UKPID MONOGRAPH ALPHA-CYPERMETHRIN 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. ALPHA-CYPERMETHRIN 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 alpha-cypermethrin 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. 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. Substance name Alpha-cypermethrin Origin of substance Cypermethrin was initially synthesized in 1974 and first marketed in 1977 (IPCS, 1989c). Alpha-cypermethrin contains more than 90 per cent of the insecticidally most active pair of the four cis isomers of cypermethrin as a racemic mixture (IPCS, 1992). Synonyms/Proprietary names Acquit Alfamethrin Alphamethrin Apex Bestox Clayton Alpa-Cyper Contest Fastac Littac Stefes Alphacypermethrin (RTECS, 1997; Pesticides 1997, 1997; The UK Pesticide Guide, 1997) Chemical group Type II synthetic pyrethroid Reference number CAS 67375-30-8 (Pesticide Manual, 1997) RTECS GZ1251400 (RTECS, 1997) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure IUPAC name: A racemate of (S)-alpha-cyano-3-phenoxybenzyl (1R)- cis-3-(2,2- dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylate and (R)-alpha-cyano-3-phenoxybenzyl (1 S)-cis-3-(2,2- dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylate C22H19Cl2NO3 (Pesticide Manual, 1997) Molecular weight 416.3 (Pesticide Manual, 1997) Physical state at room temperature Solid (crystals); technical grade is a powder. (Pesticide Manual, 1997) Colour Colourless; technical grade is white to pale. (Pesticide Manual, 1997) Odour Technical grade has a weak aromatic odour. (Pesticide Manual, 1997) Viscosity NIF pH NIF Solubility Low solubility in water: approx.1 x 10 -5 g/L at 25 °C Acetone 620 g/L at 25 °C Chlorobenzene 420 g/L at 25 °C Dichloromethane 550 g/L at 25 °C Ethyl acetate 440 g/L at 25 °C Ethylene glycol < 1.11 g/L at 20 °C Hexane 7 g/L at 25 °C O-xylene 350 g/L at 25 °C (Pesticide Manual, 1997) Autoignition temperature NIF Chemical interactions NIF Major products of combustion Combustion and/or pyrolysis of alpha-cypermethrin can lead potentially to the production of compounds such as formaldehyde, acrolein and hydrogen cyanide (Hartzell, 1996). Explosive limits NIF Flammability Burns with difficulty. (HSDB, 1997) Boiling point 200°C at 9.3 Pa (Pesticide Manual, 1997) Density 1.28 at 22°C (Pesticide Manual, 1997) Vapour pressure 2.3 x 10 -5 Pa at 20°C (Pesticide Manual,1997) Relative vapour density NIF Flash point > 80°C (closed cup) (Pesticide Manual, 1997) Reactivity NIF Uses Alpha-cypermethrin controls a wide range of chewing and sucking insects in fruit, vegetables, vines, cereals, cotton, soya beans, and other crops. It also controls cockroaches, mosquitoes, flies, and other insect pests and is used as an animal ectoparasiticide (Pesticide Manual, 1997). Hazard/risk classification Safety phases R20/21/22 - Harmful by inhalation, in contact with skin, by swallowing. R36 - Irritating to the eyes. R43 - May cause sensitization by skin contact. (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 the 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 such as cypermethrin. 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). Alpha-cypermethrin contains more than 90 percent of the insecticidally most active pair of the four cis isomers of cypermethrin. 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 340 tonnes of cypermethrin (IPCS, 1989c). Specific data for alpha-cypermethrin were not available. In spite of their long history of use, there are relatively few reports of pyrethroid, and specifically alpha-cypermethrin, toxicity. Less than ten deaths have been reported from ingestion or occupational (primarily dermal/inhalational) pyrethroid exposure with no deaths from alpha-cypermethrin 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 II pyrethroids such as alpha- cypermethrin have been clarified in experimental studies. These show that 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). 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 other pyrethroids (Nassif, et al, 1980; Chester et al, 1987; Eadsforth et al, 1988; IPCS, 1989c; Woollen et al, 1991; Chester et al, 1992; Woollen et al, 1992) dermal absorption of alpha-cypermethrin is likely to be low (less than 1.5 per cent). After application of 25 mg cypermethrin (which contains alpha-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. 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 alpha-cypermethrin (IPCS, 1992). Oral Between 19 and 57 per cent of orally administered racemic cypermethrin was absorbed in human studies (Woollen et al, 1991; Woollen et al, 1992). There are no human data specific to alpha-cypermethrin. 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 racemic 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 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 Pyrethroids are 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. After oral administration of cypermethrin (which contains alpha-cypermethrin) to volunteers, peak excretion rates 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). 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. 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, particularly after the inappropriate handling of pyrethroids, including alpha-cypermethrin (Chester et al 1987). 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 (Aldridge, 1990; Flannigan and Tucker, 1985a). 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). 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 severe 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). There are no reports of irritant skin reactions specific to alpha-cypermethrin exposure. Five of nine employees exposed to airborne cypermethrin via an air conditioning system complained of pruritis (Lessenger, 1992). Allergic reactions to pyrethroids are uncommon. 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). 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. 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. There are no reports of inhalational toxicity specific to alpha-cypermethrin exposure. 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. 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). A 24 year-old male developed no symptoms or abnormal clinical signs after ingesting 30-50 mL ten per cent cypermethrin (Peter et al, 1996). 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 cypermethrin, fenveralate or deltamethrin 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 cypermethrin, deltamethrin or fenvalerate. In this review, which included occupational exposures, anorexia occurred in 45 per cent of 573 case of acute pyrethroid poisoning (He et al, 1989). Neurotoxicity He (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 to cypermethrin, fenvalerate or deltamethrin). Cypermethrin introduced inadvertently to the air conditioning ducts of an office building produced dizziness, headache and vertigo (Lessenger, 1992). Drowsiness was the only feature present in a 30 year-old female who ingested an unknown quantity of ten per cent cypermethrin (Peter et al, 1996). 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. Cardiovascular toxicity Palpitation was reported in 13.1 per cent of 573 cases of acute pyrethroid poisoning involving oral, inhalational and dermal exposure to cypermethrin, deltamethrin or fenvalerate (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 cypermethrin, deltamethrin or fenvalerate (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 (another 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 to cypermethrin, fenvalerate or deltamethrin) 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). 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 10 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 (air concentrations of cypermethrin were not given). Sixty-four (32 per cent) complained of sneezing and increased nasal secretions but these symptoms were only present at work, against 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 10 per cent of workers respectively. MANAGEMENT Dermal exposure Decontamination Clothes contaminated with alpha-cypermethrin 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 cypermethrin (Flannigan and Tucker, 1985a) and other pyrethroids including fenvalerate (IPCS, 1990c; Tucker et al, 1984; Tucker et al, 1983), flucythrinate and permethrin (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 some alpha-cypermethrin 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 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 alpha-cypermethrin. OCCUPATIONAL DATA Maximum exposure limit International Standards Organization (ISO) limits for natural pyrethrins are: 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 (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, supercypermethrin at 1/14 LD50 for 28 days suppressed the cellular immune response (Tulinská et al, 1995), as did permethrin at a concentration of one per cent LD50 for ten days (Blaylock et al, 1995). The significance of these immunological studies to man is not known. Carcinogenicity There is no evidence that alpha-cypermethrin is carcinogenic (IPCS, 1989c). Reprotoxicity No reprotoxicity data for alpha-cypermethrin were identified. 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. 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). Tests with alpha-cypermethrin gave negative results with Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 with and without metabolic activation, with Escherichia coli WP2, WP2 uvr A with and without metabolic activation and with Saccharomyces cerevisiae JDI with and without metabolic activation (DOSE, 1997). Alpha-cypermethrin did not cause chromatid aberrations, breaks or gaps in rat liver cell cultures in vitro. In vivo 2-8 mg/kg alpha cypermethrin in rats did not increase chromosome aberrations or polyploidy in bone marrow cells (DOSE, 1997). Fish toxicity Alpha-cypermethrin 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 (96 hr) for rainbow trout is 2.8 µg/L alpha-cypermethrin (DOSE, 1997). LC50 (24 hr) for rainbow trout is 55 ppb alpha-cypermethrin (technical grade) (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. Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War chemical exposures. J Toxicol Environ Health 1996; 48: 35-56. Adamis Z, Antal A, Füzesi I, Molnár J, Nagy L, Susán M. Occupational exposure to organophosphorus insecticides and synthetic pyrethroid. 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