UKPID MONOGRAPH
LAMBDA-CYHALOTHRIN
SA Cage MSc M Inst Inf Sci
SM Bradberry BSc MB MRCP
S Meacham BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
LAMBDA-CYHALOTHRIN
Toxbase summary
Type of product
Insecticide
Toxicity
Dermal and inhalational exposures are associated usually with no or
only mild adverse effects. Following substantial ingestion, patients
may develop coma, convulsions and severe muscle fasciculations and may
take several days, occasionally weeks, to recover.
Fatalities have occurred rarely after pyrethroid exposure, usually
following ingestion (He et al, 1989). No known fatalities have been
reported after lambda-cyhalothrin exposure.
Features
Dermal exposure
- Tingling and pruritus with blotchy erythema on the face or
other exposed areas, exacerbated by sweating or touching.
Systemic toxicity may ensue following substantial exposure
(see below).
Ocular exposure
- Lacrimation and transient conjunctivitis may occur.
Inhalation
Brief exposure:
- Respiratory tract irritation with cough, mild dyspnoea,
sneezing and rhinorrhea.
Substantial and prolonged exposure:
- Systemic toxicity may ensue - see below.
Ingestion
- May cause nausea, vomiting and abdominal pain. Systemic
toxicity may ensue following substantial ingestion (see
below).
Systemic toxicity
- Systemic symptoms may develop after widespread dermal
exposure, prolonged inhalation or ingestion. Features
include headache, dizziness, anorexia and hypersalivation.
- Severe poisoning is uncommon. It usually follows
substantial ingestion and causes impaired consciousness,
muscle fasciculations, convulsions and, rarely, non-
cardiogenic pulmonary oedema.
Chronic exposure
- Long-term exposure is no more hazardous than short-term
exposure.
Management
Dermal
1. Remove soiled clothing and wash contaminated skin with soap and
water.
2. Institute symptomatic and supportive measures as required.
3. Topical vitamin E (tocopherol acetate) has been shown to reduce
skin irritation if applied soon after exposure (Flannigan et al,
1985), but it is not available as a pharmaceutical product in the
UK.
4. Symptoms usually resolve within 24 hours without specific
treatment.
Ocular
1. Irrigate with lukewarm water or 0.9 per cent saline for at least
ten minutes.
2. A topical anaesthetic may be required for pain relief or to
overcome blepharospasm.
3. Ensure no particles remain in the conjunctival recesses.
4. Use fluorescein stain if corneal damage is suspected.
5. If symptoms do not resolve following decontamination or if a
significant abnormality is detected during examination, seek an
ophthalmological opinion.
Inhalation
1. Remove to fresh air.
2. Institute symptomatic and supportive measures as required.
Ingestion
1. Do not undertake gastric lavage because solvents are present in
some formulations and lavage may increase risk of aspiration
pneumonia.
2. Institute symptomatic and supportive measures as required.
3. Atropine may be of value if hypersalivation is troublesome,
0.6-1.2 mg for an adult, 0.02 mg/kg for a child.
4. Mechanical ventilation should be instituted if non-cardiogenic
pulmonary oedema develops.
5. Isolated brief convulsions do not require treatment but
intravenous diazepam should be given if seizures are prolonged or
recur frequently. Rarely, it may be necessary to give intravenous
phenytoin or to paralyze and ventilate the patient.
References
Box SA, Lee MR.
A systemic reaction following exposure to a pyrethroid insecticide.
Hum Exp Toxicol 1996; 15: 389-90.
Flannigan SA, Tucker SB, Key MM, Ross CE, Fairchild EJ, Grimes BA,
Harrist RB.
Synthetic pyrethroid insecticides: a dermatological evaluation.
Br J Ind Med 1985; 42: 363-72.
He F, Wang S, Liu L, Chen S, Zhang Z, Sun J.
Clinical manifestations and diagnosis of acute pyrethroid poisoning.
Arch Toxicol 1989; 63: 54-8.
Lessenger JE.
Five office workers inadvertently exposed to cypermethrin.
J Toxicol Environ Health 1992; 35: 261-7.
O'Malley M.
Clinical evaluation of pesticide exposure and poisonings.
Lancet 1997; 349: 1161-6.
Substance name
Lambda-cyhalothrin
Origin of substance
Cyhalothrin was developed in 1977 as a mixture of four
stereoisomers. Lambda-cyhalothrin consists of a pair of isomers
of cyhalothrin and is more biologically active than cyhalothrin
(IPCS, 1990a). Lambda cyhalothrin was first approved for use in
the UK in 1988 (Advisory Committee on Pesticides, 1988).
Synonyms/Proprietary names
Cyhalothrin K
Hallmark
Hero
Icon
Karate
Landgold Lambda-C
PP321
Standon Lambda-C
Warrior (RTECS, 1997; Pesticide
Manual, 1997; Pesticides 1997,
1997; The UK Pesticide Guide,
1997)
Chemical group
Type II synthetic pyrethroid
Reference numbers
CAS 91465-08-6 (Pesticide Manual, 1997)
RTECS GZ1227780 (RTECS, 1997)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
IUPAC name: alpha-cyano-3-phenoxybenzyl (Z)-(1RS)- cis 3-(2-
chloro-3,3,3-trifluoropropenyl)-2,2-
dimethylcyclopropanecarboxylate
C23H19ClF3NO3 (Pesticide Manual, 1997)
Molecular weight
449.9 (Pesticide Manual, 1997)
Physical state at room temperature
Solid. Technical grade is a solidified melt.
(Pesticide Manual, 1997)
Colour
Beige. Technical grade is dark brown/green.
(Pesticide Manual, 1997)
Odour
Mild (IPCS, 1990a)
Viscosity
NIF
pH
NIF
Solubility
Low solubility in water: purified water 5 x 10 -6 g/L (pH 6.5);
buffered water 4 x 10 -6 g/L (pH 5.0)
Acetone 500 g/L
Methanol 500 g/L
Toluene 500 g/L
Hexane 500 g/L
Ethyl acetate 500 g/L (Pesticide Manual, 1997)
Autoignition temperature
NIF
Chemical interactions
NIF
Major products of combustion
Combustion and/or pyrolysis of lambda-cyhalothrin can lead
potentially to the production of compounds such as formaldehyde,
acrolein, hydrogen cyanide, hydrogen chloride and hydrogen
fluoride (Hartzell, 1996).
Explosive limits
NIF
Flammability
Burns with difficulty. (Pesticide Manual, 1997)
Boiling point
NIF
Density
1.33 at 25°C (Pesticide Manual, 1997)
Vapour pressure
2 x10-7 Pa at 20°C
2 x 10-4 Pa at 60°C (Pesticide Manual, 1997)
Relative vapour density
NIF
Flash point
NIF
Reactivity
NIF
Uses
Lambda-cyhalothrin controls a wide range of insect pests. It also
provides good control of insect-borne plant viruses (Pesticide
Manual, 1997).
Hazard/risk classification
NIF
INTRODUCTION
Pyrethrins were developed as pesticides from extracts of dried and
powdered flower heads of Chrysanthemum cinerariaefolium. The active
principles of these (see Fig. 1) are esters of chrysanthemumic acid
(R1 = CH3) or pyrethric acid (R1 = CH3O2C) (both cyclopropane
(three membered ring) carboxylic acids), with one of three
cyclopentanone alcohols (cinerolone, R2 = CH3; jasomolone, R2 =
CH2CH3; or pyrethrolone, R2 = CHCH2), giving six possible
structures. These natural pyrethrins have the disadvantage that they
are rapidly decomposed by light.
Once the basic structure of the pyrethrins had been discovered,
synthetic analogues, pyrethroids, were developed and tested. Initially
esters were produced using the same cyclopropane carboxylic acids,
with variations in the alcohol portion of the compounds.
The first commercial synthetic pyrethroid, allethrin, was produced in
1949, followed in the 1960s by others including dimethrin,
tetramethrin and resmethrin. 3-Phenoxybenzyl esters were also found to
be active as pesticides (e.g phenothrin, permethrin). Synthetic
pyrethroids with 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 below).
The insecticidal activity of synthetic pyrethroids was enhanced
further by the addition of a cyano group at the benzylic carbon atom
to give alpha-cyano (type II) pyrethroids including cyhalothrin. In
animal studies type II pyrethroids have been shown generally to
produce a typical toxic syndrome (see below).
Despite the lack of the cyclopropane ring, similar insecticidal
activity was found in a group of phenylacetic 3-phenoxybenzyl esters.
This led to the development of fenvalerate, an
alpha-cyano-3-phenoxy-benzyl ester, and other related compounds such
as fluvalinate. These all contain the alpha-cyano group and hence are
type II pyrethroids.
Animal studies suggest that the two structural types of pyrethroids
give rise generally to distinct patterns of systemic toxic effects.
Type I pyrethroids produce in animals the so-called "T (tremor)
syndrome", characterized by tremors, prostration and altered "startle"
reflexes. Type II (alpha-cyano) pyrethroids produce the so-called "CS
(choreoathetosis/salivation) syndrome" with ataxia, convulsions,
hyperactivity, choreoathetosis and profuse salivation being observed
in experimental studies.
These observations are consistent with some differences in the
mechanisms of toxicity between type I and type II pyrethroids (see
below) but the division of reactions by chemical structure is not
exclusive. Some compounds produce a combination of the two syndromes,
and different stereoisomeric forms can produce different syndromes
(Dorman and Beasley, 1991). The classification into "T" and "CS"
syndromes is not used clinically.
All pyrethroids have at least four stereoisomers, with different
orientation of the substituents on the cyclopropane ring (or the
equivalent part of the phenylacetate). The isomers have different
biological activities, as discussed below (see Mechanisms of
toxicity). Different isomers may have separate common names,
reflecting their commercial importance (Aldridge et al, 1978).
Lambda-cyhalothrin consists of a pair of isomers of cyhalothrin and is
a more potent insecticide than cyhalothrin.
Further details are given in the pyrethroid generic monograph.
EPIDEMIOLOGY
In 1989-1990, world-wide annual production of pyrethroids was at least
2000 tonnes (IPCS, 1989a; IPCS, 1989b; IPCS, 1989c; IPCS, 1990a; IPCS,
1990b; IPCS, 1990c; IPCS, 1990d; IPCS, 1990e; IPCS, 1990f).
In spite of their long history of use, there are relatively few
reports of pyrethroid, and specifically lambda-cyhalothrin, toxicity.
Less than ten deaths have been reported from ingestion or occupational
(primarily dermal/inhalational) pyrethroid exposure with no deaths
from lambda-cyhalothrin exposure (He et al, 1989; Peter et al, 1996).
MECHANISMS OF TOXICITY
In neuronal cells the generation of an action potential by membrane
depolarization involves the opening of cell membrane sodium channels
and a rapid increase in sodium influx. The closure of sodium channels
begins the process of action potential inactivation. Delayed sodium
channel closure thus increases cell membrane excitability.
Pyrethroids modify the gating characteristics of voltage-sensitive
sodium channels in mammalian and invertebrate neuronal membranes
(Eells et al, 1992; Narahashi, 1989) to delay their closure. They are
dissolved in the lipid phase of the membrane (Narahashi, 1996) and
bind to a receptor site on the alpha sub-unit of the sodium channel
(Trainer et al, 1997). This binding is to a different site from local
anaesthetics, batrachotoxin, grayanotoxin, and tetrodotoxin
(Narahashi, 1996).
The interaction of pyrethroids with sodium channels is highly
stereospecific (Soderlund and Bloomquist, 1989), with the 1R and 1S
cis isomers binding competitively to one site and the 1R and 1S
trans isomers binding non-competitively to another. The 1S forms do
not modify channel function but do block the effect of the 1R isomers
(Ray, 1991).
The prolonged opening of sodium channels by the neurotoxic isomers of
pyrethroids produces a protracted sodium influx which is referred to
as a sodium "tail current" (Miyamoto et al, 1995; Soderlund and
Bloomquist, 1989; Vijverberg and van den Bercken, 1982). This lowers
the threshold of sensory nerve fibres for the activation of further
action potentials, leading to repetitive firing of sensory nerve
endings (Vijverberg and van den Bercken, 1990) which may progress to
hyperexcitation of the entire nervous system (Narahashi et al, 1995).
At high pyrethroid concentrations, the sodium "tail current" may be
sufficiently great to depolarize the nerve membrane completely,
generating more open sodium channels (Eells et al, 1992) and
eventually causing conduction block.
Only low pyrethroid concentrations are necessary to modify sensory
neurone function. For example, when tetramethrin was added to a
preparation of rat cerebellar Purkinje neurons, only about 0.6-1 per
cent of sodium channels needed to be modified to produce:
(i) Repetitive discharges in nerve fibres and nerve terminals;
(ii) An increase in discharges from sensory neurons (due to membrane
depolarization); and
(iii) Severe disturbances of synaptic transmission (Narahashi, 1989;
Narahashi et al, 1995; Song and Narahashi, 1996).
These effects on sodium channels are common to all pyrethroids
although specific effects of type II pyrethroids such as
lambda-cyhalothrin have been clarified in experimental studies. These
show that type II compounds:
(i) Cause depolarization of myelinated nerve membranes without
repetitive discharges (Dorman and Beasley, 1991; Vijverberg and
van den Bercken, 1982);
(ii) Are associated with a decrease in action potential amplitude
(Dorman and Beasley, 1991);
(iii) Stabilize a variety of sodium channel states by reducing
transition rates between them (Dorman and Beasley, 1991; Eells
et al, 1992; Narahashi, 1989), causing a greatly prolonged open
time (Vijverberg and van den Bercken, 1982), and producing
stimulus-dependent nerve depolarization and block (Soderlund
and Bloomquist, 1989);
(iv) May act post-synaptically by interacting with nicotinic
acetylcholine and GABA receptors (Dorman and Beasley, 1991;
Eells et al, 1992);
(v) Produce effects on cultured neurons that are largely
irreversible after washing cells with a pyrethroid-free
solution (Song et al, 1996).
In addition, type II pyrethroids, such as deltamethrin, enhance
noradrenaline (norepinephrine) release (Clark and Brooks, 1989).
In human investigations, maximal conduction velocity in sensory nerve
fibres of the sural nerve showed some increase in subjects exposed to
pyrethroids, but there were no abnormal neurological signs, and other
electrophysiological studies were normal in the arms and legs (Le
Quesne et al, 1980). He et al (1991) assessed nerve excitability using
an electromyograph and pairs of stimuli at variable intervals. They
showed a prolongation of the "supernormal period" in the median nerve
in individuals who had been exposed to pyrethroids occupationally for
three days. The "supernormal period" was even more prolonged two days
after cessation of exposure. (Note: the "supernormal period" is the
period for which the action potential induced by a second stimulus is
greater than the action potential produced by an initial stimulus).
Pyrethroids are some 2250 times more toxic to insects than mammals.
This can be explained in terms of differences in their potency as
neuronal toxins and differences in rates of detoxification between
invertebrates and vertebrates (Narahashi, 1996; Narahashi et al, 1995;
Song and Narahashi, 1996).
The sensitivity of invertebrate neuronal sodium channels to
pyrethroids is ten times greater than in mammals (Song and Narahashi,
1996). Furthermore, invertebrates typically have body temperatures
some 10°C lower than mammals and in vitro studies show tetramethrin
to be more potent at evoking repetitive neuronal discharges at lower
temperatures (Song and Narahashi, 1996). In these experiments it was
noted that the recovery of sodium channels from tetramethrin
intoxication after washing was some five times faster in mammals than
invertebrates. In addition pyrethroid hepatic metabolism
(detoxification) is faster in mammals. Finally small insect size
increases the likelihood of end-organ (neuronal) toxicity prior to
detoxification (Song and Narahashi, 1996).
TOXICOKINETICS
In addition to the important differences between invertebrates and
vertebrates outlined above, the low toxicity of pyrethroid
insecticides in mammals is due to poor dermal absorption (the main
route of exposure) and metabolism to non-toxic metabolites (Bradbury
and Coats, 1989).
Absorption
Dermal
Based on excretion studies involving other pyrethroids (Nassif, et al,
1980; Chester et al, 1987; Eadsforth et al, 1988; IPCS, 1989c; Woollen
et al, 1991; Woollen et al, 1992) dermal absorption of
lambda-cyhalothrin is likely to be low (less than 1.5 per cent).
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). After handling
(with gloves) more than six litres 2.5 per cent lambda-cyhalothrin
while impregnating 512 mosquito nets during six consecutive days, two
operators had extremely low blood concentrations (0.009-0.011 ng/µL)
of one of the metabolites of lambda-cyhalothrin, with undetectable
urine concentrations (Baskaran et al, 1992).
Oral
Between 19 and 57 per cent of orally administered cypermethrin
(another type II pyrethroid) was absorbed in human studies (Woollen et
al, 1991; Woollen et al, 1992). There are no human data specific to
lambda-cyhalothrin.
Metabolism
Pyrethroids are hydrolyzed rapidly in the liver to their inactive acid
and alcohol components (Hutson, 1979; Ray, 1991), probably by
microsomal carboxylesterase (Hutson, 1979). Further degradation and
hydroxylation of the alcohol at the 4' position then occurs, and
oxidation produces a wide range of metabolites (Hutson, 1979; Leahey,
1985).
There is some stereospecificity in metabolism, with trans-isomers
being hydrolyzed more rapidly than the cis-isomers, for which
oxidation is the more important metabolic pathway (Soderlund and
Casida, 1977). Although the alpha-cyano group reduces the
susceptibility of the molecule to hydrolytic and oxidative metabolism
(Hutson, 1979; Soderlund and Casida, 1977), the cyano group is
converted to the corresponding aldehyde (with release of the cyanide
ion), followed by oxidation to the carboxylic acid, sufficiently
rapidly for efficient excretion by mammals (Leahey, 1985). Other
differences in the chemical structure of pyrethroids have less effect
on rates of metabolism (Soderlund and Casida, 1977).
The pattern of metabolites varies between oral and dermal dosing in
humans (Wilkes et al, 1993). For example, following dermal dosing with
cypermethrin (another type II pyrethroid) the ratio of trans/cis
cyclopropane acids excreted was approximately 1:1, compared to 2:1
after oral administration. Such measurements might be useful in
determining the route of exposure (Woollen et al, 1991; Woollen et al,
1992; Woollen, 1993).
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
pyrethoid (permethrin) toxicity was also enhanced by pyridostigmine
bromide and by the insect repellent N,N-diethyl-m-toluamide (DEET).
The authors hypothesized that competition for hepatic and plasma
esterases by these compounds led to decreased pyrethroid breakdown and
increased transport of the pyrethroid to neural tissues.
Elimination
Pyrethroids are excreted mainly as metabolites in urine but a
proportion is excreted unchanged in faeces. An overview of human
pyrethroid elimination data is included in the generic pyrethroid
monograph though there are no human data specific to
lambda-cyhalothrin.
CLINICAL FEATURES: ACUTE EXPOSURE
Occupationally, the main route of pyrethroid absorption is through the
skin; inhalation is much less important (Adamis et al, 1985; Chen et
al, 1991; Zhang et al, 1991). Inhalation is more likely when
pyrethroids are used in confined spaces (Llewellyn et al, 1996). The
use of protective clothing can reduce dermal exposure (Chester et al,
1987). The physical formulation also affects exposure, with inhalation
being more important for dust and powder formulations, and dermal
exposure more important for liquids (Llewellyn et al, 1996).
Dermal exposure
This is the most common route of pyrethroid exposure. Adverse effects
manifest primarily as peripheral neurotoxicity with reversible
hyperactivity of sensory nerve fibres (paraesthesiae), though erythema
and pruritus are also described (see below).
Peripheral neurotoxicity
Paraesthesiae have been reported frequently particularly after the
inappropriate handling of lambda-cyhalothrin (Advisory Committee on
Pesticides, 1988b; IPCS, 1990g; Moretto, 1991; Chester et al, 1992;
Advisory Committee on Pesticides, 1993). Paraesthesiae occur most
commonly on the face (He et al, 1991). It seems probable that
paraesthesiae are related to the repetitive firing of sensory nerve
endings in contaminated skin (Aldridge, 1990) and not to inflammation
as there is little effect on neurogenic vasodilatation (Flannigan and
Tucker, 1985b). The symptoms are exacerbated by sensory stimulation
(heat, sun, scratching (Aldridge, 1990), sweating or application of
water and may prevent sleep (Tucker and Flannigan, 1983).
Paraesthesiae generally start 30 minutes to two hours after exposure
and peak after about six hours. Recovery is usually complete within 24
hours (Aldridge, 1990; He et al, 1989; Knox and Tucker, 1982; Knox et
al, 1984; Tucker and Flannigan, 1983).
Dermal toxicity
When used at recommended doses in the treatment of scabies and lice,
pyrethroids only rarely produce adverse effects. Pruritus is the
side-effect reported most frequently (Brandenburg et al, 1986;
DiNapoli et al, 1988), although this may also be caused by the skin
infestation being treated.
Skin irritation during occupational pyrethroid exposure may occur in
up to ten per cent of workers (Kolmodin-Hedman et al, 1982) and may be
influenced by the ratio of stereoisomers used in the pyrethroid
formulation being more severe with a higher proportion of the trans
isomer. In addition to pruritus, erythema, burning and blisters have
been reported (Brandenburg et al, 1986; Kalter et al, 1987; IPCS,
1990b; Kolmodin-Hedman et al, 1995).
There are no reports of dermal toxicity specific to
lambda-cyhalothrin.
Ocular exposure
Symptoms of mild eye irritation have been reported following
occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS,
1990d; Lessenger, 1992).
Villagers handling mosquito nets pre-treated with lambda-cyhalothrin
complaining of mild burning of the eyes and lacrimation (Baskaran et
al, 1992).
Inhalation
Inhalational pyrethroid exposure typically is occupational and
produces symptoms and signs of pulmonary tract irritation. The
frequency and severity of symptoms may vary with the ratio of
different stereoisomers in a formulation, being more prevalent with a
higher proportion of the trans isomer. Systemic effects may occur
following more substantial exposure (He et al, 1989) and are described
below.
There are no reports of inhalational toxicity specific to
lambda-cyhalothrin.
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.
There are no reports of lambda-cyhalothrin ingestion.
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 to
fenvalerate, deltamethrin or cypermethrin).
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).
Cardiovascular toxicity
Palpitation was reported in 13.1 per cent of 573 cases of acute
pyrethroid poisoning involving oral, inhalational and dermal exposure
to fenvalerate, deltamethrin or cypermethrin (He et al, 1989). An
electrocardiogram (ECG) showed ST and T wave changes in eight of 71
patients. Other ECG abnormalities included sinus tachycardia,
ventricular ectopics and (rarely) sinus bradycardia (He et al, 1989).
All ECG changes resolved over 2-14 days.
Pulmonary toxicity
Chest tightness has been described following accidental or deliberate
ingestion of deltamethrin, fenvalerate or cypermethrin (He et al,
1989).
Non-cardiogenic pulmonary oedema has been reported rarely following
substantial pyrethroid ingestion, usually in association with severe
neurological complications and may contribute to a fatal outcome (He
et al, 1989).
Musculoskeletal toxicity
A case of acute polyarthralgia after skin exposure to flumethrin
(another type II pyrethroid) has been reported recently (Box and Lee,
1996).
Haemotoxicity
Among 235 cases of occupational or accidental acute pyrethroid
poisoning in whom a full blood count was performed, 15 per cent showed
a leucocytosis (He et al, 1989); this was probably a non-specific
response.
Nephrotoxicity
Urinalysis among 124 patients with acute pyrethroid poisoning
(involving oral, dermal and inhalational exposure) showed three
patients with haematuria (He et al, 1989).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Few long-term adverse effects from pyrethroids have been reported
(IPCS, 1990d; Chen et al, 1991, He, 1994). There is no confirmed
evidence that repeated exposure to pyrethroids leads to permanent
damage to sensory nerve endings (Vijverberg and van den Bercken,
1990).
One hundred and ninety-nine workers employed in a pyrethroid packaging
plant over four to five months on two occasions (winter and summer
sessions) were observed for cutaneous effects (He et al, 1988). Work
involved transferring pyrethroid emulsions (deltamethrin 2.5 per cent,
fenvalerate 20 per cent and (to a lesser extent) cypermethrin 10 per
cent, all other type II pyrethroids) 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 lambda-cyhalothrin should be removed, and
contaminated skin washed with soap and water (He, 1994).
Specific measures
Topical alpha tocopherol (vitamin E) to treat paraesthesiae
As paraesthesiae usually resolve in 12-24 hours, specific treatment is
not generally administered or required. However, the topical
application of dl-alpha tocopherol acetate (vitamin E) has been
shown to reduce the severity of skin reactions to other pyrethroids
including fenvalerate (IPCS, 1990c; Tucker et al, 1984; Tucker et al,
1983), flucythrinate, permethrin and cypermethrin (Flannigan and
Tucker, 1985a). The reaction to cypermethrin was completely inhibited
by vitamin E (Flannigan et al, 1985). Vitamin E appears to be useful
both prophylactically and therapeutically (Flannigan and Tucker,
1985a). In a controlled human volunteer study, a commercial vitamin E
oil preparation produced 98 per cent inhibition of the cutaneous
symptoms from fenvalerate when applied immediately (Flannigan et al,
1985). At four hours the inhibition was only 50 per cent (Advisory
Committee on Pesticides, 1992). The mechanism of the effect of topical
vitamin E has not been clarified, although some in vitro studies
suggest vitamin E may block the pyrethroid-induced sodium "tail
current" in neuronal membranes (Song and Narahashi, 1995).
Vitamin E is not included in the British National Formulary but is
available from health food or alternative medicine sources.
Other agents to treat paraesthesiae
Various other topical therapies have been tested for treatment of
pyrethroid-induced paraesthesiae: in human trials mineral oil, corn
oil and "A&D ointment" (Tucker et al, 1984; Tucker et al, 1983) were
almost as effective as Vitamin E cream (but the oils may lead to
defatting of skin). Butylated hydroxyanisole and an industrial barrier
cream (Tucker et al, 1984) and topical indomethacin (Flannigan and
Tucker, 1984), were of little therapeutic benefit and in two studies
zinc oxide paste exacerbated paraesthesiae (Tucker et al, 1984; Tucker
et al, 1983) .
Ocular exposure
Irrigate the affected eye with lukewarm water or 0.9 per cent saline
for at least ten minutes. A topical anaesthetic may be required for
pain relief or to overcome blepharospasm. Ensure no particles remain
in the conjunctival recesses. Use fluorescein if corneal damage is
suspected. If symptoms do not resolve following decontamination or if
a significant abnormality is detected during examination, seek an
ophthalmological opinion.
Inhalation
Removal from exposure is the priority. Mild symptoms of rhinitis
respond to oral antihistamines. Other symptomatic and supportive
measures should be dictated by the patient's condition.
Ingestion
Gut decontamination
Gastric lavage should be avoided since solvents present in some
lambda-cyhalothrin formulations may increase the risk of aspiration
pneumonia.
Systemic toxicity
Most patients exposed to lambda-cyhalothrin require only simple
supportive care. Systemic toxicity is rare but in such patients the
presence of excess salivation, muscle fasciculations and pulmonary
oedema may present diagnostic difficulty since similar features are
typical also of severe organophosphorus pesticide poisoning.
Measurement of the red cell cholinesterase activity (which is reduced
in acute organophosphorus poisoning but not in pyrethroid
intoxication) allows clarification but may not be available rapidly.
Isolated brief convulsions do not require treatment but intravenous
diazepam 5-10 mg should be given if seizures are prolonged. Rarely it
may be necessary to give intravenous phenytoin, or to paralyze and
ventilate the patient. Diazepam is useful also in the treatment of
muscle fasciculations. The role of atropine is discussed below.
Several experimental studies have investigated the role of
pharmaceuticals in the management of the neurological complications of
severe pyrethroid poisoning. However, these should be interpreted with
caution, not only because they usually have involved high-dose
parenteral pyrethroid administration, but also because there is
considerable interspecies variation with regard to therapeutic
efficacy (Casida et al, 1983; Vijverberg and van den Bercken, 1990).
Atropine for hypersalivation and pulmonary oedema
In experimental studies atropine sulphate (25 mg/kg subcutaneously)
reduced hypersalivation produced by oral fenvalerate or cypermethrin
(each at a dose exceeding the LD50), but did not increase survival
(Hiromori et al, 1986).
Intravenous atropine (0.6-1.2 mg in an adult) may be useful to control
excess salivation but care should be taken to avoid excess
administration. In a review of pyrethroid poisoning cases reported
from China (He et al, 1989), 189 of 573 patients were treated with
atropine which led to an improvement in salivation and pulmonary
oedema in a few severe cases, but eight patients developed atropine
intoxication following intravenous administration of 12-75 mg. One
patient, probably misdiagnosed as having acute organophosphorus
insecticide poisoning, died of atropine intoxication after a total
dose of 510 mg, and one patient acutely intoxicated with a
fenvalerate/dimethoate mixture could not be revived despite a total
atropine dose of 170 mg.
Atropine and ethylcarbamate
In a French study a combination of intravenous atropine 3 mg/kg and
ethylcarbamate 1000 mg/kg effectively protected rodents against the
lethal effects of intravenous deltamethrin, increasing the LD50 by a
factor of 3.48 (Leclercq et al, 1986).
Diazepam and phenobarbital for convulsions
In mice (n=10) pre-treatment with intraperitoneal diazepam (1 mg/kg),
but not phenobarbital (10-30 mg/kg), significantly increased the time
to onset of convulsions caused by the intracerebroventricular
administration of deltamethrin (p<0.005) and fenvalerate (p<0.05)
(Gammon et al, 1982). Under the same conditions diazepam was not
effective in preventing permethrin- or allethrin-induced seizures.
Propranolol and procainamide for tremor
Pre-treatment with intravenous propranolol or procainamide (each 15
µmol/kg) reduced the severity of tremor or writhing induced in rats by
the intravenous administration of deltamethrin (10 µmol/kg) (Bradbury
et al, 1983).
Ivermectin and pentobarbital for choreoathetosis
In rodents administered 2 mg/kg intravenous deltamethrin,
pre-treatment with 4 mg/kg intravenous ivermectin reduced
choreoathetosis from 3.9 to 3.2 (as graded on a scale of 1-4) (p =
0.023), and reduced salivation by 72 per cent. Pentobarbital (15 mg/kg
i.p.) reduced choreoathetosis produced by 1.5 mg/kg intravenous
deltamethrin from 3.0 to 1.3 (p = 0.004). An equi-sedative dose of
phenobarbital produced a non-significant fall to 2.4 (p = 0.11)
(Forshaw and Ray, 1997).
Mephenesin and methocarbamol
The skeletal muscle relaxant mephenesin 22 µmol/kg prevented all motor
symptoms induced in rats by the intravenous administration of
deltamethrin (10 µmol/kg) (n=4-20 in different treatment groups)
(Bradbury et al, 1983).
Mephenesin has a short half-life in vivo, but intraperitoneal
methocarbamol (a mephenesin derivative) (400 mg/kg intraperitoneally
followed by 200 mg/kg whenever tremor was observed) significantly
(p<0.01) reduced mortality in rats administered more than the oral
LD50 of fenvalerate, fenpropathrin, cypermethrin or permethrin (n=10
in each treatment group) (Hiromori et al, 1986).
There are insufficient data to advocate a clinical role for
methocarbamol in systemic pyrethroid toxicity.
Sodium-channel blockers (local anaesthetics)
In vitro studies suggest local anaesthetics may be useful as
antagonists of the effect of deltamethrin on sodium channels
(Oortgiesen et al, 1990). The relevance to human poisoning is not
known.
MEDICAL SURVEILLANCE
Avoiding dermal and inhalational exposure via adequate self-protection
and sensible use is the most important requirement to reduce adverse
effects from occupational use of lambda-cyhalothrin.
OCCUPATIONAL DATA
Maximum exposure limit
International Standards Organization (ISO) limits for natural
pyrethrins are: long-term exposure limit (8 hour TWA reference period)
5 mg/m3; short-term exposure limit (15 min reference period) 10
mg/m3 (Health and Safety Executive, 1995).
OTHER TOXICOLOGICAL DATA
Endocrine toxicity
In vitro studies show that several pyrethroids interact
competitively with human skin fibroblast androgen receptors and with
sex hormone binding globulin (Eil and Nisula, 1990). A possible
anti-androgenic effect of pyrethroids in humans was suggested
following an outbreak of gynaecomastia in refugees exposed to
fenothrin, but there was insufficient evidence to confirm this (Eil
and Nisula, 1990).
Animal studies evaluating other endocrine effects of pyrethroids have
produced conflicting results (Akhtar et al, 1996; Kaul et al, 1996).
Immunotoxicity
In oral dosing studies in rodents, several pyrethroids suppressed the
cellular immune response (Blaylock et al, 1995; Tulinská et al, 1995)
or produced thymus atrophy (Madsen et al, 1996).
The significance of these immunological studies to man is not known.
Carcinogenicity
There is no evidence that lambda-cyhalothrin is carcinogenic (IPCS,
1990a).
Reprotoxicity
No specific reprotoxicity data for lambda-cyhalothrin were identified,
though in a variety of animal studies there was no evidence that
cyhalothrin was teratogenic, embryotoxic or fetotoxic (IPCS, 1990a)
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, including lambda-cyhalothrin (Advisory Committee
on Pesticides, 1988b; Advisory Committee on Pesticides, 1993),
conclude that there is insufficient evidence for it to be considered
genotoxic or mutagenic.
Fish toxicity
Lambda-cyhalothrin is toxic to fish. It is more toxic at cooler
temperatures, and thus more toxic to cold than warm water fish, but
the toxicity of pyrethroids is little affected by pH or water hardness
(Mauck et al, 1976).
LC50 for bluegill sunfish is 0.21 µg/L lambda-cyhalothrin, and for
rainbow trout is 0.24 µg/L lambda-cyhalothrin (Pesticide Manual,
1997).
EC Directive on Drinking Water Quality 80/778/EEC
Maximum admissible concentration (any pesticide) 0.1 µg/L (EC
Directive, 1980).
AUTHORS
SA Cage MSc M Inst Inf Sci
SM Bradberry BSc MB MRCP
S Meacham BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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