UKPID MONOGRAPH DELTAMETHRIN 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. DELTAMETHRIN 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. Ingestion of deltamethrin 2 mg/kg body weight caused coma in a four year old child. Recovery was uneventful (O'Malley, 1977). Fatalities have occurred rarely after pyrethroid exposure, usually following ingestion (He et al, 1989). Three fatalities have been reported after deltamethrin exposure (He et al, 1989; Peter et al, 1996). 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. Peter JV, John G, Cherian AM. Pyrethroid poisoning. J Assoc Physicians India 1996; 44: 343-344. Substance name Deltamethrin Origin of substance Deltamethrin was first synthesized in 1974 and is marketed as a single isomer [1R, cis; alpha S]. Synonyms/Proprietary names Butox Crackdown Decamethrin Decis Deleet Deltagran Kordon K-Othrin Landgold deltaland OMS 1988 Sadethrin Standon deltamethrin Thripstick (Pesticides 1997, 1997; RTECS, 1997; The UK Pesticide Guide, 1997) Chemical group Type II synthetic pyrethroid Reference numbers CAS 52918-63-5 (Pesticide Manual, 1997) RTECS GZ1233000 (RTECS, 1997) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure IUPAC name: (S)-alpha-cyano-3-phenoxybenzyl (1 R)-cis-3-(2,2-dibromovinyl)-2,2-dimethyl- cyclopropanecarboxylate C22H19Br2NO3 (Pesticide Manual, 1997) Molecular weight 505.2 (Pesticide Manual, 1997) Physical state at room temperature Solid (crystals) (Pesticide Manual, 1997) Colour Colourless (Pesticide Manual, 1997) Odour Odourless (HSDB, 1997) Viscosity NIF pH NIF Solubility Low solubility in water: < 2 x 10-7 g/L at 25°C Acetone 500 g/L at 20°C Benzene 450 g/L at 20°C Cyclohexanone 750 g/L at 20°C Dichloromethane 700 g/L at 20°C Dimethyl sulphoxide 450 g/L at 20°C Ethanol 15 g/L at 20°C Isopropanol 6 g/L at 20°C Xylene 250 g/L at 20°C (Pesticide Manual, 1997) Autoignition temperature NIF Chemical interactions NIF Major products of combustion Combustion and/or pyrolysis of deltamethrin can lead potentially to the production of compounds such as formaldehyde, acrolein, hydrogen cyanide and hydrogen bromide (Hartzell, 1996). Explosive limits NIF Flammability Burns with difficulty. (HSDB, 1997) Boiling point NIF Density 0.55 at 25°C (Pesticide Manual, 1997) Vapour pressure 1.24 x 10 -8 Pa (25°C saturation method) (Pesticide Manual, 1997) Relative vapour density NIF Flash point NIF Reactivity NIF Uses Deltamethrin is a potent insecticide effective by contact and ingestion against a wide range of pests in cereals, cotton, fruit and vegetables. It is used against indoor crawling and flying insects and pests in stored grain and timber. Deltamethrin is also used as an animal ectoparasiticide (Pesticide Manual, 1997). Hazard/risk classification NIF 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 deltamethrin. 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 tremors, 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) though deltamethrin is marketed as a single isomer. 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 some 250 tonnes of deltamethrin (IPCS, 1990d). In spite of their long history of use, there are relatively few reports of pyrethroid, and specifically deltamethrin, toxicity and fewer than ten deaths have been reported from ingestion or occupational (primarily dermal/inhalational) exposure, though three deaths from deltamethrin poisoning have been reported (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 deltamethrin 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); (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). 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 involving other pyrethroids (Nassif, et al, 1980; Chester et al, 1987; Eadsforth et al, 1988; IPCS, 1989c; Woollen et al, 1991; Chester, 1992; Woollen et al, 1992; ) dermal absorption of deltamethrin is likely to be low (less than 1.5 per cent). When protective clothing was used the concentrations of deltamethrin and metabolites in urine at the end of a working day were at the limit of detection (IPCS, 1990d). Oral Between 19 and 57 per cent of orally administered cypermethrin (another type II pyrethroid) was absorbed in human studies (Woollen et al, 1991; Woollen et al, 1992) though there are no human data specific to deltamethrin. 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 (another type II pyrethroid) 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 Deltamethrin 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. After occupational exposure, deltamethrin and metabolites were detectable in urine for up to 12 hours (Zhang et al, 1991). Deltamethrin and metabolites were detectable in the urine of workers spraying the pyrethroid early on the first day of spraying, and persisted for up to two days after spraying had ceased (He et al, 1991). 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 after deltamethrin exposure (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), 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 than after other pyrethroid exposure (Aldridge, 1990; Flannigan and Tucker, 1985a). 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). 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 sever 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). Dermatitis with blisters and miliary papules has been reported in those occupationally exposed to deltamethrin (Wang et al, 1988; He et al, 1989). Ocular exposure Symptoms of mild eye irritation have been reported following occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS, 1990d; Lessenger, 1992) though there are no reports specific to deltamethrin. 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. Irritation of the respiratory tract was reported among workers producing an aerosol of deltamethrin (IPCS, 1990d). 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 deltamethrin 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 and other pyrethroids. 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 (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 poisoning 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. A 30 year-old male was unresponsive on arrival a hospital some ten hours after allegedly consuming 30 mL deltamethrin (Peter et al, 1996). He had radiological evidence of aspiration pneumonia and biochemical evidence of renal failure. He was treated supportively but developed convulsions and died within 48 hours. 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 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 (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 deltamethrin and other pyrethroids) 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 have been 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 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 deltamethrin ambient air concentrations of 0.005-0.012 mg/m3 and 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 deltamethrin 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 other pyrethroids including 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 deltamethrin 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 deltamethrin. 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 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 is not known. Carcinogenicity There is no evidence that deltamethrin is carcinogenic (IPCS, 1990d; IARC, 1991). Reprotoxicity In a variety of animal studies, there was no evidence that deltamethrin was teratogenic, embryotoxic or fetotoxic (IPCS, 1990d; Reprotox, 1997). 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 deltamethrin conclude that there is insufficient evidence for deltamethrin to be considered genotoxic or mutagenic (IPCS, 1990d; DOSE, 1997). Tests with deltamethrin showed no genotoxicity with Salmonella typhimurium TA98, TA100 or with Escherichia coli WP2 with or without metabolic activation. Deltamethrin did not cause DNA damage in Saccharomyces cerevisiae with or without metabolic activation (DOSE, 1997). Deltamethrin induced chromosomal aberrations in root meristerm cells of Allium cepa but did not induce gene mutation in Chinese hamster V79 cells, with or without metabolic activation. No chromosomal aberrations were observed in mouse bone marrow cells in vivo but morphological sperm abnormalities were induced in mice (DOSE, 1997). Fish toxicity Deltamethrin 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 mirror carp, rainbow trout, cichlid and pumpkinseed sunfish range from 0.5 to 1.8 µg/L deltamethrin (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. Int Arch Occup Environ Health 1985; 56: 299-305. Advisory Committee on Pesticides. Evaluation number 55: Esfenvalerate. London: Ministry of Agriculture Fisheries and Food, 1992. Akhtar N, Kayani SA, Ahmad MM, Shahab M. Insecticide-induced changes in secretory activity of the thyroid gland in rats. J Appl Toxicol 1996; 16: 397-400. Aldridge WN, Clothier B, Forshaw P, Johnson MK, Parker VH, Price RJ, Skilleter DN, Verschoyle RD, Stevens C. The effect of DDT and the pyrethroid cismethrin and decamethrin on the acetyl choline and cyclic nucleotide content of rat brain. Biochem Pharmacol 1978; 27: 1703-6. Aldridge WN. An assessment of the toxicological properties of pyrethroids and their neurotoxicity. Crit Rev Toxicol 1990; 21(2): 89-104. Barrueco C, Herrera A, Caballo C, de la Pena E. Cytogenetic effects of permethrin in cultured human lymphocytes. Mutagenesis 1992; 7: 433-7. Barrueco C, Herrera A, Caballo C, de la Peńa E. Induction of structural chromosome aberrations in human lymphocyte cultures and CHO cells by permethrin. Teratogenesis Carcinog Mutagen 1994; 14: 31-8. Box SA, Lee MR. A systemic reaction following exposure to a pyrethroid insecticide. Hum Exp Toxicol 1996; 15: 389-90. Bradbury JE, Forshaw PJ, Gray AJ, Ray DE. The action of mephenesin and other agents on the effects produced by two neurotoxic pyrethroids in the intact and spinal rat. Neuropharmacology 1983; 22: 907-14. Bradbury SP, Coats JR. Comparative toxicology of the pyrethroid insecticides. Rev Environ Contam Toxicol 1989; 108: 133-77. Brandenburg K, Deinard AS, DiNapoli J, Englender SJ, Orthoefer J, Wagner D. 1% permethrin cream rinse vs 1% lindane shampoo in treating pediculosis capitis. Am J Dis Child 1986; 140: 894-6. Casida JE, Gammon DW, Glickman AH, Lawrence LJ. Mechanisms of selective action of pyrethroid insecticides. Annu Rev Pharmacol Toxicol 1983; 23: 413-38. Chen S, Zhang Z, He F, Yao P, Wu Y, Sun J, Liu L, Li Q. An epidemiological study on occupational acute pyrethroid poisoning in cotton farmers. Br J Ind Med 1991; 48: 77-81. Chester G, Hatfield LD, Hart TB, Leppert BC, Swaine H, Tummon OJ. Worker exposure to, and absorption of cypermethrin during aerial application of an "ultra low volume" formulation to cotton. Arch Environ Contam Toxicol 1987; 16: 69-78. Chester G, Sabapathy NN, Woollen BH. Exposure and health assessment during application of lambda-cyhalothrin for malaria vector control in Pakistan. Bull World Health Organ 1992; 70: 615-9. Clark JM, Brooks MW. Neurotoxicology of pyrethroids: single or multiple mechanisms of action? Environ Toxicol Chem 1989; 8: 361-72. DiNapoli JB, Austin RD, Englender SJ, Gomez MP, Barrett JF. Eradication of head lice with a single treatment. Am J Public Health 1988; 78: 978-80. Dolara P, Salvadori M, Capobianco T, Torricelli F. Sister-chromatid exchanges in human lymphocytes induced by dimethoate, omethoate, deltamethrin, benomyl and their mixture. Mutat Res 1992; 283: 113-8. Dorman DC, Beasley VR. Neurotoxicology of pyrethrin and the pyrethroid insecticides. Vet Hum Toxicol 1991; 33: 238-43. DOSE/Dictionary of substances and their effects. (CD-ROM). Cambridge: Royal Society of Chemistry, 1997. Eadsforth CV, Bragt PC, van Sittert NJ. Human dose-excretion studies with pyrethroid insecticides cypermethrin and alphacypermethrin: relevance for biological monitoring. Xenobiotica 1988; 18: 603-14. EC Directive. EC Directive relating to the quality of water intended for human consumption, 80/778/EEC. Luxembourg: Office for Official Publications of the European Communities, 1980. Eells JT, Bandettini PA, Holman PA, Propp JM. Pyrethroid insecticide-induced alterations in mammalian synaptic membrane potential. J Pharmacol Exp Ther 1992; 262: 1173-81. Eil C, Nisula BC. The binding properties of pyrethroids to human skin fibroblast androgen receptors and to sex hormone binding globulin. J Steroid Biochem 1990; 35: 409-14. Enan E, Pinkerton KE, Peake J, Matsumura F. Deltamethrin-induced thymus atrophy in male Balb/c mice. Biochem Pharmacol 1996; 51: 447-54. 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. Flannigan SA, Tucker SB. Topical indomethacin for synthetic pyrethroid exposure. Contact Dermatitis 1984; 11: 55-6. Flannigan SA, Tucker SB. Variation in cutaneous sensation between synthetic pyrethroid insecticides. Contact Dermatitis 1985a; 13: 140-7. Flannigan SA, Tucker SB. Variation in cutaneous perfusion due to synthetic pyrethroid exposure. Br J Ind Med 1985b; 42: 773-6. Forshaw PJ, Ray DE. Development of therapy for type II pyrethroid insecticide poisoning. Hum Exp Toxicol 1997; 16: 382. Gammon DW, Lawrence LJ, Casida JE. Pyrethroid toxicology: protective effects of diazepam and phenobarbital in the mouse and the cockroach. Toxicol Appl Pharmacol 1982; 66: 290-6. Grant SMB. An unusual case of burning mouth sensation. Br Dent J 1993; 175: 378-80. Hartzell GE. Overview of combustion toxicology. Toxicology 1996; 115: 7-23. He F, Sun J, Han K, Wu Y, Yao P, Wang S, Liu L. Effects of pyrethroid insecticides on subjects engaged in packaging pyrethroids. Br J Ind Med 1988; 45: 548-51. 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. He F, Zhang Z, Chen S, Sun J, Yao P, Liu L, Li Q. Effects of combined exposure to pyrethroids and methamidophos on sprayers. Arch Complex Environ Stud 1990; 2: 31-6. He F, Deng H, Ji X, Zhang Z, Sun J, Yao P. Changes of nerve excitability and urinary deltamethrin in sprayers. Int Arch Occup Environ Health 1991; 62: 587-90. He F. Synthetic pyrethroids. Toxicology 1994; 91: 43-9. Health and Safety Executive. EH40/95: Occupational exposure limits 1995. Sudbury: Health and Safety Executive, 1995. Herrera A, Barrueco C, Caballo C, Pena E. Effect of permethrin on the induction of sister chromatid exchanges and micronuclei in cultured human lymphocytes. Environ Mol Mutagen 1992; 20: 218-22. Hiromori T, Nakanashi T, Kawaguchi S, Sako H, Suzuki T, Miyamoto J. Therapeutic effects of methocarbamol on acute intoxication by pyrethroids in rats. J Pestic Sci 1986; 11: 9-14. HSDB/Hazardous Substances Data Bank. In: Tomes plus. Environmental Health and Safety Series I. CD-ROM. Vol 35. Washington DC: National Library of Medicine, 1997. Husain R, Husain R, Adhami VM, Seth PK. Behavioral, neurochemical, and neuromorphological effects of deltamethrin in adult rats. J Toxicol Environ Health 1996; 48: 515-26. Hutson DH. The metabolic fate of synthetic pyrethroid insecticides in mammals. In: Bridges JW, Chasseaud LF, eds. Progress in drug metabolism. New York: John Wiley & Sons, 1979; 215-52. IARC/International Agency for Research on Cancer. Deltamethrin. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 1991; 53: 251-67. IPCS/International Programme on Chemical Safety. Environmental health criteria 87. Allethrins: allethrin, d-allethrin, bioallethrin, s-bioallethrin. Geneva: World Health Organization, 1989a. IPCS/International Programme on Chemical Safety. Environmental health criteria 92. Resmethrins: resmethrin, bioresmethrin, cismethrin. Geneva: World Health Organization, 1989b. IPCS/International Programme on Chemical Safety. Environmental health criteria 82. Cypermethrin. Geneva: World Health Organization, 1989c. IPCS/International Programme on Chemical Safety. Environmental health criteria 99. Cyhalothrin. Geneva: World Health Organization, 1990a. IPCS/International Programme on Chemical Safety. Environmental health criteria 94. Permethrin. Geneva: World Health Organization, 1990b. IPCS/International Programme on Chemical Safety. Environmental health criteria 95. Fenvalerate. Geneva: World Health Organization, 1990c. IPCS/International Programme on Chemical Safety. Environmental health criteria 97. Deltamethrin. Geneva: World Health Organization, 1990d. IPCS/International Programme on Chemical Safety. Environmental health criteria 98. Tetramethrin. Geneva: World Health Organization, 1990e. IPCS/International Programme on Chemical Safety. Environmental health criteria 96. d-Phenothrin. Geneva: World Health Organization, 1990f. Kalter DC, Sperber J, Rosen T, Matarasso S. Treatment of pediculosis pubis. Clinical comparison of efficacy and tolerance of 1% lindane shampoo vs 1% permethrin creme rinse. Arch Dermatol 1987; 123: 1315-9. Kaul PP, Rastogi A, Hans RK, Seth TD, Seth PK, Srimal RC. Fenvalerate-induced alterations in circulatory thyroid hormones and calcium stores in rat brain. Toxicol Lett 1996; 89: 29-33. Knox JM, Tucker SB, Flannigan SA. Paresthesia from cutaneous exposure to a synthetic pyrethroid insecticide. Arch Dermatol 1984; 120: 744-6. Knox JM, Tucker SB. A new cutaneous sensation caused by synthetic pyrethroids. Clin Res 1982; 30: 915a. Kolmodin-Hedman B, Swensson A, Akerblom M. Occupational exposure to some synthetic pyrethroids (permethrin and fenvalerate). Arch Toxicol 1982; 50: 27-33. Kolmodin-Hedman B, Akerblom M, Flato S, Alex G. Symptoms in forestry workers handling conifer plants treated with permethrin. Bull Environ Contam Toxicol 1995; 55: 487-93. Le Quesne PM, Maxwell IC, Butterworth STG. Transient facial sensory symptoms following exposure to synthetic pyrethroids: A clinical and electrophysiological assessment. Neurotoxicology 1980; 2: 1-11. Leahey JP. Metabolism and environmental degradation. In: Leahey JP, ed. The pyrethroid insecticides. London: Taylor & Francis, 1985; 263-342. Leclercq M, Cotonat J, Foulhoux P. Recherche d'un antagonisme ŕ l'intoxication par la deltaméthrine. J Toxicol Clin Exp 1986; 6: 85-93. Lessenger JE. Five office workers inadvertently exposed to cypermethrin. J Toxicol Environ Health 1992; 35: 261-7. Llewellyn DM, Brazier A, Brown R, Cocker J, Evans ML, Hampton J, Nutley BP, White J. Occupational exposure to permethrin during its use as a public hygiene insecticide. Ann Occup Hyg 1996; 40: 499-509. Madsen C, Claesson MH, Röpke C. Immunotoxicity of the pyrethroid insecticides deltamethrin and alpha-cypermethrin. Toxicology 1996; 107: 219-27. Mauck WL, Olson LE, Marking LL. Toxicity of natural pyrethrins and five pyrethroids to fish. Arch Environ Contam Toxicol 1976; 4: 18-29. Miyamoto J, Kaneko H, Tsuji R, Okuno Y. Pyrethroids, nerve poisons: How their risks to human health should be assessed. Toxicol Lett 1995; 82-83: 933-40. Narahashi T. The role of ion channels in insecticide action. In: Narahashi T, Chambers JE, eds. Insecticide action: from molecule to organism. Plenum Press, 1989; 55-84. Narahashi T, Carter DB, Frey J, Ginsburg K, Hamilton BJ, Nagata K, Roy ML, Song J-H, Tatebayashi H. Sodium channels and GABAA receptor-channel complex as targets of environmental toxicants. Toxicol Lett 1995; 82-83: 239-45. Narahashi T. Neuronal ion channels as the target sites of insecticides. Pharmacol Toxicol 1996; 78: 1-14. Nassif M, Brooke JP, Hutchinson DBA, Kamel OM, Savage EA. Studies with permethrin against bodylice in Egypt. Pestic Sci 1980; 11: 679-84. Newton JG, Breslin ABX. Asthmatic reactions to a commonly used aerosol insect killer. Med J Aust 1983; 1: 378-80. O'Malley M. Clinical evaluation of pesticide exposure and poisonings. Lancet 1997; 349: 1161-6. Oortgiesen M, van Kleef RGDM, Vijverberg HPM. Block of deltamethrin-modified sodium current in cultured mouse neuroblastoma cells: local anesthetics as potential antidotes. Brain Res 1990; 518: 11-8. Pesticides 1997. Ministry of Agriculture, Fisheries and Food (MAFF) and the Health and Safety Executive (HSE). Pesticides 1997. Pesticides approved under the control of pesticides regulations 1986. London: Her Majesty's Stationary Office, 1997. Pesticide Manual. Tomlin CDS, ed. The Pesticide Manual. London: The British Crop Protection Council, 1997. Peter JV, John G, Cherian AM. Pyrethroid poisoning. J Assoc Physicians India 1996; 44: 343-344. Poisindex. In: Micromedex International Healthcare Series. Vol 90. Colorado: Micromedex, Inc., 1996. Puig M, Carbonell E, Xamena N, Creus A, Marcos R. Analysis of cytogenetic damage induced in cultured human lymphocytes by the pyrethroid insecticides cypermethrin and fenvalerate. Mutagenesis 1989; 4: 72-4. Ray DE. Pesticides derived from plants and other organisms. 13.2 Pyrethrum and related compounds. In: Hayes WJ, Jr., Laws ER, Jr. eds. Handbook of pesticide toxicology. Vol 2. San Diego, California: Academic Press, 1991; 585-636. Reprotox. In: Tomes plus. Environmental Health and Safety Series I. CD-ROM. Vol 35. Washington DC: Fabro S, Scialli AR. Reproductive Toxicology Center, Columbia Hospital for Women, 1997. RTECS. Registry of Toxic Effects of Chemical Substances. In: Tomes plus. Environmental Health and Safety Series I. CD-ROM. Vol 35. Washington DC: National Institute for Occupational Safety and Health (NIOSH), 1997. Soderlund DM, Bloomquist JR. Neurotoxic actions of pyrethroid insecticides. Annu Rev Entomol 1989; 34: 77-96. Soderlund DM, Casida JE. Effects of pyrethroid structure on rates of hydrolysis and oxidation by mouse liver microsomal enzymes. Pestic Biochem Physiol 1977; 7: 391-401. Song J-H, Nagata K, Tatebayashi H, Narahashi T. Interactions of tetramethrin, fenvalerate and DDT at the sodium channel in rat dorsal root ganglion neurons. Brain Res 1996; 708: 29-37. Song J-H, Narahashi T. Selective block of tetramethrin-modified sodium channels by (+/-)- alpha-tocopherol (vitamin E). J Pharmacol Exp Ther 1995; 275: 1402-11. Song J-H, Narahashi T. Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin. J Pharmacol Exp Ther 1996; 277: 445-53. Surrallés J, Xamena N, Creus A, Catalán J, Norppa H, Marcos R. Induction of micronuclei by five pyrethroid insecticides in whole-blood and isolated human lymphocyte cultures. Mutat Res Genet Toxicol 1995; 341: 169-84. The UK Pesticide Guide. Whitehead R, ed. Centre for Agriculture and Biosciences (CAB) International and the British Crop Protection Council. The UK Pesticide Guide. Cambridge: University Press, 1997. Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D, Demoute J-P, Guedin D, Catterall WA. High affinity binding of pyrethroids to the alpha subunit of brain sodium channels. Mol Pharmacol 1997; 51: 651-7. Tucker SB, Flannigan SA, Smolensky MH. Comparison of therapeutic agents for synthetic pyrethroid exposure. Contact Dermatitis 1983; 9: 316. Tucker SB, Flannigan SA, Ross CE. Inhibition of cutaneous paresthesia resulting from synthetic pyrethroid exposure. Int J Dermatol 1984; 23: 686-9. Tucker SB, Flannigan SA. Cutaneous effects from occupational exposure to fenvalerate. Arch Toxicol 1983; 54: 195-202. Vijverberg HPM, van den Bercken J. Action of pyrethroid insecticides on the vertebrate nervous system. Neuropathol Appl Neurobiol 1982; 8: 421-40. Vijverberg HPM, van den Bercken J. Neurotoxicological effects and the mode of action of pyrethroid insecticides. Crit Rev Toxicol 1990; 21: 105-26. Wang S, Zheng Q, Yu L, Xu B, Li Y. Health survey among farmers exposed to deltamethrin in the cotton fields. Ecotoxicol Environ Safety 1988; 15: 1-6. Wilkes MF, Woollen BH, Marsh JR, Batten PL, Chester G. Biological monitoring for pesticide exposure - the role of human volunteer studies. Int Arch Occup Environ Health 1993; 65: S189-92. Woollen BH, Marsh JR, Chester G. Metabolite profiles of a pyrethroid insecticide following oral and dermal absorption in man. Proceedings of a Conference on Percutaneous Penetration 1991; 10-12 April 1991: 20-5. Woollen BH, Marsh JR, Laird WJD, Lesser JE. The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration. Xenobiotica 1992; 22: 983-91. Woollen BH. Biological monitoring for pesticide absorption. Ann Occup Hyg 1993; 37: 525-40. Zhang Z, Sun J, Chen S, Wu Y, He F. Levels of exposure and biological monitoring of pyrethroids in spraymen. Br J Ind Med 1991; 48: 82-6.