6 Neurotoxicity of Permethrin

Permethrin is neurotoxic at high doses. It produces a variety of clinical neurotoxic effects in animals. Some of those effects are tremors, salivation, paresthesia, splayed gait, depressed reflexes, and tiptoe gait; reversible axonal injury occurs at high doses (Brammer, 1989; Robinson, 1989a,b). These symptoms appear to be universal for pyrethroids.

The primary action of pyrethroids on the peripheral nervous system is to induce pronounced repetitive activity—i.e., continuous rather than single nerve impulses (van den Bercken, 1977; van den Bercken et al., 1979). Pyrethroids interact with a fraction of the voltage-dependent sodium channels in excitable membranes that produce a prolongation of the inward sodium current during excitation in which the channels remain open much longer than normal (see review by Vijverberg and van den Bercken, 1990). Membrane depolarization might also occur, resulting in enhanced neurotransmitter release and eventually blockage of excitation. Although postsynaptic neurotransmitter responses can be suppressed by pyrethroids, doses must be higher than those that produce effects on sodium channels. Pyrethroids also increase concentrations of β-glucuronidase and β-galactosidase, which are thought to be associated with repair process, in peripheral nerves (Aldridge, 1990).



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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms 6 Neurotoxicity of Permethrin Permethrin is neurotoxic at high doses. It produces a variety of clinical neurotoxic effects in animals. Some of those effects are tremors, salivation, paresthesia, splayed gait, depressed reflexes, and tiptoe gait; reversible axonal injury occurs at high doses (Brammer, 1989; Robinson, 1989a,b). These symptoms appear to be universal for pyrethroids. The primary action of pyrethroids on the peripheral nervous system is to induce pronounced repetitive activity—i.e., continuous rather than single nerve impulses (van den Bercken, 1977; van den Bercken et al., 1979). Pyrethroids interact with a fraction of the voltage-dependent sodium channels in excitable membranes that produce a prolongation of the inward sodium current during excitation in which the channels remain open much longer than normal (see review by Vijverberg and van den Bercken, 1990). Membrane depolarization might also occur, resulting in enhanced neurotransmitter release and eventually blockage of excitation. Although postsynaptic neurotransmitter responses can be suppressed by pyrethroids, doses must be higher than those that produce effects on sodium channels. Pyrethroids also increase concentrations of β-glucuronidase and β-galactosidase, which are thought to be associated with repair process, in peripheral nerves (Aldridge, 1990).

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms HUMAN DATA A paucity of data are available on the neurotoxic effects of pyrethroids in humans—especially for permethrin. However, in a review of 573 cases of acute pyrethroid poisonings of humans in China (229 occupational and 344 accidental; cases mainly involved deltamethrin (325), fenvalerate (196), and cypermethrin (45)), the initial symptoms from occupational exposures were burning, itching, or tingling sensation (subjective irritation) of the face or dizziness that usually developed after 4-6 hr of exposure (He et al., 1989). Systemic symptoms that occurred in the most serious cases were mainly digestive, including epigastric pain, nausea, and vomiting. Vijverberg and van den Bercken (1990) in their review of pyrethroid insecticides report that the systemic symptoms in humans are burning, itching, or tingling sensation of the face, epigastric pain, anoxemia, nausea, vomiting, dizziness, headache, fatigue, convulsions, and coma. Nerve conduction studies and interviews of 23 laboratory technicians involved with several pyrethroids in field trials, formulation, or other laboratory work showed no evidence of nerve impairment associated with exposure to permethrin (Le Quesne et al., 1980). Symptoms of facial paresthesia and occasional pruritic rashes were reported among those workers, but symptoms were not clearly related to permethrin. Staff involved with bagging, mixing, or spraying a 5% preparation of permethrin (cis/trans ratio, 25:75) in Nigeria were evaluated with a questionnaire and urinalysis (Rishikesh et al., 1978). Regardless of the protective equipment worn by spraymen, only 2 mg of permethrin was absorbed after exposure to 6 kg of permethrin, which was excreted in 24 hr. ANIMAL DATA Neurotoxic Effects Rats Peripheral nerve damage has been reported to occur in laboratory animals at near lethal doses of pyrethroids (Aldridge, 1990; Vijverberg and van den Bercken, 1990).

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms In an acute dermal toxicity study, Robinson (1989a) exposed rats to permethrin at 2 g/kg and observed neurotoxic signs such as tip-toe gait, upward curvature of the spine, and urinary incontinence in some of the exposed animals. Based on these results, Robinson (1989a) estimated the LOAEL to be 2 g/kg and also estimated the NOAEL to be 200 mg/kg by using an uncertainty factor of 10 to the LOAEL. Hend and Butterworth (1977) fed permethrin to male and female Charles River rats (six of each sex per group) in diet at concentrations of 0 or 6,000 mg/kg for up to 14 days. Severe clinical signs of poisoning were seen in all the permethrin-treated rats. Only one permethrin-treated male survived the 14-day trial. Histological examination showed fragmented and swollen sciatic nerve axons and myelin degeneration in four of five permethrin-treated animals. Dayan (1980) fed permethrin (cis/trans ratio, 25:75) (94.5% pure) to groups of 10 male and 10 female Sprague-Dawley rats at 4,000, 6,000, or 9,000 mg/kg for 21 days. All animals developed severe trembling and lost weight. Some rats of each sex in the 9,000-mg/kg group died. Histopathological examination of brain, spinal cord, trigeminal and dorsal root ganglia, proximal and distal root trunks, and terminal motor and sensory nerves showed no consistent abnormalities. Groups of 10 Wistar rats that were administered permethrin in their diet at concentrations of 0, 2,500, 3,000, 3,750, 4,500, 5,000, or 7,500 ppm (1, 125, 150, 187.5, 225, 250, or 375 mg/kg per day) for 14 days developed peripheral nerve toxicities (Glaister et al., 1977). Deaths occurred among the animals administered 5,000 or 7,500 ppm, and minor histological and ultrastructural changes occurred in the sciatic nerves of the animals in the 5,000-ppm group. The lesions included swelling and increased vesiculation of unmyelinated nerves, hypertrophy of Schwann's cells, contraction of axoplasm and formulation of myelin whorls in residual spaces, and fragmentation of myelinated axons. Similarly, swelling, nodal demyelination, and disintegration of the sciatic nerves were observed in rats fed permethrin at 6,000 ppm (300 mg/kg per day) for 8 days (Okuno et al., 1976b). In another study (James et al., 1977), vacuolation of myelinated nerve fibers occurred in rats fed permethrin at 6,000 ppm (300 mg/kg per day) for 18 days. Dyck et al. (1984) conducted a detailed morphological evaluation of the nervous system of rats in two chronic feeding studies of permethrin. In the first study, Long-Evans rats were fed diets containing permethrin

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms at concentrations of 0, 20, 100, or 500 mg/kg for 2 years, and five male and five female animals (randomly selected) from each dose group were examined. In the second study, Long-Evans rats were fed diets containing permethrin at concentrations of 0, 20, or 100 mg/kg for three successive generations, and five male and five female rats from each group were randomly selected from the third-generation parental animals. Examination of central and peripheral nerves, teased myelinated fibers of distal sural and tibial nerves, and the maxillary division of the fifth cranial nerve did not show any changes attributable to the feeding of the permethrin (Dyck et al., 1984). Hens Millner and Butterworth (1977) administered permethrin orally (cis/trans ratio, 50:50) as a 40% wt/vol solution in dimethylsulfoxide to hens at daily doses of 1 g/kg of body weight for 5 days. After 3 weeks, the dosing regimen was repeated, and the hens were maintained for an additional 3 weeks before being killed. No signs of neurological disturbance were seen, and there was no mortality. All hens treated with tri-ortho-cresyl phosphate (TOCP) (positive control chemical) showed clinical and histopathological evidence of neurotoxicity; none of the hens treated with permethrin showed signs of neurotoxicity. Histological examination of nerve tissues revealed no abnormalities. Permethrin was considered to have no delayed neurotoxic potential such as that seen with certain organophosphates (Millner and Butterworth, 1977). Ross and Prentice (1977) orally administered permethrin to 15 hens at 9 g/kg of body weight and again 21 days later. After an additional 21 days, the hens were killed. All positive control animals (given TOCP at 500 mg/kg) manifested signs of delayed neurotoxicity ranging from slight muscular incoordination to paralysis. No signs of ataxia were seen in any of the hens in the permethrin-treated or negative control animals. Histopathological examination of the nervous tissues of permethrin-treated animals showed none of the degenerative changes observed in the tissues of the animals from positive control groups.

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Neurobehavioral Effects Pyrethroids can affect behavior patterns. Mice exposed to Ambush (25.6% permethrin) at 0.5, 5.0, or 50 mg/kg orally or 30 or 300 mg/kg dermally displayed an increase in activity (Digiscan optimal animal activity monitor) at the 50- and 300-mg/kg oral and dermal doses, respectively (Mitchel et al., 1988). Additional behavioral studies are necessary to further evaluate the behavioral effects of permethrin. Sherman (1979) studied the behavior of immature male Sprague-Dawley rats that were habituated to inhalation of permethrin aerosols. Habituation of rats was achieved by exposing three groups of rats (five per group) to aerosols of permethrin at 500 mg/m3 for 21 days and then again at 1,000 mg/m3 for an additional 21 days. Three other groups of rats (five per group) served as controls; they were similarly treated but were not exposed to permethrin. At the end of this conditioning period, all rats, including the control animals, were exposed to a permethrin aerosol at 5,000 mg/m3 for 4 hr. At the end of the habituation period, there were no differences in retention of avoidance training or the ability to learn the same task between control animals and permethrin-exposed groups. However, after exposure to permethrin at 5,000 mg/m3, retention capacity was significantly lower among nonhabituated control rats than among habituated rats. The nonhabituated control rats also showed decreases in coordination and balance and a higher incidence of conflict behavior and tremors. The performance of the rats in the habituated groups was not changed (Sherman, 1979). CONCLUSIONS Permethrin is neurotoxic in animals at high doses. The neurotoxic symptoms of pyrethroid toxicity in humans appear to mimic those observed in animals. The estimated NOEL for neurotoxicity in rats by dermal route is 200 mg/kg (Robinson, 1989a). In the committee's judgment, 125 mg/kg is the LOAEL for permethrin from oral exposure in rats (Glaister et al., 1977; ICI, 1984). Based on a NOAEL of 200 mg/kg per day from the available neuro-

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms toxicity data, the margin of safety (MOS) associated with daily human exposure to permethrin from permethrin-treated BDUs at a level of 6.8 × 10−5 mg/kg per day is approximately 3 million. Because the daily lifetime dose for garment workers (3 × 10−5 mg/kg per day) is less than the daily dose for military personnel, the MOS for garment workers is even higher—6.8 million. Therefore, neurotoxicity that could result from wearing permethrin-impregnated BDUs or working with treated fabric should not be a concern. RECOMMENDATIONS Animal data clearly demonstrate the neurotoxic properties of permethrin; however, human data are lacking and need to be substantiated in epidemiological or case studies. The subcommittee recommends that data should be collected on neurotoxicity of permethrin in humans from epidemiological studies of workers or from studies of accidental human exposures.