Pyrethrins/Pyrethroids

DE Ray,y School of Biomedical Sciences, Medical School, Queen’s Medical Centre, University of Nottingham, UK
SA Burr, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
Ó 2014 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by David E. Ray, volume 3, pp 574–579, Ó 2005, Elsevier Inc.

l Chemical Names: Natural pyrethrins and synthetic

pyrethroids
l Representative Chemicals: Pyrethrin I, pyrethrin II, cyflu-
thrin, cypermethrin, deltamethrin, permethrin
l Chemical Abstracts Service Registry Numbers: 121-21-1
(pyrethrin I), 121-29-9 (pyrethrin II), 68359-37-5
(cyfluthrin), 52315-07-8 (cypermethrin), 52918-63-5
(deltamethrin), 52645-53-1 (permethrin)
l Synonyms: Pyrethrin I [(1S)-2-methyl-4-oxo-3-[(2Z)-penta-
2,4-dien-1-yl]cyclopent-2-en-1-yl(1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-en-1-yl)cyclopropanecarboxylate],
PubChem CID 5281045; pyrethrin II [[2-methyl-4-oxo-3-
[(2E)-penta-2,4-dienyl]cyclopent-2-en-1-yl](3S)-3-[(Z)-3-
methoxy-2-methyl-3-oxoprop-1-enyl]-2,2-dimethylcyclo-
propane-1-carboxylate], PubChem CID 5320807; pyrethrum
contains both pyrethrin I and pyrethrin II
l Classification: Ester insecticides
l Molecular Formulas: pyrethrin I, C21H28O3, molecular
weight 328.44522; pyrethrin II, C22H28O5, molecular
weight 372.45472 Pyrethrin II
l Chemical Structures:

Cyfluthrin

Pyrethrin I

y
Deceased

1152 Encyclopedia of Toxicology, Volume 3 http://dx.doi.org/10.1016/B978-0-12-386454-3.00191-3


Cypermethrin
Deltamethrin
Permethrin
Background
From the nineteenth century until the 1970s only pyrethrin
mixtures obtained by solvent extraction of pyrethrum
(powdered chrysanthemum flowers, usually Chrysanthemum
cinerariaefolium) were available for use. However, the devel-
opment by Martin Elliott of the cheaper and more light-stable
synthetic pyrethroids from the 1970s led to their becoming
a major pesticide class. Over 1000 pyrethroid structures have
been synthesized, some of which show considerable divergence
from the original pyrethrins.
Uses
Both the naturally occurring pyrethrins and the synthetic
pyrethroids are widely used as potent insecticides and insect
repellents in agricultural, public health, and domestic appli-
cations. They are also used as ectoparisiticides in veterinary
and human medicine. Attractive features are their low
Pyrethrins/Pyrethroids 1153
environmental persistence and their rapid knockdown activity,
whereby flying insects very quickly become uncoordinated and
unable to fly before they are killed. The natural pyrethroids are
now largely restricted to indoor domestic uses where light
stability is less important. The pyrethroids are major agricul-
tural pesticides in terms of treated land area (although not
tonnage as they are more potent than most other pesticide
classes). However, many insect populations have begun to
develop resistance via cuticle thickening to reduce pyrethroid
absorption, induction of CYP6P3 to increase detoxification,
and preventing pyrethroid binding by modifications to the
sodium channel target site.
Environmental Fate
Environmental residues of pyrethrins and pyrethroids are
degraded by photolysis and hydrolysis, and so do not accu-
mulate in most ecosystems. Pyrethroids are moderately
persistent in soil by binding strongly to soil particles,
reducing the risk of leaching. Once in water, free concentra-
tions of pyrethroids can decrease rapidly due to adsorption to
sediments and other particulates, and uptake by plants.
Pyrethroids are less persistent in soil with a low organic
content (e.g., sand rather than clay-based soil). Degradation
rates in water are similar to soil. Hydrolytic degradation is
catalyzed by ultraviolet light, microbial action, aerobic, and
especially by alkali conditions. The environmental half-life
can thus vary considerably from 2 to 600 days. Pyrethroids are
typically less persistent in aerobic soil (where half-lives range
from 3 to 96 days) than in anaerobic soil (where half-lives
range from 5 to 430 days). The main environmental hazard
associated with pyrethroid use is contamination of freshwater
by acute runoff after use as an agricultural pesticide or ecto-
parisitide near to water, which can lead to death of aquatic
invertebrates or fish (which have very limited pyrethroid
detoxification capacity).
Exposure
All pyrethroids and pyrethrins have low volatility (104–
108 mmHg), and so occupational and domestic exposure is
primarily via dermal contamination or inhalation/ingestion of
spray droplets. Consumers are exposed to low-level residues of
agricultural pyrethroids in many foods. Residues of domestic
pyrethroids and pyrethrins have been found in house dust.
Toxicokinetics
Although the inherent toxic potential of pyrethroids and
pyrethrins can be high (intravenous lethal dose 50% (LD50)
values range from 0.5 to 4250 mg kg1), this is limited in
practice by rapid detoxification in skin, blood, and liver. The
half-life of pyrethroids in blood ranges from 19 min to 10 h
(typically a few hours), and oral intoxication is correspond-
ingly short lasting. The dermal toxicity of pyrethroids is further
limited by low absorption through the skin and the capacity for
local detoxification of pyrethroids in the skin during
1154 Pyrethrins/Pyrethroids
absorption. In man, the bioavailability of dermal pyrethroids is
1–17%, compared with 3–50% for gastric absorption,
depending on the formulation. Hence, the dermal route of
exposure presents less risk of systemic poisoning, although in
the few cases of very severe skin contamination that have been
reported, intoxication has lasted for several weeks, possibly due
to a large reservoir of pyrethroid bound to the epidermis. Once
absorbed, pyrethroids rapidly distribute throughout the body;
their high lipophilicity and lack of exclusion by the adenosine
triphosphate-binding cassette multidrug transporters ensures
ubiquitous entry into all tissues and blood–brain barrier
passage into the central nervous system, with longer-term
accumulation in fat and myelin. The pyrethrins and allethrin
are broken down mainly by oxidation of the isobutenyl side
chain of the acid moiety and of the unsaturated side chain of
the alcohol moiety, with ester hydrolysis playing an unim-
portant part, but for the other pyrethroids ester hydrolysis
predominates. The acid and alcohol components of pyre-
throids have very little toxic potential, so hydrolysis represents
a one-step detoxification. These reactions can take place in liver
and plasma and are followed by hydroxylation and conjuga-
tion to glucuronides or sulfates, which are then excreted in
urine. A number of factors modify the rate of breakdown,
notably stereospecificity; trans isomer hydrolysis is catalyzed by
esterases but cis isomer hydrolysis is catalyzed at a lower rate by
oxidases. This slower breakdown of cis isomers may contribute
to their greater mammalian toxicity, but their higher inherent
affinity for the sodium channel complex is thought to be the
predominant factor. An additional influence on the rate of
metabolism is the presence of an alpha-cyano group, which
slows both hydrolysis and oxidation. Ester cleavage of alpha-
cyano pyrethroids releases cyanide ions, which are in turn
converted to thiocyanate.
Many developmental studies remain equivocal, although at
the extreme, neonatal rats have been shown to be 6 and 17
times more vulnerable than adults to the acute lethality of type
I and II pyrethroids, respectively. This is entirely attributable to
their lesser capacity for metabolic detoxification, and does not
extrapolate to lower dose effects. Insect knockdown rate and
lethality are improved by application at lower ambient
temperatures. The high relative sensitivity of insects to pyre-
thrins and pyrethroids is attributable (in roughly equal
proportions) to their slower metabolic disposal, their lower
body temperature, and the inherently higher sensitivity of their
target sites. Although there are few, if any, toxic actions of the
pyrethroids in insects that do not have their counterpart in
man, these three quantitative factors combine to give insect–
mammalian toxicity ratios of 2–3 orders of magnitude
difference.
Mechanism of Toxicity
The pyrethrins and the pyrethroids are primarily functional
neurotoxins: causing death by hyperexcitation; only causing
direct cytotoxicity in mammalian cells at concentrations
much higher than are reached in the brain of severely
intoxicated animals (although there is some evidence of
neuronal loss with repeated dermal exposures). The main
target of the pyrethrins and the pyrethroids is the voltage-
gated sodium channel family. This is responsible for the
generation of the inward sodium current that produces the
action potential in most cells, which is closed at normal
resting potentials. Sodium channels consist of an alpha
subunit that forms the trans-membrane pore. They resemble
those of other voltage-gated ion channels and can take several
possible isoforms. The beta 1 and beta 2 subunits modify the
basic function of the alpha subunit. There are many variant
forms of the alpha subunit (ten have been characterized in the
rat), and channels are also subject to glycosylation and
phosphorylation, which further modify function. These
variant forms also show very different sensitivity to pyre-
throids. Unfortunately, there is no standard nomenclature for
many channel isoforms, and descriptions based on pharma-
cological properties (e.g., tetrodotoxin resistant) or tissue
source (e.g., brain I, II, III) are widely used. The interaction of
pyrethroids with the sodium channel has the effect of slowing
both its activation and its inactivation processes, causing the
pyrethroid-modified channel to adopt a hyperexcitable state.
This hyperexcitable condition is sustained until the pyrethroid
is removed and the channel returns to normal. Since there is
a far higher density of expression of sodium channels in most
cells than is needed to maintain normal excitability, only
0.1% of sodium channels need to be modified by a pyrethroid
for the extra current that they generate to render the whole cell
hyperexcitable. Although activation is slowed at the single-
channel level, the high density of sodium channels also means
that sufficient unmodified channels are always present to
ensure that the activation phase of the action potential is not
appreciably delayed. However, in the falling (inactivation)
phase of the action potential, even a low proportion of
modified channels can generate enough extra current to delay
inactivation. This slower rate of inactivation of pyrethroid-
modified channels generates a prolonged depolarizing tail
current that follows the normal action potential. This tail will
trigger a second action potential if the current is large enough
and lasts longer than the 0.5–1 ms needed for the normal
sodium channels to reactivate. In this situation, what would
normally be a single action potential can become multiple
action potentials or a continuous uncontrolled discharge.
Action potential amplitude normally remains constant, so
this uncontrolled excitation produces marked functional
disruption, although very high concentrations of pyrethroids
or hyperactivity beyond that which the cell can sustain will
eventually cause depolarization and conduction block. This
depolarization is more readily produced by those pyrethroids
that hold the sodium channel open longest.
An important characteristic of the pyrethroid generated tail
current is that its amplitude and duration are independent. The
current amplitude is dependent only on the proportion of
sodium channels modified, and hence shows a saturable rela-
tionship with pyrethroid concentration or dose. The current
duration, however, is dependent only on the pyrethroid
structure: type I pyrethroids, such as permethrin, hold the
channel open for a few milliseconds (rapid insect knockdown),
and type II pyrethroids, such as deltamethrin, hold it open for
tens–hundreds of milliseconds (effective insect kill). Individual
pyrethroids thus generate a characteristic time constant for
prolongation of the sodium channel tail current that is virtually
independent of dose.

Different forms of the sodium channel show differential
sensitivity to pyrethroids. Pyrethroids are ten times more
potent on the tetrodotoxin-resistant subtype of the sodium
channel, which is expressed in the developing mammalian
brain and in adult dorsal root ganglia. The different forms
can also show structure-specific sensitivity: the rat brain IIa
form is sensitive to type II but not type I pyrethroids.
Some of the selectivity of action of pyrethroids within the
nervous system parallels the distribution of sensitive
sodium channel subtypes, although there are at present
only limited data to support this. Peripheral nerve sodium
channels (SNS/PN3) are highly sensitive to pyrethroids,
and action at these channels may be relevant to the
production of paresthesia. Pyrethroid action on the sodium
channel shows a marked stereospecificity: the 1R and 1S cis
isomers bind competitively to one site, and the 1R and 1S
trans isomers bind noncompetitively to another. The 1S
forms do not modify the channel function but do block
the effect of the 1R isomers. In whole mammals, the 1R
isomers are thus active and the 1S isomers are inactive and
essentially nontoxic. Isomerism at the third carbon of the
cyclopropane ring gives cis and trans isomers; the cis
isomers are about ten times more potent than the trans
isomers. A final chiral center is generated if a cyano
substituent is added to the alcohol, giving eight possible
isomers. Again this affects potency, and only the alpha-S
and not the alpha-R forms are toxic. A practical conse-
quence of this is that the toxicity of products such as
permethrin, which are sold as variable isomeric mixtures,
can vary from batch to batch. Thus, the rat oral LD50 value
of commercial samples of permethrin can vary from 430 to
8900 mg kg1 depending on the cis isomer content.
Many target sites other than the sodium channel have been
suggested to be relevant to poisoning in mammals. Most
show insufficient potency to be relevant at the concentrations
of 1–30 nmol g1 tissue that are seen during severe poisoning
in rats. Nevertheless, the complex effects on the central
nervous system have led to suggestions that some pyrethroids
also act via antagonism of g-aminobutyric acid (GABAA)-
mediated inhibition, by modulation of nicotinic cholinergic
transmission, or by enhancement of norepinephrine release.
However, most neurotransmitter release is secondary to
increased sodium entry. Actions at both voltage-gated chlo-
ride and calcium channels have also been proposed. Voltage-
gated chloride channels are found in brain, nerve, muscle, and
salivary gland, and their function is to control cell excitability.
The pyrethroids deltamethrin and fenvalerate decrease chlo-
ride channel currents at low enough concentrations to be
relevant to mammalian poisoning, but others do not. These
pyrethroids decrease chloride channel current, increasing
excitability, and so indirectly synergize with pyrethroid
actions on the sodium channel. Voltage-gated calcium chan-
nels are certainly pyrethroid targets in insects, and some
mammalian calcium channels, such as those in the cardiac
sinoatrial node, are also sensitive. The mechanism whereby
pyrethroids interact with ion channels is not yet understood,
since their high lipophilicity makes investigation difficult, but
type II pyrethroids have been shown to directly stimulate
protein kinase C-dependent protein phosphorylation at very
low concentrations. Since ion channel activity is modulated
Pyrethrins/Pyrethroids 1155
by phosphorylation state, this could be an important
mechanism of action.
Acute and Short-Term Toxicity
Animal
The acute effects of high oral or intravenous doses of the
pyrethrins and most non–cyano pyrethroids closely resemble
those of dichlorodiphenyltrichloroethane (DDT) (which acts
similarly on the sodium channel). They are characterized
by fine continuous tremors, which may be severe enough to
cause hyperthermia, and by marked reflex hyperexcitability.
Consciousness is preserved up to the point of death. This is
variously described as T (tremor) or type I syndrome. However,
with the development of the first cyano-substituted pyrethroids
such as deltamethrin it was realized that these produced a very
different acute poisoning syndrome in both insects and
mammals known as chorea salivation or type II syndrome. This
is characterized progressively by chewing, salivation, hind-limb
rigidity, and finally by electroencephalographic spiking, chor-
eoathetosis and tonic–clonic seizures with loss of conscious-
ness. The last three are initially precipitated by sensory stimuli,
but become spontaneous at near-lethal doses. In dogs, upper
airway hypersecretion and gastrointestinal symptoms are more
prominent than in rats. Some pyrethroids such as cyphenothrin
produce mixed syndromes with both sets of symptoms super-
imposed, and for all pyrethroids at low doses it can be difficult
to distinguish the two syndromes. In rodents, low-dose oral
exposure can decrease operant conditioning, grip strength, and
coordination; furthermore, pyrethroids with an alpha-cyano
group (e.g., cyfluthrin, cypermethrin, deltamethrin) decrease
acoustic-evoked startle reflexes, whereas those without an
alpha-cyano group (e.g., bifenthrin, cismethrin, permethrin)
increase acoustic-evoked startle reflexes. Few pyrethroids have
sufficient toxic potential to produce severe acute signs by the
dermal route, although those with relatively long blood half-
lives such as the type II pyrethroid cyhalothrin, can do so.
The nature of the poisoning syndrome can be predicted
from the duration of the pyrethroid-induced sodium channel
after-potential: type I pyrethroids produce shorter time
constants, type II pyrethroids produce longer time constants,
and mixed type I/II pyrethroids have intermediate time
constants. All type II pyrethroids have a cyano substituent, but
not all type I pyrethroids lack one: the trans and cis isomers of
flurocyphenothrin produce type I and II effects, respectively.
Both pyrethroid classes have a similar range of mammalian
toxicity but, of commercial pesticides, type II pyrethroids, such
as deltamethrin and cypermethrin, are generally more toxic
than type I pyrethroids, such as permethrin. The extent to
which the two classes of pyrethroids truly differ is not yet clear,
but in isolated neonatal rat dorsal root ganglion cells the
actions of the type I tetramethrin and the type II fenvalerate
appear to be mutually exclusive. Both type I and II pyrethroids
cause marked adrenal activation in rats, probably by a direct
activation of norepinephrine release. The type II pyrethroid
deltamethrin causes increased corticosteroid secretion, and
even moderate pyrethroid poisoning occurs against a back-
ground of profound adrenal activation, with corresponding
behavioral and cardiovascular consequences. With type II
1156 Pyrethrins/Pyrethroids
pyrethroids there is a direct increase in cardiac contractility,
although blood pressure remains well controlled.
Electrophysiological studies have shown that all of the type
I motor signs of systemic pyrethroid intoxication are generated
at the spinal level, although type II poisoning involves the
whole central nervous system. Dermal application of pyre-
throids can also directly activate peripheral nerves and produce
paresthesia (as described in the next section).
Human
Fortunately, there have been few reports of systemic poisoning,
as the use of adequate protective clothing prevents intoxication
even under tropical conditions. However, systemic poisoning
can occur under conditions of misuse or inadequate user
protection.
There have been fatalities following ingestion of substantial
amounts of pyrethroid insecticide. Almost all reports of human
poisoning relate to the more potent type II pyrethroids, so it is
not certain how well the two syndromes seen in animals apply
to man, although what has been seen in man fits quite well
with the animal observations. Human type II poisoning seems
to be characterized by paresthesia (if via the dermal route),
dizziness, nausea, lethargy, and muscular fasciculations. More
severe poisoning causes epigastric pain and vomiting (if via the
oral route), hypersalivation and pulmonary edema, opistho-
tonos, seizures, and coma. Given the common formulation of
pyrethroids with volatile solvents such as xylene, symptoms of
poisoning can be complicated by solvent toxicity, which in turn
may also introduce additional skin effects. Mild poisoning
symptoms may also be amplified by anxiety, precipitated by
fear or by the disconcerting paresthesia resulting from dermal
contact with pyrethroids. Although systemic toxicity is very
rare, local effects are more commonly reported: skin contami-
nation produces paresthesia, ingestion produces gastrointes-
tinal irritation, and inhalation yields upper respiratory tract
irritation. All of these effects are reversible. The gastrointestinal
irritation is rare (limited to cases of ingestion) and has not been
well studied, but presumably is a phenomenon similar to the
more common dermal paresthesia. Respiratory tract irritation
can be produced at comparable thresholds in rats and man, but
is rarely reported. Dermal exposures far below the threshold for
systemic poisoning can lead to local paresthesia, which is
evoked by all classes (the pyrethrins and type I and II pyre-
throids), with a severity roughly in proportion to their systemic
toxic potential. Paresthesia is by far the most commonly
described toxic effect of pyrethroid exposure. Pyrethroid-
induced paresthesia is dose dependent in severity and duration,
lasting for 4–30 h after a single application. When mild, the
sensation is of continuous tingling or pricking, but when more
severe, it manifests as burning. Paresthesia is more commonly
felt in the face where the skin is thinner than the hands, even
when the hands are the primary site of contamination.
Erythema is not normally seen unless the sufferer scratches the
area. Paresthesia is annoying but not disabling and does not
appear to be associated with any lasting ill effects.
In animals, electrophysiological tests show peripheral nerve
hyperexcitability lasting up to 24 h after exposure, and such
tests have been used to monitor local pyrethroid effects in man.
The mechanism of paresthesia has not been studied directly,
but presumably results from abnormal pyrethroid-induced
repetitive activity in skin nerve terminals. Dermal and respira-
tory sensitization have both been reported after exposure to
pyrethroids, but very rarely considering their widespread usage,
and always in association with other potential allergens. In the
past, impure pyrethrin extracts have given rise to contact
dermatitis.
Chronic Toxicity
Animal
Near-lethal doses of all classes of pyrethroids can give rise to an
axonal degeneration in peripheral nerves closely resembling
Wallerian degeneration. This effect is inherently reversible and is
only seen at dose levels that produce prolonged and severe
motor signs. Central neuropathology has been described in one
study of adult rats given repeated near-lethal doses of the type II
pyrethroid deltamethrin, but others have found no such
pathology. A study of repeated low doses of permethrin has also
described central pathology when given in combination with
other agents known to produce central neuropathology at
higher doses. A number of effects of exposure to pyrethroids
during early development have been described in mice. The
pyrethroids permethrin and deltamethrin (in addition to DDT,
polychlorinated biphenyls (PCBs), nicotine, and paraquat) have
also been reported to induce permanent changes in behavior
and neurochemistry of adult mice when administered directly to
the neonate. These effects were seen at dose levels that were not
acutely toxic. These results contrast with a lack of longer-term
effects with dietary administration of pyrethroids to rats in
studies conducted for regulatory purposes using different end
points, and at present the relevance of the results for mice to
human health is uncertain. In other studies, delayed develop-
ment of the blood–brain barrier has been reported in rat pups
given pyrethroids at doses high enough to reduce body weight,
although it is likely that this effect was nonspecific in nature.
Human
Long-term ill-health of a variable and somewhat nonspecific
nature has occasionally been ascribed to pyrethroid exposure,
and this has been the subject of public concern and legal claims
in Germany. Pyrethroids have been detected in domestic house
dust at a low level, but no clear clinical or epidemiological
studies have shown a causal relationship between pyrethrin or
pyrethroid exposure and ill-health. The few descriptions of
systemic acute pyrethroid poisoning and the larger number of
paresthesia cases that have been reported all described
complete recovery.
In Vitro Toxicity
Inexcitable mammalian cells are little affected by pyre-
thrins or pyrethroids. Growth inhibition has been shown at
105 mol l1 for mouse fibroblasts exposed to deltamethrin,
and decreased hepatocyte viability has been described after
treatment with permethrin at 100 ng (106 cells)1, a level that
is approximately 10–100 times higher than that reached in the

brain of lethally intoxicated animals. By contrast, excitable
tissue (neurons, synaptosomes, and isolated nerve fibers) has
been invaluable for research into mechanisms of action; effects
are seen from 1010 mol l1. However, the very low water
solubility of pyrethroids (109 mol l1) has meant that most
such studies have been carried out using aqueous pyrethroid
suspensions that then dissolve into tissue lipids, making
absolute half maximal effective dose (ED50) values difficult to
determine. This solubility problem also causes most in vitro
effects to be irreversible, since there is no route for removal of
the pyrethroid, in marked contrast to the effects seen in vivo. In
vitro irreversibility has been interpreted by some authors as
providing potential for irreversible pyrethroid toxicity in man,
but when toxicokinetic differences are taken into account, in
vitro and in vivo data are generally in good agreement.
Clinical Management
The most commonly encountered sign of pyrethroid poisoning
is dermal paresthesia. This can be treated by washing of the
contaminated skin with oils, but not by soap and water, as
pyrethroids bind to skin and are poorly water soluble. Vitamin
E cream has also been found to be effective for treating pares-
thesia in clinical trials. When applied to the skin from 29 h
before to 15 min after exposure, the pyrethroid protection
lasted for more than 5 h. The concentration required to give
greater protection than that of the corn oil solvent alone was
very high (50%) and similar relief can be obtained by use of
presumably inert preparations such as corn oil or petroleum
jelly. Topical treatment with local anesthetics has been
described in humans and in animals, but anesthesia may be
more inconvenient than the paresthesia. With cases of inges-
tion, gastric decontamination with activated charcoal may be of
benefit within the first hour. Gastric lavage should be avoided
when formulations contain solvents that may increase the risk
of aspiration pneumonia. If systemic toxicity does occur, the
central signs of poisoning can be difficult to control and may
be confused with intoxication by other pesticides such as
anticholinesterases, which also cause salivation and hyperex-
citability, although pyrethroids do not inhibit acetylcholines-
terase. Respiratory support may be needed and control of
metabolic acidosis may require sodium bicarbonate. Atropine
may be useful to control hypersalivation. Single short-lived
seizures may not require treatment. Since pyrethroids do not
usually produce morphological damage and are rapidly
removed from the body, only symptomatic treatment is
needed. There are two approaches possible to achieve this:
antagonize the primary ion channel effects of the pyrethroids,
or control the secondary consequences mediated by specific
neurotransmitter systems. Since pyrethroids act via ion chan-
nels on multiple neurotransmitter systems, most successful
attempts at therapy have been based on ion channel or
membrane-stabilizing drugs. An ideal therapeutic agent would
antagonize the abnormal, pyrethroid-evoked, sodium current
but leave the normal one unchanged. In vitro, phenytoin,
phenobarbitone, and valproate act equally on the pyrethroid-
evoked and normal sodium current; and diazepam and
mephenesin have less action on the abnormal pyrethroid-
evoked current than on the normal one. Hence, mephenesin
Pyrethrins/Pyrethroids 1157
and methocarbimol are effective in rats only at maximum
tolerated doses, and diazepam was found to be ineffective in
man. A combination of methocarbimol and atropine pre-
vented all deaths at LD80 doses of pyrethroids in rats. However,
pentobarbitone, which is both a membrane stabilizer and
chloride channel agonist, is effective against all the type II
motor signs caused by deltamethrin at 25% of the anesthetic
dose in rats. An equisedative dose of phenobarbitone (which
does not act on chloride channels) is much less effective.
Although phenobarbitone has been tried and found ineffective
as a type II pyrethroid antidote in man, pentobarbitone does
not appear to have been tested in man. Since type II poisoning
involves a combined action on the central nervous system,
adrenal glands, autonomic system, and muscle, multidrug
therapy may be needed.
Other Hazards
Pyrethrins and pyrethroids present no other hazards but are
usually formulated in organic solvents that may be
inflammable.
Exposure Standards and Guidelines
The acceptable daily intakes set by the Food and Agriculture
Organization/World Health Organization Joint Meeting on
Pesticide Residues for cypermethrin, deltamethrin, and
permethrin are 0.01–0.02 mg kg1 body weight, with acute
oral reference doses for deltamethrin or permethrin of
0.05 mg kg1 body weight. The US National Institute for
Occupational Safety and Health maximum allowable concen-
tration for pyrethrins at an 8-h time-weighted average is
5 mg m3.
Miscellaneous
The pyrethrins and some pyrethroids are commonly cofor-
mulated with the synergist, piperonyl butoxide. This inhibits
both oxidative and hydrolytic detoxification reactions, thus
enhancing pyrethrin and pyrethroid toxicity, and itself has
developmental neurotoxic potential.
See also: Cyfluthrin; Cypermethrin; Deltamethrin; Neurotoxicity;
Permethrin; Pesticides.
Further Reading
Aldridge, W.N., 1990. An assessment of the toxicological properties of pyrethroids and
their neurotoxicity. Crit. Rev. Toxicol. 21, 89–104.
Barlow, S.M., Sullivan, F.M., Lines, J., 2001. Risk assessment of the use of deltamethrin
on bednets for the prevention of malaria. Food Chem. Toxicol. 39, 407–422.
Bradberry, S.M., Cage, S.A., Proudfoot, A.T., Vale, J.A., 2005. Poisoning due to
pyrethroids. Toxicol. Rev. 24 (2), 93–106.
Breckenridge, C.B., Holden, L., Sturgess, N., et al., 2009. Evidence for a separate
mechanism of toxicity for the Type I and the Type II pyrethroid insecticides.
Neurotoxicology 30 (1), S17–S31.
1158 Pyrethrins/Pyrethroids
Davies, T.G.E., Field, L.M., Usherwood, P.N.R., Williamson, M.S., 2007.
DDT, pyrethrins, pyrethroids and insect sodium channels. IUBMB Life 59 (3),
151–162.
Eriksson, P., Talts, U., 2000. Neonatal exposure to neurotoxic pesticides
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Relevant Websites
http://toxnet.nlm.nih.gov – TOXNET, Toxicology Data Network, National Library of
Medicine, Search for Pyrethrins/Pyrethroids.
http://www.who.int – World Health Organization, Search for Pyrethrins/Pyrethroids.