UKPID MONOGRAPH
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.
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).
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).
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
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
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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Int Arch Occup Environ Health 1985; 56: 299-305.
Advisory Committee on Pesticides.
Evaluation number 3: Cyfluthrin.
London: Ministry of Agriculture Fisheries and Food, 1988a.
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