/Proprietary names Ambush Anomethrin N Chinetrin Coopex WP Corsair Darmycel Agarifume Smoke Generator Dragnet Ecsmin Ectiban Efmethrin Exmin Fumite Permethrin Smoke Indothrin Ipitox Kafil Kestrel Outflank Perigen Permasect 10 EC Permasect 25 EC Permit Picket Pounce Pramex Sanathrin Stomoxin Tubair Permethrin (RTECS, 1997; Pesticide Manual, 1997; Pesticides 1997, 1997; The UK Pesticide Guide, 1997) Chemical group Type I synthetic pyrethroid Reference numbers CAS 52645-53-1 (Pesticide Manual, 1997) RTECS GZ1255000 (RTECS, 1997) UN NIF HAZCHEM CODE NIF EEC 258-067-9 Physicochemical properties Chemical structure IUPAC name: 3-phenoxybenzyl (1 RS)-cis,trans-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate C21H20Cl2O3 (Pesticide Manual, 1997) Molecular weight 391.3 (Pesticide Manual, 1997) Physical state at room temperature Technical grade is a liquid, which sometimes tends to crystallize partly at room temperature. (Pesticide Manual, 1997) Colour The technical grade is yellow brown to brown. (Pesticide Manual, 1997) Odour NIF Viscosity NIF pH NIF Solubility Low solubility in water: approx. 2 x 10-4 g/L at 30°C Xylene, hexane > 900 g/L Methanol 204 g/L (Pesticide Manual, 1997) Autoignition temperature NIF Major products of combustion When heated to decomposition toxic fumes of hydrogen chloride are emitted. (HSDB, 1997) Explosive limits NIF Flammability Burns with difficulty. (HSDB, 1997) Boiling point 200°C at 0.1 mm Hg (13.3 Pa) >290°C at 760 mm Hg (1 x 105 Pa) (Pesticide Manual, 1997) Density 1.19-1.27 at 20°C (Pesticide Manual, 1997) Vapour pressure 7 x 10-5 Pa at 20 °C cis- 2.5 x 10-6 Pa at 20°C trans- 1.5 x 10-6 Pa at 20°C (Pesticide Manual, 1997) Relative vapour density NIF Flash point 'Perigen' > 100°C (Pesticide Manual, 1997) Reactivity NIF Uses Permethrin is a contact insecticide which is effective against a broad range of pests (Pesticide Manual, 1997). Topical permethrin is recommended for the treatment of scabies and head lice (BNF, 1997). Hazard/risk classification EC Risk: Xn (R22) sensitizing, harmful if swallowed. (Pesticide Manual, 1997) 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, was produced in 1949, followed in the 1960s by others including dimethrin, tetramethrin and resmethrin. 3-Phenoxybenzyl esters were also found to be active as pesticides (e.g. phenothrin, permethrin). 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 below). 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. In animal studies type II pyrethroids have been shown generally to produce a typical toxic syndrome (see below). Despite the lack of the cyclopropane ring, similar insecticidal activity was found in a group of phenylacetic 3-phenoxybenzyl esters. This led to the development of fenvalerate, an alpha-cyano-3-phenoxy-benzyl ester, and other related compounds such as fluvalinate. These all contain the alpha-cyano group and hence are type II pyrethroids. Animal studies suggest that the two structural types of pyrethroids give rise generally to distinct patterns of systemic toxic effects. Type I pyrethroids produce in animals 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 being observed in experimental studies. 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, reflecting their commercial importance (Aldridge et al, 1978). Further details are given in the pyrethroid generic monograph. EPIDEMIOLOGY In 1989-1990, world-wide annual production of pyrethroids was at least 2000 tonnes (IPCS, 1989a; IPCS, 1989b; IPCS, 1989c; IPCS, 1990a; IPCS, 1990b; IPCS, 1990c; IPCS, 1990d; IPCS, 1990e; IPCS, 1990f) including approximately 600 tonnes of permethrin (IPCS, 1990b). In spite of their long history of use, there are relatively few reports of pyrethroid, and specifically permethrin, toxicity. Less than ten deaths have been reported from ingestion or occupational (primarily dermal/inhalational) pyrethroid exposure with no deaths from permethrin exposure (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. 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; (ii) An increase in discharges from sensory neurons (due to membrane depolarization); and (iii) Severe disturbances of synaptic transmission (Narahashi, 1989; Narahashi et al, 1995; Song and Narahashi, 1996). These effects on sodium channels are common to all pyrethroids although specific effects of type I pyrethroids, such as permethrin, have been clarified in experimental studies. These show that 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). 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 involving permethrin and other pyrethroids (Nassif et al, 1980; Chester et al, 1987; Eadsforth et al, 1988; van der Rhee et al, 1989; IPCS, 1990f; Woollen et al, 1991; Woollen et al, 1992), dermal absorption of permethrin is likely to be low (less than 1.5 per cent). 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 body lice, 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). When protective clothing was used the concentrations of permethrin metabolites in urine at the end of a working day were at the limit of detection (Desi et al, 1986). Oral Between 19 and 57 per cent of orally administered cypermethrin (a type II pyrethroid) was absorbed in human studies (Woollen et al, 1991; Woollen et al, 1992). There are no human data specific to permethrin. 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). The pattern of metabolites varies between oral and dermal dosing in humans (Wilkes et al, 1993). For example, following dermal dosing with cypermethrin (a type II pyethroid) 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). 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 pyrethroid (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 Permethrin is excreted mainly as metabolites in urine but a proportion is excreted unchanged in faeces. An overview of human pyrethroid elimination data is included in the generic pyrethroid monograph. 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). 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 following permethrin exposure (Le Quesne et al, 1980; Kolmodin-Hedman et al, 1982; Flannigan and Tucker, 1985a; IPCS, 1990b), particularly after inappropriate handling. 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 and may prevent sleep (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 (Flannigan and Tucker, 1985a; Aldridge, 1990). Ten of 52 workers handling fenvalerate developed paraesthesiae compared to none handling permethrin (Kolmodin-Hedman et al, 1982). 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, permethrin only rarely produces 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. 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). 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). In another study, cutaneous symptoms were more severe from permethrin formulations containing a higher proportion of the trans isomer (Kolmodin-Hedman et al, 1982). The most common symptoms were: itching (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 (none and 12 per cent respectively); blisters (none and ten per cent respectively) and a "dry feeling in the face" (12 per cent after 75/25 trans/cis permethrin exposure only). 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 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). Ocular exposure Symptoms of mild eye irritation have been reported following occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS, 1990d; Lessenger, 1992). Eye irritation was reported after permethrin was splashed in the eye (Kolmodin-Hedman et al, 1982). Inhalation Inhalational pyrethroid exposure typically is occupational and produces symptoms and signs of pulmonary tract irritation. The frequency and severity of symptoms may vary with the ratio of different stereoisomers in a formulation, being more prevalent with a higher proportion of the trans isomer. Systemic effects may occur following more substantial exposure (He et al, 1989) and are described below. Thirteen 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). Cough and dyspnoea were reported in eight and two per cent of 42 workers exposed to permethrin trans/cis 75/25, but none of 45 workers exposed to permethrin trans/cis 60/40 (Kolmodin-Hedman et al, 1982). 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. In one 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). There are no reports of severe systemic toxicity following permethrin exposure. 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). 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 (not specified) poisoning showed repetitive muscle discharges without denervation potentials (He et al, 1989). 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 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 in 2-14 days. Pulmonary toxicity Chest tightness has been described following accidental or deliberate pyrethroid ingestion (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 (a type II pyrethroid) 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 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 a study of 199 workers exposed for several months to deltamethin, fenvalerate and cypermethrin (all type II pyrethroids) in a packaging plant, the symptoms described were identical to those following acute pyrethroid exposure and did not last more than 24 hours once subjects were away from the work environment (He et al, 1988). This suggests there are no true chronic effects from repeated pyrethroid exposure. Inhalation Sixty-four (32 per cent) of the 199 workers described above 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 permethrin 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 permethrin (Flannigan and Tucker, 1985a) and other pyrethroids including fenvalerate (IPCS, 1990c; Tucker et al, 1984; Tucker et al, 1983), flucythrinate 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 clinical 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 permethrin formulations may increase the risk of aspiration pneumonia. Systemic toxicity Most patients exposed to permethrin 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 Avoiding dermal and inhalational exposure via adequate self-protection and sensible use is the most important requirement to reduce adverse effects from occupational use of permethrin. 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 limit (15 min reference 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 evaluating other endocrine effects of pyrethroids have produced conflicting results (Akhtar et al, 1996; Kaul et al, 1996). Immunotoxicity In oral dosing studies in rodents, permethrin at a concentration of one per cent LD50 for ten days suppressed the cellular immune response (Blaylock et al, 1995). The significance of this study to man is not known. Carcinogenicity The International Agency for Research on Cancer has concluded that permethrin is unclassifiable as to its carcinogenicity to humans (IARC, 1991). Reprotoxicity There is no evidence that permethrin is teratogenic, embryotoxic or fetotoxic (IPCS, 1990b; Reprotox, 1997). No teratogenic effects were observed among the offspring of mice fed 15-150 mg/kg/day of permethrin during pregnancy (IPCS, 1990b). Similarly, the frequency of malformations was not increased among the offspring of rats or rabbits fed permethrin during pregnancy in doses of 4-225 mg/kg/day or 16-1800 mg/kg/day (IPCS, 1990b). There are no human reprotoxicity data for permethrin. 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, including permethrin (IPCS, 1990b), conclude that there is insufficient evidence for them to be considered genotoxic or mutagenic. Permethrin showed no genotoxicity in Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 with or without metabolic activation, or in an Escherichia coli reverse mutation test with or without metabolic activation. Permethrin was non-mutagenic in vitro in Chinese hamster V79 cells with and without metabolic activation (DOSE, 1997). The IC50 for in vitro human lymphocytes cell growth inhibition was 54.7 mg/L permethrin and the IC50 for protein synthesis inhibition was 48.9 mg/L permethrin (DOSE, 1997). The IC50 for in vitro mouse L1210 lymphoblastoid cell growth inhibition was 43.0 mg/L permethrin and the IC50 for protein synthesis was 43.0 mg/L permethrin (DOSE, 1997). Permethrin did not cause chromosomal loss in Drosophilia melanogaster and did not increase chromosomal aberrations in rat bone marrow cells in vitro (DOSE, 1997). Fish toxicity Permethrin is toxic to fish. It is more toxic at cooler temperatures, and thus more toxic to cold than warm water fish, but the toxicity of pyrethroids is little affected by pH or water hardness (Mauck et al, 1976). LC50 (48 hr) for rainbow trout and bluegill sunfish are 5.4 and 1.8 µg/L permethrin respectively (DOSE, 1997). 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 permethrin respectively (DOSE, 1997). Permethrin in concentrations of 1.25, 2.5, 5.0, 10, 20 and 40 µg/L had no effect on embryo survival of sheepshead minnow; 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 S Meacham BSc 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. 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. Date of last revision 28/1/98 REFERENCES Abou-Donia MB, Wilmarth KR, Jensen KF, Oehme FW, Kurt TL. 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