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    PYRETHROIDS




    SA Cage MSc M Inst Inf Sci
    SM Bradberry BSc MB MRCP
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service
    (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Birmingham B18 7QH


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    PYRETHROIDS

    Toxbase summary

    Type of product

    Insecticides

    Toxicity

    Dermal and inhalational exposures are associated usually with no or
    only mild adverse effects. Following substantial ingestion, patients
    may develop coma, convulsions and severe muscle fasciculations and may
    take several days, occasionally weeks, to recover.

    Fatalities have occurred rarely, usually following ingestion (He et
    al, 1989).

    Ingestion of deltamethrin 2 mg/kg caused coma in a four year-old
    child. Recovery was uneventful (O'Malley, 1997).

    Features

    Dermal exposure

         -    Tingling and pruritus with blotchy erythema on the face or
              other exposed areas, exacerbated by sweating or touching.
              Systemic toxicity may ensue following substantial exposure
              (see below).

    Ocular exposure

         -    Lacrimation and transient conjunctivitis may occur.

    Inhalation

    Brief exposure:

         -    Respiratory tract irritation with cough, mild dyspnoea,
              sneezing and rhinorrhea.

    Substantial and prolonged exposure:
         -    Systemic toxicity may ensue - see below.

    Ingestion

         -    May cause nausea, vomiting and abdominal pain. Systemic
              toxicity may ensue following substantial ingestion (see
              below).

    Systemic toxicity

         -    Systemic symptoms may develop after widespread dermal
              exposure, prolonged inhalation or ingestion. Features
              include headache, dizziness, anorexia and hypersalivation.
         -    Severe poisoning is uncommon. It usually follows substantial
              ingestion and causes impaired consciousness, muscle
              fasciculations, convulsions and, rarely, non-cardiogenic
              pulmonary oedema.

    Chronic exposure

         -    Long-term exposure is no more hazardous than short-term
              exposure.

    Management

    Dermal

    1.   Remove soiled clothing and wash contaminated skin with soap and
         water.
    2.   Institute symptomatic and supportive measures as required.
    3.   Topical vitamin E (tocopherol acetate) has been shown to reduce
         skin irritation if applied soon after exposure (Flannigan et al,
         1985), but it is not available as a pharmaceutical product in the
         UK.
    4.   Symptoms usually resolve within 24 hours without specific
         treatment.

    Ocular

    1.   Irrigate with lukewarm water or 0.9 per cent saline for at least
         ten minutes.
    2.   A topical anaesthetic may be required for pain relief or to
         overcome blepharospasm.
    3.   Ensure no particles remain in the conjunctival recesses.
    4.   Use fluorescein stain if corneal damage is suspected.
    5.   If symptoms do not resolve following decontamination or if a
         significant abnormality is detected during examination, seek an
         ophthalmological opinion.

    Inhalation

    1.   Remove to fresh air.
    2.   Institute symptomatic and supportive measures as required.

    Ingestion

    1.   Do not undertake gastric lavage because solvents are present in
         some formulations and lavage may increase risk of aspiration
         pneumonia.
    2.   Institute symptomatic and supportive measures as required.

    3.   Atropine may be of value if hypersalivation is troublesome,
         0.6-1.2 mg for an adult, 0.02 mg/kg for a child.
    4.   Mechanical ventilation should be instituted if non-cardiogenic
         pulmonary oedema develops.
    5.   Isolated brief convulsions do not require treatment but
         intravenous diazepam should be given if seizures are prolonged or
         recur frequently. Rarely, it may be necessary to give intravenous
         phenytoin or to paralyze and ventilate the patient.

    References

    Box SA, Lee MR.
    A systemic reaction following exposure to a pyrethroid insecticide.
    Hum Exp Toxicol 1996; 15: 389-90.

    Flannigan SA, Tucker SB, Key MM, Ross CE, Fairchild EJ, Grimes BA,
    Harrist RB.
    Synthetic pyrethroid insecticides: a dermatological evaluation.
    Br J Ind Med 1985; 42: 363-72.

    He F, Wang S, Liu L, Chen S, Zhang Z, Sun J.
    Clinical manifestations and diagnosis of acute pyrethroid poisoning.
    Arch Toxicol 1989; 63: 54-8.

    Lessenger JE.
    Five office workers inadvertently exposed to cypermethrin.
    J Toxicol Environ Health 1992; 35: 261-7.

    O'Malley M.
    Clinical evaluation of pesticide exposure and poisonings.
    Lancet 1997; 349: 1161-6.

    INTRODUCTION

    Pyrethrins were developed as pesticides from extracts of dried and
    powdered flower heads of  Chrysanthemum cinerariaefolium. The active
    principles of these (see Fig. 1) are esters of chrysanthemumic acid
    (R1 = CH3) or pyrethric acid (R1 = CH3O2C) (both cyclopropane
    (three membered ring) carboxylic acids), with one of three
    cyclopentanone alcohols (cinerolone, R2 = CH3; jasomolone, R2 =
    CH2CH3; or pyrethrolone, R2 = CHCH2), giving six possible
    structures. These natural pyrethrins have the disadvantage that they
    are rapidly decomposed by light.

    FIGURE 1

    Once the basic structure of the pyrethrins had been discovered,
    synthetic analogues, pyrethroids, were developed and tested. Initially
    esters were produced using the same cyclopropane carboxylic acids,
    with variations in the alcohol portion of the compounds. The first
    commercial synthetic pyrethroid, allethrin (Fig. 2), was produced in
    1949, followed in the 1960s by dimethrin, tetramethrin, resmethrin
    (Fig. 2), prothrin, and proparthrin. 3-Phenoxybenzyl esters were also
    found to be active as pesticides (phenothrin, permethrin) (Fig. 3).
    Synthetic pyrethroids with this basic cyclopropane carboxylic ester
    structure (and no cyano group substitution) are known as type I
    pyrethroids. In animal studies type I pyrethroids have been shown
    generally to produce a typical toxic syndrome (see page 10).

    FIGURE 2

    FIGURE 3

    The insecticidal activity of synthetic pyrethroids was enhanced
    further by the addition of a cyano group at the benzylic carbon atom
    to give alpha-cyano (type II) pyrethroids. Examples of type II
    pyrethroids include cyphenothrin and cypermethrin (Fig. 4). In animal
    studies type II pyrethroids have been shown generally to produce a
    typical toxic syndrome (see page 10).

    FIGURE 4

    Similar insecticidal activity was found in a group of phenylacetic
    3-phenoxybenzyl esters, despite the lack of the cyclopropane ring.
    This led to the development of fenvalerate, an
    alpha-cyano-3-phenoxy-benzyl ester, and other related compounds (Fig.
    5). These all contain the alpha-cyano group and hence are type II
    pyrethroids. Some common type I and type II pyrethroids are shown in
    Table 1.

    Table 1. Type I and type II pyrethroids

                                                     

    Type I                  Type II
                                                     

    Allethrin               Cyfluthrin
    Bioallethrin            Cyhalothrin
    Bifenthrin              Lambda-cyhalothrin
    Permethrin              Cypermethrin
    d-Phenothrin            Alpha-cypermethrin
    Prallethrin             Deltamethrin
    Resmethrin              Fenpropathrin
    Bioresmethrin           Fenvalerate
    Tefluthrin              Esfenvalerate
    Tetramethrin            Flucythrinate
                            Flumethrin
                            Tau-fluvalinate
                                                     

    FIGURE 5

    Animal studies suggest that the two structural types of pyrethroids
    give rise generally to distinct patterns of systemic toxic effects.
    Type I pyrethroids produce the so-called "T (tremor) syndrome",
    characterized by tremor, prostration and altered "startle" reflexes.
    Type II (alpha-cyano) pyrethroids produce the so-called "CS
    (choreoathetosis/salivation) syndrome" with ataxia, convulsions,
    hyperactivity, choreoathetosis and profuse salivation.

    These observations are consistent with some differences in the
    mechanisms of toxicity between type I and type II pyrethroids (see
    below) but the division of reactions by chemical structure is not
    exclusive. Some compounds produce a combination of the two syndromes,
    and different stereoisomeric forms can produce different syndromes
    (Dorman and Beasley, 1991). The classification into "T" and "CS"
    syndromes is not used clinically.

    All pyrethroids have at least four stereoisomers, with different
    orientation of the substituents on the cyclopropane ring (or the
    equivalent part of the phenylacetate). The isomers have different
    biological activities, as discussed below (see Mechanisms of
    toxicity). Different isomers may have separate common names (Table 2),
    reflecting their commercial importance (Aldridge et al, 1978).

    In general, only the cyclopropane carboxylic acid esters with the R
    absolute configuration at the cyclopropane C1 atom, and
    alpha-cyano-3-phenoxy benzyl esters with the S absolute configuration
    at C-alpha (see Fig. 6) are toxic to man or insects (R and S refer to
    variations in the three dimensional structure of the molecule).

    Table 2. Pyrethroids with commercially available isomers

                                                                  

    Pyrethroid          Isomers
    Resmethrin          bioresmethrin, cisresmethrin
    Allethrin           d-allethrin, bioallethrin, esbiothrin,
                        s-bioallethrin
    Fenvalerate         esfenvalerate
    Cyhalothrin         lambda-cyhalothrin
    Phenothrin          d-phenothrin
    Cypermethrin        alpha-cypermethrin

                                                                  

    FIGURE 6

    EPIDEMIOLOGY

    In 1989-1990, world-wide annual production of pyrethroids included
    approximately 1000 tonnes of fenvalerate (IPCS, 1990c), 600 tonnes of
    permethrin (IPCS, 1990b), several hundred tonnes of allethrin and its
    isomers (IPCS, 1989a), 340 tonnes of cypermethrin (IPCS, 1989c), about
    250 tonnes of deltamethrin (IPCS, 1990d), a few hundred tonnes of
    tetramethrin (IPCS, 1990e), 70-80 tonnes of d-phenothrin (IPCS, 1990f)
    and 20-30 tonnes of resmethrin (IPCS, 1989b). No data on cyhalothrin
    and lambda-cyhalothrin production were available in 1990 (IPCS,
    1990a).

    In spite of their long history of use, there are relatively few
    reports of pyrethroid toxicity. Less than ten deaths have been
    reported from ingestion of or occupational (primarily
    dermal/inhalational) exposure to fenvalerate and deltamethrin (He et
    al, 1989; Peter et al 1996).

    MECHANISMS OF TOXICITY

    In neuronal cells the generation of an action potential by membrane
    depolarization involves the opening of cell membrane sodium channels
    and a rapid increase in sodium influx. The closure of sodium channels
    begins the process of action potential inactivation. Delayed sodium
    channel closure thus increases cell membrane excitability.

    Pyrethroids modify the gating characteristics of voltage-sensitive
    sodium channels in mammalian and invertebrate neuronal membranes
    (Eells et al, 1992; Narahashi, 1989) to delay their closure. They are
    dissolved in the lipid phase of the membrane (Narahashi, 1996) and
    bind to a receptor site on the alpha sub-unit of the sodium channel
    (Trainer et al, 1997). This binding is to a different site from local
    anaesthetics, batrachotoxin, grayanotoxin, and tetrodotoxin
    (Narahashi, 1996).

    The interaction of pyrethroids with sodium channels is highly
    stereospecific (Soderlund and Bloomquist, 1989), with the 1R and 1S
     cis isomers binding competitively to one site and the 1R and 1S
     trans isomers binding non-competitively to another. The 1S forms do
    not modify channel function but do block the effect of the 1R isomers
    (Ray, 1991).

    The prolonged opening of sodium channels by the neurotoxic isomers of
    pyrethroids produces a protracted sodium influx which is referred to
    as a sodium "tail current" (Miyamoto et al, 1995; Soderlund and
    Bloomquist, 1989; Vijverberg and van den Bercken, 1982). This lowers
    the threshold of sensory nerve fibres for the activation of further
    action potentials, leading to repetitive firing of sensory nerve
    endings (Vijverberg and van den Bercken, 1990) which may progress to
    hyperexcitation of the entire nervous system (Narahashi et al, 1995).
    At high pyrethroid concentrations, the sodium "tail current" may be
    sufficiently great to depolarize the nerve membrane completely,
    generating more open sodium channels (Eells et al, 1992) and
    eventually causing conduction block.

    The depolarizing activity is specific for the neurotoxic isomers
    (Eells et al, 1992), and parallels mammalian toxicity:
    deltamethrin > cypermethrin > fenvalerate >> permethrin (Clark and
    Marion, 1989; Eells et al, 1992).

    Only low pyrethroid concentrations are necessary to modify sensory
    neurone function. For example, when tetramethrin was added to a
    preparation of rat cerebellar Purkinje neurons, only about 0.6-1 per
    cent of sodium channels needed to be modified to produce:

    (i)    Repetitive discharges in nerve fibres and nerve terminals;
           An increase in discharges from sensory neurons (due to
           membrane depolarization); and

    (ii)   Severe disturbances of synaptic transmission (Narahashi, 1989;
           Narahashi et al, 1995; Song and Narahashi, 1996).

    Although both type I and type II pyrethroids primarily affect sodium
    channels, experimental studies have identified some specific
    differences in their effects. These are summarized below and may, in
    part, account for the differences in clinical manifestations observed
    following experimental intoxication with type I and type II
    pyrethroids.

    Type I pyrethroids (without the alpha-cyano group)
    Type I compounds:

    (i)    Keep sodium channels open (Narahashi, 1989);

    (ii)   Produce repetitive firing of sensory nerve endings (Soderlund
           and Bloomquist, 1989; Vijverberg and van den Bercken, 1982);

    (iii)  Modify sodium channels in the resting or closed state so that
           they subsequently open more slowly (Dorman and Beasley, 1991);

    (iv)   Show a more pronounced positive temperature-dependent capacity
           for developing repetitive discharges (more likely to occur at
           higher temperatures) and negative temperature dependence for
           nerve-blocking action (more likely to occur at lower
           temperatures) (Clark and Marion, 1989; Dorman and Beasley,
           1991; Narahashi, 1989); and

    (v)    Produce effects on cultured neurons that are easily reversed
           by washing with a pyrethroid-free solution (Song et al, 1996).

    Type II pyrethroids (mainly alpha-cyano-3-phenoxybenzyl esters)
    Type II compounds:

    (i)    Cause depolarization of myelinated nerve membranes without
           repetitive discharges (Dorman and Beasley, 1991; Vijverberg
           and van den Bercken, 1982);

    (ii)   Are associated with a decrease in action potential amplitude
           (Dorman and Beasley, 1991);

    (iii)  Stabilize a variety of sodium channel states by reducing
           transition rates between them (Dorman and Beasley, 1991; Eells
           et al, 1992; Narahashi, 1989), causing a greatly prolonged
           open time (Vijverberg and van den Bercken, 1982), and
           producing stimulus-dependent nerve depolarization and block
           (Soderlund and Bloomquist, 1989);

    (iv)   May act post-synaptically by interacting with nicotinic
           acetylcholine and GABA receptors (Dorman and Beasley, 1991;
           Eells et al, 1992); and

    (v)    Produce effects on cultured neurons that are largely
           irreversible after washing cells with a pyrethroid-free
           solution (Song et al, 1996).

    In addition, type II pyrethroids, such as deltamethrin, enhance
    noradrenaline (norepinephrine) release (Clark and Brooks, 1989).
    Tetramethrin (Clark and Marion, 1989), but not deltamethrin or
    fenvalerate (Narahashi, 1989), also blocks voltage-dependent calcium
    channels.

    Oral deltamethrin increases monoamine oxidase activity selectively in
    different parts of rat brains, and produces morphological changes in
    Purkinje neurons in the cerebellum (Husain et al, 1996).

    In human investigations, maximal conduction velocity in sensory nerve
    fibres of the sural nerve showed some increase in subjects exposed to
    pyrethroids, but there were no abnormal neurological signs, and other
    electrophysiological studies were normal in the arms and legs (Le
    Quesne et al, 1980). He et al (1991) assessed nerve excitability using
    an electromyograph and pairs of stimuli at variable intervals. They
    showed a prolongation of the "supernormal period" in the median nerve
    in individuals who had been exposed to pyrethroids occupationally for
    three days. The "supernormal period" was even more prolonged two days
    after cessation of exposure. (Note: the "supernormal period" is the
    period for which the action potential induced by a second stimulus is
    greater than the action potential produced by an initial stimulus).

    Pyrethroids are some 2250 times more toxic to insects than mammals.
    This can be explained in terms of differences in their potency as
    neuronal toxins and differences in rates of detoxification between
    invertebrates and vertebrates (Narahashi, 1996; Narahashi et al, 1995;
    Song and Narahashi, 1996).

    The sensitivity of invertebrate neuronal sodium channels to
    pyrethroids is ten times greater than in mammals (Song and Narahashi,
    1996). Furthermore, invertebrates typically have body temperatures
    some 10°C lower than mammals and  in vitro studies show tetramethrin
    to be more potent at evoking repetitive neuronal discharges at lower
    temperatures (Song and Narahashi, 1996). In these experiments it was
    noted that the recovery of sodium channels from tetramethrin
    intoxication after washing was some five times faster in mammals than
    invertebrates. In addition pyrethroid hepatic metabolism
    (detoxification) is faster in mammals. Finally small insect size
    increases the likelihood of end-organ (neuronal) toxicity prior to
    detoxification (Song and Narahashi, 1996).

    TOXICOKINETICS

    In addition to the important differences between invertebrates and
    vertebrates outlined above, the low toxicity of pyrethroid
    insecticides in mammals is due to poor dermal absorption (the main
    route of exposure) and metabolism to non-toxic metabolites (Bradbury
    and Coats, 1989).

    Absorption

    Dermal

    Based on excretion studies, dermal absorption of pyrethroids is low,
    reaching a maximum of 1.5 per cent (Nassif et al, 1980).

    After application of 25 mg cypermethrin in a hydrocarbon solvent to
    human volunteers, the mean dermal absorption as assessed by excretion
    studies was 0.1 per cent (Eadsforth et al, 1988). The mean dermal
    absorption of cypermethrin was estimated to be 1.2 per cent after
    application of a spray formulation containing 31 mg cypermethrin to
    volunteers (Woollen et al, 1991; Woollen et al, 1992). Excretion of
    cypermethrin and its metabolites in most urine samples was below the
    limit of detection in workers exposed, by spraying, to cypermethrin
    1.5-46.1 mg/h, implying limited absorption (IPCS, 1989c). Dermal
    exposure of three mixer/loaders to cypermethrin 0.25-5.27 mg/8h
    resulted in urinary excretion of 12-23 µg cypermethrin equivalents on
    the day of exposure (Chester et al, 1987); these data also suggest
    that pyrethroid absorption is limited.

    Only about 0.0001 per cent (54 µg) of lambda-cyhalothrin handled and
    sprayed each day by spraymen was absorbed, based on estimation of
    metabolites in urine and serum (Chester et al, 1992).

    Some 0.5 per cent of the total dose of permethrin cream (5 per cent)
    applied to the skin of patients with scabies was excreted (as
    metabolites) in the first 48 hours after application, implying limited
    absorption (van der Rhee et al, 1989). When permethrin was applied in
    a powder formulation to patients with bodylice, less than one per cent
    of a 125 mg dose and some 1.5 per cent of a 250 mg dose was retrieved
    as metabolites in urine (Nassif et al, 1980).

    d-Phenothrin applied to head and pudendal hair of volunteers
    (0.44-0.67 mg/kg body weight) gave blood metabolite concentrations
    below the limit of detection (IPCS, 1990f), suggesting very limited
    absorption.

    When protective clothing was used the concentrations of cypermethrin
    and permethrin metabolites in urine at the end of a working day were
    at the limit of detection (Desi et al, 1986). Similar results were
    found for deltamethrin (IPCS, 1990d) and alpha-cypermethrin (IPCS,
    1992).

    Oral

    Between 19 and 57 per cent of orally administered cypermethrin was
    absorbed in human studies (Woollen et al, 1991; Woollen et al, 1992).

    Metabolism

    Pyrethroids are hydrolyzed rapidly in the liver to their inactive acid
    and alcohol components (Hutson, 1979; Ray, 1991), probably by
    microsomal carboxylesterase (Hutson, 1979). Further degradation and
    hydroxylation of the alcohol at the 4' position then occurs, and
    oxidation produces a wide range of metabolites (Hutson, 1979; Leahey,
    1985).

    There is some stereospecificity in metabolism, with  trans-isomers
    being hydrolyzed more rapidly than the  cis-isomers, for which
    oxidation is the more important metabolic pathway (Soderlund and
    Casida, 1977). Although the alpha-cyano group reduces the
    susceptibility of the molecule to hydrolytic and oxidative metabolism
    (Hutson, 1979; Soderlund and Casida, 1977), the cyano group is
    converted to the corresponding aldehyde (with release of the cyanide
    ion), followed by oxidation to the carboxylic acid, sufficiently
    rapidly for efficient excretion by mammals (Leahey, 1985). Other
    differences in the chemical structure of pyrethroids have less effect
    on rates of metabolism (Soderlund and Casida, 1977).

    The pattern of metabolites varies between oral and dermal dosing in
    humans (Wilkes et al, 1993). For example, following dermal dosing with
    cypermethrin the ratio of  trans/cis cyclopropane acids excreted was
    approximately 1:1, compared to 2:1 after oral administration. Such
    measurements might be useful in determining the route of exposure
    (Woollen, 1993; Woollen et al, 1991; Woollen et al, 1992).

    Animal studies have shown that pyrethroid hydrolysis is inhibited by
    dialkylphosphorylating agents such as organophosphorus insecticides
    (Abou-Donia et al, 1996; He et al, 1990; Hutson, 1979), and urinary
    excretion of unchanged pyrethroid was higher in sprayers using a
    methamidophos/ deltamethrin or methamidophos/fenvalerate mixture than
    from those using the pyrethroid alone (Zhang et al, 1991).

    Experiments with chickens (Abou-Donia et al, 1996) showed that
    permethrin toxicity was also enhanced by pyridostigmine bromide and by
    the insect repellent N,N-diethyl-m-toluamide (DEET). The authors
    hypothesized that competition for hepatic and plasma esterases by
    these compounds led to decreased pyrethroid breakdown and increased
    transport of the pyrethroid to neural tissues.

    Elimination

    Pyrethroids are excreted mainly as metabolites in urine but a
    proportion is excreted unchanged in faeces.

    When permethrin was used in a five per cent cream to treat scabies,
    about 0.5 per cent of the total dose was excreted as metabolites in 48
    hours, but metabolites were still detectable in urine collected on day
    seven in three of ten patients, and on day 14 in one patient (van der
    Rhee et al, 1989). No detectable metabolites were found 30 or 60 days
    after patients had been treated with a powder formulation of
    permethrin for body lice (Nassif et al, 1980).

    After oral administration of cypermethrin to volunteers, peak
    excretion rates in urine were seen between eight and 24 hours, and
    about 24 per cent of the administered dose was excreted as metabolites
    (Woollen et al, 1991; Woollen et al, 1992). In human volunteer studies
    the oral administration of cypermethrin 1:1  cis/trans mixture in

    corn oil in gelatine capsules resulted in the mean excretion of 78 per
    cent of the  trans isomer and 49 per cent of the  cis isomer dose as
    free or conjugated cyclopropane carboxylic acid (Eadsforth and
    Baldwin, 1983). Alpha-cypermethrin showed similar results, with 43 per
    cent excreted as the free cyclopropane carboxylic acid in 24 hours
    (Eadsforth et al, 1988).

    After occupational exposure, deltamethrin and fenvalerate metabolites
    were detectable in urine: deltamethrin was detectable for up to 12
    hours, whereas fenvalerate was still detectable after 24 hours (Zhang
    et al, 1991). Fenvalerate metabolites were still present in the urine
    of workers five days after packaging the pyrethroid (He et al, 1988).
    In another study, deltamethrin and metabolites were detectable in
    urine early on the first day of spraying, and persisted for up to two
    days (He et al, 1991).

    In two field studies, urinary excretion of cypermethrin metabolites
    increased with time during five days of exposure (IPCS, 1989c), but
    decreased 24 hours after spraying had ceased. In another field study,
    urinary excretion of permethrin metabolites peaked in the first 24
    hours after exposure, but persisted for at least 40 hours (Asakawa et
    al, 1996). Pyrethroid metabolites could be detected in 24 hour urine
    samples of 9/12 pest control operators, and metabolites remained
    detectable for up to 3.5 days after spraying cyfluthrin (Leng et al,
    1996).

    CLINICAL FEATURES: ACUTE EXPOSURE

    Occupationally, the main route of pyrethroid absorption is through the
    skin; inhalation is much less important (Adamis et al, 1985; Chen et
    al, 1991; Zhang et al, 1991). Inhalation is more likely when
    pyrethroids are used in confined spaces (Llewellyn et al, 1996). The
    use of protective clothing can reduce dermal exposure (Chester et al,
    1987). The physical formulation also affects exposure, with inhalation
    being more important for dust and powder formulations, and dermal
    exposure more important for liquids (Llewellyn et al, 1996).

    Dermal exposure

    This is the most common route of pyrethroid exposure. Adverse effects
    manifest primarily as peripheral neurotoxicity with reversible
    hyperactivity of sensory nerve fibres (paraesthesiae), though erythema
    and pruritus are also described (see below).

    Peripheral neurotoxicity

    Paraesthesiae have been reported frequently (Table 3) particularly
    after the inappropriate handling of pyrethroids. Paraesthesiae occur
    most commonly on the face (He et al, 1991). It seems probable that
    paraesthesiae are related to the repetitive firing of sensory nerve
    endings in contaminated skin (Aldridge, 1990) and not to inflammation
    as there is little effect on neurogenic vasodilatation (Flannigan and

    Tucker, 1985b). The symptoms are exacerbated by sensory stimulation
    (heat, sun, scratching) (Aldridge, 1990), sweating or application of
    water (Tucker and Flannigan, 1983).

    In two studies, paraesthesiae were reportedly more severe after
    deltamethrin and flucythrinate exposure, less after cypermethrin and
    fenvalerate, and least after permethrin exposure (Aldridge, 1990;
    Flannigan and Tucker, 1985a). The cutaneous symptoms following
    exposure to fenvalerate may be severe enough to prevent sleeping
    (Tucker and Flannigan, 1983). Ten of 52 workers handling fenvalerate
    developed paraesthesiae compared to none handling permethrin
    (Kolmodin-Hedman et al, 1982).

    Twenty-two of 44 farmers exposed to airborne deltamethrin 2.5 per cent
    (by inhalation and skin contact) complained of "itching and burning
    sensations" on their faces, but deltamethrin in the urine was below
    0.2 µg/L, the limit of detection (Wang et al, 1988).

    Table 3. Reports of paraesthesiae after pyrethroid exposure

                                                                        
    Pyrethroid             Studies
                                                                        
    Alpha-cypermethrin     Chester et al, 1987
    Bifenthrin             Advisory Committee on Pesticides, 1989a
    Cyfluthrin             Advisory Committee on Pesticides, 1988a
    Cyhalothrin            IPCS, 1990g; IPCS, 1990a
    Cypermethrin           Chen et al, 1991; Flannigan and Tucker, 1985a;
                           He et al, 1988; IPCS, 1989c; Le Quesne et al,
                           1980
    Deltamethrin           Chen et al, 1991; He et al, 1988; He et al,
                           1989; IPCS, 1990d; Le Quesne et al, 1980; Wang
                           et al, 1988; Zhang et al, 1991
    Fenpropathrin          Boshard, 1993; Le Quesne et al, 1980
    Fenvalerate            Advisory Committee on Pesticides, 1992; Chen et
                           al, 1991; Flannigan and Tucker, 1985a; He et al,
                           1988; He et al, 1989; Knox and Tucker, 1982;
                           Knox et al, 1984; Kolmodin-Hedman et al, 1982;
                           Kolmodin-Hedman et al, 1995; Le Quesne et al,
                           1980; Tucker and Flannigan, 1983; Zhang et al,
                           1991
    Flucythrinate          Flannigan and Tucker, 1985a; Flannigan and
                           Tucker, 1985b
    Lambda-cyhalothrin     Advisory Committee on Pesticides, 1988b; 
                           Chester et al, 1992; IPCS, 1990g; Moretto, 
                           1991, Advisory Committee on Pesticides, 1993
    Permethrin             Flannigan and Tucker, 1985a; IPCS, 1990b;
                           Kolmodin-Hedman et al, 1982; Le Quesne et al,
                           1980
    Tau-fluvalinate        Advisory Committee on Pesticides, 1997
    Tefluthrin             Advisory Committee on Pesticides, 1991
                                                                        

    After treating an area with a combination of cypermethrin and
    cyfluthrin, several pesticide sprayers complained of paraesthesiae
    (Wagner, 1994). Contamination of face, hands and feet with large
    quantities of 2.5 per cent deltamethrin resulted in severe pain and
    numbness in the extremities with muscle tremor; these symptoms
    disappeared within seven days (Wang et al, 1988). One drop of 2.5 per
    cent deltamethrin dripped into an open foot wound caused local pain
    but no inflammation (He et al, 1989).

    Paraesthesiae generally start 30 minutes to two hours after exposure
    and peak after about six hours. Recovery is usually complete within 24
    hours (Aldridge, 1990; He et al, 1989; Knox and Tucker, 1982; Knox et
    al, 1984; Tucker and Flannigan, 1983).

    Dermal toxicity

    When used at recommended doses in the treatment of scabies and lice,
    pyrethroids only rarely produce adverse effects. Pruritus is the
    side-effect reported most frequently (Brandenburg et al, 1986;
    DiNapoli et al, 1988), although this may also be caused by the skin
    infestation being treated.

    Skin irritation during occupational pyrethroid exposure may occur in
    up to ten per cent of workers (Kolmodin-Hedman et al, 1982) and may be
    influenced by the ratio of stereoisomers used in the pyrethroid
    formulation, being more prevalent with a higher proportion of the
     trans isomer. In addition to pruritus, erythema, burning and
    blisters have been reported (Brandenburg et al, 1986; Kalter et al,
    1987; IPCS, 1990b; Kolmodin-Hedman et al, 1995).

    In one clinical trial of permethrin scabies treatment, none of the ten
    patients treated with 21-32 g five per cent permethrin cream reported
    any side effects (van der Rhee et al, 1989). In a second trial, 1/28
    patients treated with one per cent permethrin, developed mild
    testicular erythema and irritation 12 hours after application (Kalter
    et al, 1987). In trials of head lice treatments, only three of ten
    patients treated with 15-40 mL one per cent permethrin solution
    reported mild erythema (IPCS, 1990b). In a further study (Brandenburg
    et al, 1986) involving 287 patients given a single application of one
    per cent permethrin, pruritus was the side-effect reported most
    frequently occurring in 5.6 per cent of patients. A burning sensation
    occurred in the affected area in 3.1 per cent of cases; erythema was
    present in 1.4 per cent, and tingling occurred in 1.0 per cent of
    patients (Brandenburg et al, 1986). Ten volunteers who wore
    permethrin-treated clothes, giving an average exposure of 3.8 mg/day,
    reported no irritation (IPCS, 1990b).

    A powder formulation of phenothrin or d-phenothrin applied to the head
    and pudendal hair of eight volunteers resulted in no significant
    effects (IPCS, 1990f).

    In a double-blind study of occupational exposure, skin symptoms could
    not be related to the degree of dermal permethrin exposure
    (Kolmodin-Hedman et al, 1995). Fenvalerate (a type II pyrethroid)
    produced more symptoms than permethrin in planters handling treated
    conifer seedlings (Kolmodin-Hedman et al, 1982). Symptoms were more
    severe from permethrin formulations containing a higher proportion of
    the  trans isomer. The most common symptoms were: itching (ten per
    cent of 52 workers exposed to fenvalerate, two per cent of 45 workers
    exposed to permethrin with a  trans/cis ratio 60/40, none of 42
    workers exposed to permethrin with a  trans/cis ratio 75/25); burning
    (ten per cent, none, 12 per cent respectively); blisters (eight per
    cent, none, ten per cent respectively) and a "dry feeling in the face"
    (12 per cent, after 75/25  trans/cis permethrin exposure only).

    Five of nine employees exposed to airborne cypermethrin via an air
    conditioning system complained of pruritus (Lessenger, 1992).

    Allergic reactions to pyrethroids are uncommon. Lisi (1992) assessed
    230 volunteers for irritant or delayed contact sensitivity reactions
    to a range of pyrethroids. Two (non-atopic) patients had irritant
    reactions to five per cent resmethrin and a further two had positive
    patch tests to one per cent fenvalerate. There were no positive
    reactions to allethrin, deltamethrin, fenothrin or permethrin. In
    other patch test studies tetramethrin was neither a primary irritant
    nor skin sensitizer (IPCS, 1990e).

    In a double blind study of occupational permethrin exposure, two of 18
    workers who developed mucosal blisters, and one who had eczematous
    changes on the leg, gave negative skin tests to permethrin
    (Kolmodin-Hedman et al, 1995). Dermatitis with blisters and miliary
    papules have been reported in those occupationally exposed to
    deltamethrin (Wang et al, 1988; He et al, 1989). Possible exposure to
    spilt cypermethrin resulted in a general urticarial eruption the
    following day, which progressed to involve the eyelids (Wagner, 1994).

    Ocular exposure

    Symptoms of mild eye irritation have been reported following
    occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS,
    1990d; Lessenger, 1992).

    Transient conjunctivitis was reported among workers employed in the
    production of a deltamethrin aerosol (IPCS, 1990d).

    Eye contact with tefluthrin gave a "cold sensation" which lasted for
    about six hours (Advisory Committee on Pesticides, 1991). Eye
    irritation was also reported after permethrin was splashed in the eye
    (Kolmodin-Hedman et al, 1982).

    Employees exposed to cypermethrin via an air conditioning system
    complained of burning eyes (Lessenger, 1992).

    Inhalation

    Inhalational pyrethroid exposure typically is occupational and
    produces symptoms and signs of pulmonary tract irritation; systemic
    effects may occur following more substantial exposure (He et al, 1989)
    and are described below.

    Nineteen per cent of 52 workers handling fenvalerate-treated seedlings
    and 13 per cent of 42 workers handling permethrin ( trans/cis 75/25)-
    treated seedlings but only two per cent of 45 workers handling
    permethrin ( trans/cis 60/40)-treated seedlings complained of
    increased nasal secretions during a six hour exposure (Kolmodin-Hedman
    et al, 1982). "A slight nose tickle" has been reported after
    fenpropathrin exposure (Advisory Committee on Pesticides, 1989b;
    Boshard, 1993).

    Irritation of the respiratory tract was reported among workers
    producing an aerosol of deltamethrin (IPCS, 1990d).

    Cypermethrin, introduced inadvertently to the air conditioning ducts
    of an office building, produced wheezing and shortness of breath which
    persisted seven months after exposure in three smokers and one
    non-smoker, all with no previous pulmonary problems (Lessenger, 1992).
    One of these patients (a smoker) showed a mild restrictive pulmonary
    function defect.

    Cough and dyspnoea were also reported in six and four per cent of
    those exposed to fenvalerate and eight and two per cent of those
    exposed to permethrin (Kolmodin-Hedman et al, 1982).

    A respiratory challenge test with a formulation containing
    tetramethrin and pyrethrins produced chest tightness with severe
    non-productive cough, sneezing, rhinorrhea and lacrimation in six of
    seven patients but only one had a significant fall in FEV1 (Newton
    and Breslin, 1983).

    Ingestion

    Pyrethroid ingestion typically gives rise to nausea, vomiting and
    abdominal pain within minutes. In one series (He et al, 1989)
    involving some 344 cases, vomiting was a prominent feature in 56.8 per
    cent. The Chinese literature includes a case of erosive gastritis with
    haematemesis following ingestion of 900 mL deltamethrin solution
    (concentration not given) (Poisindex, 1996). In another case,
    permethrin/pyrethrins accidentally sprayed directly into the mouth
    resulted in a burning sensation which commenced several hours after
    exposure, and only gradually improved over five months, with
    persistent disordered taste sensation (Grant, 1993).

    Substantial pyrethroid ingestion may give rise to neurological
    features and other systemic effects as discussed below.

    Systemic effects

    Systemic effects generally have occurred after inappropriate
    occupational handling of pyrethroids. This may involve using too
    concentrated solutions, prolonged exposure, spraying against the wind
    or using unprotected hands or mouth to unblock congested sprayers (He
    et al, 1989). Most reported cases have involved dermal, inhalational
    and sometimes also oral exposure to fenveralate, deltamethrin or
    cypermethrin with systemic features occurring between four and 48
    hours after spraying (He et al, 1989). Intentional ingestion may also
    produce systemic effects (He et al, 1989; Peter et al, 1996). Most
    patients recover over two to four days with only seven fatalities
    among 573 cases in one review (He et al, 1989). Four of the seven
    fatalities developed convulsions, one patient died from
    non-cardiogenic pulmonary oedema, one from "atropine intoxication" and
    one death followed exposure to a pyrethroid/organophosphorus pesticide
    combination.

    A further death has been reported recently in a patient who became
    comatose within ten hours of 30 mL deltamethrin ingestion and died
    from aspiration pneumonia complicated by renal failure (Peter et al,
    1996).

    Gastrointestinal toxicity

    As discussed above gastrointestinal irritation is common following
    pyrethroid ingestion. Vomiting was a prominent symptom also in 16 per
    cent of  occupational cases (He et al, 1989) in whom ingestion was
    not suspected, but where exposure involved deltamethrin, cypermethrin
    or fenvalerate. In this review, which included occupational exposures,
    anorexia occurred in 45 per cent of 573 cases of acute pyrethroid
    poisoning (He et al, 1989).

    Neurotoxicity

    He et al (1989) described dizziness in 60.6 per cent, headache in 44.5
    per cent, fatigue in 26 per cent, increased salivation in 20 per cent
    and blurred vision in seven per cent of 573 cases of acute pyrethroid
    poisoning (229 occupational and 344 accidental exposures).
    Cypermethrin introduced inadvertently to the air conditioning ducts of
    an office building produced dizziness, headache and vertigo
    (Lessenger, 1992).

    Limb muscle fasciculations, coma and convulsions may complicate severe
    acute pyrethroid poisoning, and have occurred as soon as 20 minutes
    after ingestion (He et al, 1989). "Convulsions" was the stated cause
    of death in four of seven fatalities among 573 cases of acute
    pyrethroid poisoning (He et al, 1989) but further details were not
    given.

    An electromyelogram (EMG) in one case of acute pyrethroid poisoning
    (not specified) showed repetitive muscle discharges without
    denervation potentials (He et al, 1989). Transient slow and sharp
    waves with high amplitude were seen on electroencephalogram in a 23
    year-old female following three days "heavy dermal exposure" to
    deltamethrin. She did not have a seizure but complained of headache,
    nausea, dizziness, anorexia and fatigue with clinical evidence of
    muscle fasciculations (He et al, 1989). She recovered over several
    weeks with symptomatic and supportive care.

    O'Malley (1997) described a four year-old who was found unconscious
    less than 20 minutes after ingesting approximately 2 mg/kg
    deltamethrin (as a chalk containing 0.98 per cent pyrethroid). She
    recovered uneventfully within a few hours.

    A 21 year-old female developed headache and muscle fasciculations some
    five hours after ingesting 30 mL 2.5 per cent deltamethrin with
    suicidal intent (He et al, 1989). Eight hours later she developed
    convulsions which persisted for two weeks and were treated with
    diazepam and baclofen. An electromyelogram, electrocardiogram and
    electroencephalogram were normal. She was discharged in good health 21
    days after exposure.

    A 25 year-old female sprayed cotton fields for three days using a
    1:9000 dilution of 2.5 per cent deltamethrin:water, without a
    protective mask and clothing such that her clothes became "heavily
    soaked with deltamethrin" (He et al, 1989). She developed a burning,
    tingling sensation in her cheeks in association with headache,
    vomiting, limb-muscle fasciculations and convulsions (He et al, 1989).
    The initial diagnosis was acute organophosphorus insecticide poisoning
    but there was no improvement with oxime therapy. She recovered over
    four weeks with symptomatic and supportive care.

    There is animal evidence that the neurotoxicity of permethrin is
    increased by pyridostigmine and by DEET (Abou-Donia et al, 1996;
    McCain et al, 1997).

    Cardiovascular toxicity

    Palpitation was reported in 13.1 per cent of 573 cases of acute
    pyrethroid poisoning involving oral, inhalational and/or dermal
    exposure (He et al, 1989). An electrocardiogram (ECG) showed ST and T
    wave changes in eight of 71 patients. Other ECG abnormalities included
    sinus tachycardia, ventricular ectopics and (rarely) sinus bradycardia
    (He et al, 1989). All ECG changes resolved over 2-14 days.

    Pulmonary toxicity

    Chest tightness has been described following accidental or deliberate
    ingestion of deltamethrin, fenvalerate or cypermethrin (He et al,
    1989).

    Non-cardiogenic pulmonary oedema has been reported rarely following
    substantial pyrethroid ingestion, usually in association with severe
    neurological complications and may contribute to a fatal outcome (He
    et al, 1989).

    Musculoskeletal toxicity

    A case of acute polyarthralgia after skin exposure to flumethrin has
    been reported recently (Box and Lee, 1996).

    Haemotoxicity

    Among 235 cases of occupational or accidental acute pyrethroid
    poisoning in whom a full blood count was performed, 15 per cent showed
    a leucocytosis (He et al, 1989); this was probably a non-specific
    response.

    Nephrotoxicity

    Urinalysis among 124 patients with acute pyrethroid poisoning
    (involving oral, dermal and/or inhalational exposure) showed three
    patients with haematuria (He et al, 1989).

    CLINICAL FEATURES: CHRONIC EXPOSURE

    Dermal exposure

    Few long-term adverse effects from pyrethroids have been reported
    (IPCS, 1990d; Chen et al, 1991, He, 1994). There is no confirmed
    evidence that repeated exposure to pyrethroids leads to permanent
    damage to sensory nerve endings (Vijverberg and van den Bercken,
    1990).

    In plant workers dermally exposed to deltamethrin, slight desquamation
    occurred (which could be due to the hydrocarbon solvent). The
    desquamation was restricted to the area contaminated with
    deltamethrin, and was sometimes accompanied by pruritus (IPCS, 1990d).

    One hundred and ninety-nine workers employed in a pyrethroid packaging
    plant over four to five months on two occasions (winter and summer
    sessions) were observed for cutaneous effects (He et al, 1988). Work
    involved transferring pyrethroid emulsions (deltamethrin 2.5 per cent,
    fenvalerate 20 per cent and (to a lesser extent) cypermethrin ten per
    cent) in xylene, from large containers to fill some 50,000 100 mL
    bottles daily. Gloves (and gauze masks) were used in winter only with
    no protective measures in summer. One hundred and forty of 199 (70 per
    cent) workers complained of "abnormal facial sensation" with burning,
    tingling, itching, tightness or numbness. Symptoms were more prevalent
    (p<0.05) in summer, occurring in 92 per cent of summer workers (n=87)
    compared to only 54 per cent of winter workers (n=112). Red miliary,
    mildly pruritic papules were found in 14 per cent of all workers,
    mainly on the face and chest and again were more prevalent (p<0.05)

    in summer. This was probably due to increased sweating during summer
    months (which tends to exacerbate cutaneous symptoms), but may also
    have been contributed to by the absence of protective measures during
    summer (He et al, 1988). The symptoms described in this study are
    identical to those following acute pyrethroid exposure and did not
    last more than 24 hours once subjects were away from the work
    environment. This suggests there are no true  chronic effects from
    repeated pyrethroid exposure.

    Inhalation

    The 199 workers described above were exposed to estimated fenvalerate
    and deltamethrin ambient air concentrations of 0.012-0.055 mg/m3 and
    0.005-0.012 mg/m3 respectively. Sixty-four (32 per cent) complained
    of sneezing and increased nasal secretions but these symptoms were
    only present at work, again suggesting no difference in effect between
    chronic or acute pyrethroid exposure. Systemic symptoms of dizziness,
    fatigue and nausea were mild and reported by only 14, nine and ten per
    cent of workers respectively.

    MANAGEMENT

    Dermal exposure

    Decontamination

    Clothes contaminated with pyrethroids should be removed, and
    contaminated skin washed with soap and water (He, 1994).

    Specific measures

    Topical alpha tocopherol (vitamin E) to treat paraesthesiae
    As paraesthesiae usually resolve in 12-24 hours, specific treatment is
    not generally administered or required. However, the topical
    application of  dl-alpha tocopherol acetate (vitamin E) has been
    shown to reduce the severity of skin reactions to fenvalerate (IPCS,
    1990c; Tucker et al, 1984; Tucker et al, 1983), flucythrinate,
    permethrin and cypermethrin (Flannigan and Tucker, 1985a). The
    reaction to cypermethrin was completely inhibited by vitamin E
    (Flannigan et al, 1985). Vitamin E appears to be useful both
    prophylactically and therapeutically (Flannigan and Tucker, 1985a). In
    a controlled human volunteer study, a commercial vitamin E oil
    preparation produced 98 per cent inhibition of the cutaneous symptoms
    from fenvalerate when applied immediately (Flannigan et al, 1985). At
    four hours the inhibition was only 50 per cent (Advisory Committee on
    Pesticides, 1992). The mechanism of the effect of topical vitamin E
    has not been clarified, although some  in vitro studies suggest
    vitamin E may block the pyrethroid-induced sodium "tail current" in
    neuronal membranes (Song and Narahashi, 1995).

    Vitamin E is not included in the British National Formulary but is
    available from health food or alternative medicine sources.

    Other agents to treat paraesthesiae

    Various other topical therapies have been tested for treatment of
    pyrethroid-induced paraesthesiae: in human trials mineral oil, corn
    oil and "A&D ointment" (Tucker et al, 1984; Tucker et al, 1983) were
    almost as effective as Vitamin E cream (but the oils may lead to
    defatting of skin). Butylated hydroxyanisole and an industrial barrier
    cream (Tucker et al, 1984) and topical indomethacin (Flannigan and
    Tucker, 1984) were of little therapeutic benefit and in two studies
    zinc oxide paste exacerbated paraesthesiae (Tucker et al, 1984; Tucker
    et al, 1983).

    Ocular exposure

    Irrigate the affected eye with lukewarm water or 0.9 per cent saline
    for at least ten minutes. A topical anaesthetic may be required for
    pain relief or to overcome blepharospasm. Ensure no particles remain
    in the conjunctival recesses. Use fluorescein if corneal damage is
    suspected. If symptoms do not resolve following decontamination or if
    a significant abnormality is detected during examination, seek an
    ophthalmological opinion.

    Inhalation

    Removal from exposure is the priority. Mild symptoms of rhinitis
    respond to oral antihistamines. Other symptomatic and supportive
    measures should be dictated by the patient's condition.

    Ingestion

    Gut decontamination

    Gastric lavage should be avoided since solvents present in many
    formulations may increase the risk of aspiration pneumonia.

    Systemic toxicity

    Most patients exposed to pyrethroids require only simple supportive
    care. Systemic toxicity is rare but in such patients the presence of
    excess salivation, muscle fasciculations and pulmonary oedema may
    present diagnostic difficulty since similar features are typical also
    of severe organophosphorus pesticide poisoning. Measurement of the red
    cell cholinesterase activity (which is reduced in acute
    organophosphorus poisoning but not in pyrethroid intoxication) allows
    clarification but may not be available rapidly.

    Isolated brief convulsions do not require treatment but intravenous
    diazepam 5-10 mg should be given if seizures are prolonged. Rarely it
    may be necessary to give intravenous phenytoin, or to paralyze and
    ventilate the patient. Diazepam is useful also in the treatment of
    muscle fasciculations. The role of atropine is discussed below.

    Several experimental studies have investigated the role of
    pharmaceuticals in the management of the neurological complications of
    severe pyrethroid poisoning. However, these should be interpreted with
    caution, not only because they usually have involved high-dose
    parenteral pyrethroid administration, but also because there is
    considerable interspecies variation with regard to therapeutic
    efficacy (Casida et al, 1983; Vijverberg and van den Bercken, 1990).

    Atropine for hypersalivation and pulmonary oedema

    In experimental studies atropine sulphate (25 mg/kg subcutaneously)
    reduced hypersalivation produced by oral fenvalerate or cypermethrin
    (each at a dose exceeding the LD50), but did not increase survival
    (Hiromori et al, 1986).

    Intravenous atropine (0.6-1.2 mg in an adult) may be useful to control
    excess salivation but care should be taken to avoid excess
    administration. In a review of pyrethroid poisoning cases reported
    from China (He et al, 1989), 189 of 573 patients were treated with
    atropine which led to an improvement in salivation and pulmonary
    oedema in a few severe cases, but eight patients developed atropine
    intoxication following intravenous administration of 12-75 mg. One
    patient, probably misdiagnosed as having acute organophosphorus
    insecticide poisoning, died of atropine intoxication after a total
    dose of 510 mg, and one patient acutely intoxicated with a
    fenvalerate/dimethoate mixture could not be revived despite a total
    atropine dose of 170 mg.

    Atropine and ethylcarbamate

    In a French study a combination of intravenous atropine 3 mg/kg and
    ethylcarbamate 1000 mg/kg effectively protected rodents against the
    lethal effects of intravenous deltamethrin, increasing the LD50 by a
    factor of 3.48 (Leclercq et al, 1986).

    Diazepam and phenobarbital for convulsions

    In mice (n=10) pre-treatment with intraperitoneal diazepam (1 mg/kg),
    but not phenobarbital (10-30 mg/kg), significantly increased the time
    to onset of convulsions caused by the intracerebroventricular
    administration of deltamethrin (p<0.005) and fenvalerate (p<0.05)
    (Gammon et al, 1982). Under the same conditions diazepam was not
    effective in preventing permethrin- or allethrin-induced seizures.

    Propranolol and procainamide for tremor

    Pre-treatment with intravenous propranolol or procainamide (each 15
    µmol/kg) reduced the severity of tremor or writhing induced in rats by
    the intravenous administration of deltamethrin (10 µmol/kg) (Bradbury
    et al, 1983).

    Ivermectin and pentobarbital for choreoathetosis

    In rodents administered 2 mg/kg intravenous deltamethrin,
    pre-treatment with 4 mg/kg intravenous ivermectin reduced
    choreoathetosis from 3.9 to 3.2 (as graded on a scale of 1-4) 
    (p = 0.023), and reduced salivation by 72 per cent. Pentobarbital 
    (15 mg/kg i.p.) reduced choreoathetosis produced by 1.5 mg/kg
    intravenous deltamethrin from 3.0 to 1.3 (p = 0.004). An equi-sedative
    dose of phenobarbital produced a non-significant fall to 2.4 
    (p = 0.11) (Forshaw and Ray, 1997).

    Mephenesin and methocarbamol

    The skeletal muscle relaxant mephenesin 22 µmol/kg prevented all motor
    symptoms induced in rats by the intravenous administration of
    deltamethrin (10 µmol/kg) (n=4-20 in different treatment groups)
    (Bradbury et al, 1983).

    Mephenesin has a short half-life in vivo, but intraperitoneal
    methocarbamol (a mephenesin derivative) (400 mg/kg intraperitoneally
    followed by 200 mg/kg whenever tremor was observed) significantly
    (p<0.01) reduced mortality in rats administered more than the oral
    LD50 of fenvalerate, fenpropathrin, cypermethrin or permethrin (n=10
    in each treatment group) (Hiromori et al, 1986).

    There are insufficient data to advocate a clinical role for
    methocarbamol in systemic pyrethroid toxicity.

    Sodium-channel blockers (local anaesthetics)

     In vitro studies suggest local anaesthetics may be useful as
    antagonists of the effect of deltamethrin on sodium channels
    (Oortgiesen et al, 1990). The relevance to human poisoning is not
    known.

    MEDICAL SURVEILLANCE

    Although blood and urine pyrethroid/pyrethroid metabolite
    concentrations are useful as biological exposure indicators for
    research purposes, avoiding dermal and inhalational exposure via
    adequate self-protection and sensible use is the most important
    requirement to reduce adverse effects from occupational pyrethroid
    use.

    OCCUPATIONAL DATA

    Maximum exposure limit

    International Standards Organization (ISO) limits for natural
    pyrethrins: long-term exposure limit (8 hour TWA reference period) 5
    mg/m3, short term exposure (15 min ref period) 10 mg/m3 (Health
    and Safety Executive, 1995).

    OTHER TOXICOLOGICAL DATA

    Endocrine toxicity

     In vitro studies show that several pyrethroids interact
    competitively with human skin fibroblast androgen receptors and with
    sex hormone binding globulin (with the relative potency being
    bioallethrin > fenvalerate > fenothrin > fluvalinate > permethrin
    > resmethrin) (Eil and Nisula, 1990). A possible anti-androgenic
    effect of pyrethroids in humans was suggested following an outbreak of
    gynaecomastia in refugees exposed to fenothrin, but there was
    insufficient evidence to confirm this (Eil and Nisula, 1990).

    Animal studies regarding other endocrine effects of pyrethroids have
    produced conflicting results. For example oral bifenthrin 0.5 mg daily
    or lambda-cyhalothrin 0.2 mg daily for 21 days suppressed serum
    tri-iodothyronine and thyroxine concentrations with concomitant
    stimulation of thyrotrophin in rats (Akhtar et al, 1996), whereas
    intraperitoneal fenvalerate 100-200 mg/kg body weight daily for 45
    days increased circulating tri-iodothyronine and thyroxine
    concentrations (Kaul et al, 1996).

    Immunotoxicity

    In oral dosing studies in rodents, supercypermethrin at 1/14 LD50
    for 28 days suppressed the cellular immune response (Tulinská et al,
    1995) as did permethrin at one per cent LD50 for ten days (Blaylock
    et al, 1995).

    Oral deltamethrin 5-10 mg/kg body weight daily for 28 days produced
    thymus atrophy in rodents (Madsen et al, 1996) and a single
    intraperitoneal dose of deltamethrin 6-50 mg/kg also caused a
    reduction in thymus weight, which was dose- and time-dependant
    (maximum effect two weeks after dosing) (Enan et al, 1996).

    The significance of these immunological studies to man are not known.

    Carcinogenicity

    The International Agency for Research on Cancer has concluded there is
    inadequate evidence to assess the carcinogenicity of deltamethrin
    (IARC, 1991b), fenvalerate (IARC, 1991a) or permethrin (IARC, 1991c).

    In a variety of animal studies there was no evidence for
    carcinogenicity for the following pyrethroids: allethrin and its
    isomers (IPCS, 1989a), cyhalothrin or lambda-cyhalothrin (IPCS,
    1990a), cypermethrin (IPCS, 1989c), deltamethrin (IPCS, 1990d),
    prallethrin (Advisory Committee on Pesticides, 1995), resmethrin and
    its isomers (IPCS, 1989b).

    Reprotoxicity

    In a variety of animal studies, there were no indications of
    teratogenicity, embryotoxicity or fetotoxicity for the following
    pyrethroids: allethrin (and isomers) (IPCS, 1989a), bifenthrin
    (Advisory Committee on Pesticides, 1989a), cyfluthrin (Advisory
    Committee on Pesticides, 1988a), cyhalothrin (IPCS, 1990a)
    cypermethrin (IPCS, 1989c), deltamethrin (IPCS, 1990d), fenopropathrin
    (Advisory Committee on Pesticides, 1989b), fenvalerate (Advisory
    Committee on Pesticides, 1992, IPCS, 1990c), tau-fluvalinate (Advisory
    Committee on Pesticides, 1997) permethrin (IPCS, 1990b), d-phenothrin
    (IPCS, 1990f), prallethrin (Advisory Committee on Pesticides, 1995),
    resmethrin (and isomers) (IPCS, 1989b), tefluthrin (Advisory Committee
    on Pesticides, 1991) or tetramethrin (IPCS, 1990e).

    Genotoxicity

    Data regarding the potential genotoxicity of pyrethroids provide
    conflicting results (Puig et al, 1989; Barrueco et al, 1992; Herrera
    et al, 1992; Dolara et al, 1992; Barrueco et al, 1994; Surrallés et
    al, 1995), though toxicity reviews of  in vitro and  in vivo data
    for most compounds conclude there is insufficient evidence for them to
    be considered genotoxic or mutagenic. Pyrethroids for which this is
    the case include allethrin (IPCS, 1989a), bifenthrin (Advisory
    Committee on Pesticides, 1989a), cyfluthrin (Advisory Committee on
    Pesticides, 1988a), cyhalothrin (IPCS, 1990a) or lambda-cyhalothrin
    (Advisory Committee on Pesticides, 1988b, 1993), deltamethrin (IPCS,
    1990d), fenpropathrin (Advisory Committee on Pesticides, 1989b),
    fenvalerate (IPCS, 1990c) or esfenvalerate (Advisory Committee on
    Pesticides, 1992), tau-fluvalinate (Advisory Committee on Pesticides,
    1997), permethrin (IPCS, 1990b), d-phenothrin (IPCS, 1990f),
    prallethrin (Advisory Committee on Pesticides, 1995) resmethrin (IPCS,
    1989b), tefluthrin (Advisory Committee on Pesticides, 1997),
    tetramethrin (IPCS, 1990e).

    Cypermethrin showed some mutagenicity  in vivo in mouse and Chinese
    hamster bone marrow, although it showed no evidence of mutagenicity in
     in vitro studies (IPCS, 1989c).

    Fish toxicity

    Pyrethroids are more toxic at cooler temperatures, and thus more toxic
    to cold than warm water fish, but toxicity is little affected by pH or
    water hardness (Mauck et al, 1976).

    Some examples of specific fish toxicity data for commonly encountered
    pyrethroids are given here. See individual pyrethroid monographs for
    other specific data.

    Cypermethrin:

    LC50 (96 hr) for brown trout is 2-2.8 µg/L.
    LC50 (96 hr) for Atlantic salmon is 2-2.4 µg/L (DOSE, 1997).

    Deltamethrin:

    LC50 (96 hr) for minor carp, rainbow trout, cichlid, pumpkinseed
    sunfish range from 0.5-1.8 µg/L (DOSE, 1997).

    Fenvalerate:

    LC50 (24 hr) for rainbow trout and carp are between 20 and 76 µg/L.

    Exposure to fenvalerate 10µg/L for 6-48 hours inhibited magnesium and
    sodium-potassium ATPases in the gill, brain, liver and muscle of carp
    (DOSE, 1997).

    Permethrin:

    LC50 (48 hr) for rainbow trout and bluegill sunfish are 5.4 and 1.8
    µg/L respectively.

    LC50 (96 hr) for channel catfish, largemouth bass, brook trout and
    desert pupfish are 1.1, 8.5, 3.2 and 5.0 µg/L respectively.

    Permethrin in a concentration of 1.25, 2.5, 5.0, 10, 20 and 40 µg/L
    had no effect on sheepshead minnow embryo survival. Fry were
    unaffected by permethrin 10 µg/L but only 19 per cent survived at 20
    µg/L (DOSE, 1997).

    EC Directive on Drinking Water Quality 80/778/EEC

    Maximum admissible concentration (any pesticide) 0.1 µg/L (EC
    Directive, 1980).

    AUTHORS

    SA Cage MSc M Inst Inf Sci
    SM Bradberry BSc MB MRCP
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH
    UK

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. 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

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