Professional Documents
Culture Documents
10
WHO/PCS/RA/2005.1
SAFETY OF
PYRETHROIDS FOR
PUBLIC HEALTH USE
11
1 INTRODUCTION
Pyrethroids are widely used in public health because of their
relative safety for humans, high insecticidal potency at low
dosages and rapid knock-down effects. The safety and efficacy
of pyrethroids for different applications in vector control, as
well as in disinsection of aircrafts, have been assessed by the
World Health Organization (WHO). WHO recommendations on
the use of pyrethroids include the following compounds:
22
publications. A systematic search in the literature database
PubMed, with particular attention to papers published after
1990, was also carried out. Furthermore, reports on cases were
considered where exposure to pesticides, notably from aircraft
disinsection, was alleged to have induced adverse health effects.
The available literature is listed at the end of this document.
33
4
Table 1. Development of JECFA/JMPR acceptable daily intakes for WHO-recommended pesticides for public
health use, 1981–2004
Pesticide 1981 1982 1984 1987 1988 1992 1993 1996 1997 1999 2000 2002 2004
Bifenthrin 0.02
Cyfluthrin 0.02 0.02
Cyhalothrina 0.02 0.002t 0.002b 0.002
Alpha- 0.02 0.02
cypermethrin
Cypermethrin 0.05 0.05
Deltamethrin 0.01 0.01
Etofenprox 0.03
Permethrin 0.05 0.05 0.05 0.05
D-phenothrin 0.2 0.04 0.07
JECFA/JMPR = Joint FAO/WHO Expert Committee on Food Additives/Joint FAO/WHO Meeting on Pesticide Residues.
a
No JECFA or JMPR assessment has been done on �-cyhalothrin.
b
Temporary acceptable daily intake.
4
2 PYRETHROIDS – STRUCTURE AND
INSECTICIDAL ACTIVITY
Pyrethroids (also known as synthetic pyrethroids) are
insecticides chemically similar to pyrethrins found in natural
pyrethrum extracted from the flowers of chrysanthemum, known
for centuries for their insecticidal activity (CPCN, 2001). First
developed in 1973, pyrethroids are more stable to light than
natural pyrethrum and possess very good insecticidal activity.
The first pyrethroid (fenvalerate) was commercialized in 1978.
At present, the class of pyrethroids includes 42 active
ingredients, differing in chemical structure or in relative
stereoisomer composition (NPTN, 1998).
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This stereospecificity extends to compounds such as fenvalerate,
in which the 2S configuration of the non-cyclopropane acid
moiety is structurally congruent with 1R cyclopropane-
carboxylates and gives insecticidal esters, whereas the
corresponding 2R esters are inactive (Soderlund et al., 2002).
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3 MECHANISMS OF TOXICITY
Pyrethroids are historically divided into two types, according to
their chemical structure: type I pyrethroids, which do not
contain an alpha-cyano group in their molecule (for example,
allethrin, resmethrin, D-phenothrin, and permethrin) and which
cause mainly tremors (T-syndrome); and type II pyrethroids,
which do contain an alpha-cyano group (for example,
deltamethrin, cypermethrin, cyfluthrin and fenvalerate) and
which cause choreoathetosis and salivation (CS-syndrome)
(Tordoir et al., 1994). However, it should be noted that the
syndromes are dependent on the animal model used. Many
pyrethroids, such as permethrin, exhibit both T and CS
characteristics, and sometimes these two syndromes combine
(Soderlund et al., 2002, Aldridge, 1990).
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(EXTOXNET, 1994a–e; EPA, 2000). Invertebrates and some
cold-blooded species are more susceptible to the toxic effects of
pyrethroids than vertebrates (Narahashi et al., 1998).
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4 TOXICOKINETICS
Absorption of pyrethroids through the gastrointestinal tract and
the skin is variable and depends on the vehicle of administration
(Soderlund et al., 2002; Bateman, 2000; Clark, 1995). From
comparative toxicity studies it has been concluded that
absorption from the respiratory tract is effective. While for the
general population the main route of exposure to agricultural
pesticides is through residues in food, studies carried out on
workers suggest that, similarly to any other pesticide, dermal
exposure is the most significant route of absorption for
agricultural applicators and sprayers (Zhonghua et al., 1991;
Zhang et al., 1991). The exposure scenario for pesticides used
for public health purposes is quite variable, from exposure to
larvicides in drinking-water, to dermal and inhalation exposure
from bednets, or from space spraying and vapour of household
insecticides (e.g. mosquito coil).
99
Since a number of carboxylesterases responsible for this
reaction are inhibited or competed by organophosphates (OPs),
simultaneous exposure to OPs may increase pyrethroid toxicity
(Ray & Forshaw, 2000).
The ratio of excretion between urine and faeces varies with the
compound and the route of administration (Soderlund et al.,
2002, Vijverberg & van den Bercken, 1990). Non-metabolized
pyrethroids (allethrin, bifenthrin, cyfluthrin, cyhalothrin,
cypermethrin, fenpropathrin, flucythrinate, fluvalinate,
permethrin, pyrethrins, tetramethrin, but not deltamethrin,
esfenvalerate, fenvalerate) were detected in breast milk from
women not exposed to pyrethroids at work, at concentrations of
0.015–0.34 mg/kg fat (Zehringer & Herrmann, 2001).
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deltamethrin (Maroni et al., 2000; Leng, 1997, 2003). In
occupationally exposed subjects, the unchanged parent
compounds may also be detected in urine (Zhang et al., 1991;
Chen et al., 1991).
5 TOXICITY IN EXPERIMENTAL
ANIMALS
5.1 Acute toxicity
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Systemic toxicity after dermal exposure to pyrethroids is low
(Table 2; Clark, 1995), but pyrethroids have localized effects on
the skin: after local application to guinea-pigs of six pyrethroids
(cypermethrin, deltamethrin, esfenvalerate, fenvalerate,
flucythrinate and permethrin), the animals showed an increase in
scratching, licking or biting at the site of dermal application.
The symptoms usually occurred within 1 hour after application
(Cagen et al., 1984).
12
12
Table 2. Acute oral and dermal toxicity of pyrethroid insecticides
commonly used for public health purposes (IPCS, 2002)
13
13
5.2 Short-term toxicity
14
indicate that the observed effects are non-cumulative and
reversible in nature (Pauluhn, 1996).
5.3 Carcinogenicity
15
The study showed an increase also in the incidence of preputial
gland adenomas and carcinomas, with incidences at 0, 300, 1000
and 3000 ppm of 1, 1, 1 and 4 adenomas and 0, 0, 1 and
3 carcinomas, respectively. The 1988 JMPR considered this
finding unlikely to be of toxicological significance (IPCS,
1989).
16
16
Cyfluthrin was tested for carcinogenicity in rats and mice and
did not show carcinogenic potential (IPCS, 1997b).
5.4 Genotoxicity
17
17
DNA synthesis (UDS) in rats (slightly positive at a high dose
level; IPCS, 1993).
18
18
seminiferous tubules in the group treated with the highest dose
(4 mg/kg).
Neonates and weanling rats are more sensitive than adults to the
acute lethal effects of type II pyrethroids deltamethrin and
cypermethrin; clinical signs were also produced at lower levels
of these pyrethroids in weanling rats than in adults (Sheets,
2000). However, when weanling rats were treated with
relatively low doses of cismethrin (3, 6, 12 mg/kg), permethrin
(30, 60, 120 mg/kg), deltamethrin (1, 2, 4 mg/kg) or
cypermethrin (9, 29, 38 mg/kg), the dose–response of the startle
response of the young animals was not different from adults.
Studies on brain concentrations of deltamethrin seem to support
the notion that the increased susceptibility of the neonate to high
doses is probably related to a limited metabolic detoxification
capacity (Sheets, 2000).
19
19
Physiological and neurochemical studies of pyrethroid-
intoxicated animals confirm that acute pyrethroid intoxication is
associated with altered nerve function, principally involving
neuroexcitatory effects in the brain, spinal cord and peripheral
nervous system. There is no single region of the nervous system
that is the locus of pyrethroid intoxication and that identifies a
mechanism of toxic action (Soderlund et al., 2002).
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20
�60 mg/kg cypermethrin or �75 mg/kg permethrin (McDaniel &
Moser, 1993). Some neurobehavioural parameters, but not all,
were affected in rats by a single oral (not specified) dose of
10 mg fenvalerate/kg, approximately 1/10 of a dose required for
convulsions to occur (Moniz et al., 1994). At a dose level of
7 mg/kg bw/day (enough to significantly decrease body-weight
development), changes were observed in the activities of
monoamine oxidase, acetylcholinesterase and Na-K-ATPase,
concomitant with behavioural changes in rats (Husain et al.,
1996).
21
of distal sural and tibial nerves, and of the maxillary division of
the fifth cranial nerve, did not reveal any change that could be
attributed to the treatment (Dyck et al., 1984).
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throughout pregnancy, no differences were observed in the
locomotion of inhibitory avoidance test of offspring at 90 days
of age, but exploratory behaviour was decreased (Gomes et al.,
1991b).
23
23
5.8 Immunotoxicity
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and mean cell volume of red blood cells. The maximum of
delayed-type hypersensitivity reaction decreased at all the three
doses (Institoris et al., 1999).
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significant increase in thyroid hormones’ (T3 and T4) serum
concentration (Kaul, 1996). However, a study conducted in rats
treated for 21 days at a daily dose of 0.2 mg/rat 1 of a
commercial formulation containing lambda-cyhalothrin at the
concentration of 20% showed a reduction of T3 and T4 serum
concentrations, with a concomitant increase of TSH serum
levels (Akhtar et al., 1996).
1
The weight of rats is not given.
26
6 EFFECTS ON HUMANS
Occupational exposure to pyrethroids may occur through dermal
contact and inhalation of dust and sprays. While inhalation is the
main route of exposure in industrial workers, the skin is the
main route of exposure in workers applying the compounds in
agriculture or public health (IPCS, 1990).
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Symptomatic acute cases generally follow accidental
overexposure or lack of care in handling the compounds at the
workplace, whereas accidental ingestion of high doses is the
main cause of poisonings for the general population. Acute
poisoning very rarely poses a life-threatening risk to the exposed
subjects, but severe poisonings and even potential for causing
mortality may arise if concentrated formulations are swallowed
(Hayes, 1982; Bateman, 2000).
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28
The use of pyrethroid/organophosphorous mixtures may
accentuate human poisonings. The volatile solvents usually
present in the commercial formulations may also enhance
pyrethroid toxicity (Ray & Forshaw, 2000). Other synergists
(piperonyl butoxide and sulfoxide) block the mixed function
oxidases, enzymes which detoxify a wide variety of compounds.
However, this kind of interaction is observed only in the
experimental model after high-dose administration, and has not
been demonstrated after exposure at the workplace or in public
health uses.
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29
6.2 Paraesthesia
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30
(for example after local application of large doses of active
ingredients – 13.8 mg/cm2 skin) (Aldridge, 1990).
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6.3 Allergic reactions
6.4 Carcinogenicity
32
6.5 Effects observed in public health uses
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33
Even though data on the levels of exposure of bednet users are
scarce, some studies available in the literature are adequate for
risk assessment purposes. In 1995, Boman carried out an
experimental study on a net measuring 9.5 m2 impregnated with
a dose of 50 mg cyfluthrin/m2. The net was hung in a closed
room, at tropical temperature and humidity. Samples were taken
daily for the first 9 days and after a 30-day period. Each sample
was collected over a 6-hour period. Mean cyfluthrin levels
10 cm inside the net ranged from 0.02 to 0.055 µg/m3, while
concentrations outside the net were slightly lower. The
difference was attributed by the author to a better air exchange
(Boman, 1995).
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and co-workers suggested as able to cause the onset of the
symptom (Zhang et al., 1991), that is 0.01–0.89 µg/m3.
Moreover, the estimated maximum quantities that could be
deposited on the skin (Barlow, 2001) were within the range of
magnitude (20–160 µg/day) potentially able to trigger
paraesthesia.
35
35
36
Table 3. Estimates of the relative safety of insecticides for over-the-counter supply (updated and modified
from WHO, 1999)
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37
affected subjects to aircraft disinsection (Bonvie & Bonvie,
1993, 1994, 1995a–b, 1998; Sutton et al., 2003).
2
Pyrethrum is not a WHO-recommended insecticide for aircraft disinsection.
38
38
The pyrethrin 3 concentrations measured during the spraying
operation and over a time period of 40 minutes afterwards
varied between 3 and 80 µg/m3 (piperonyl butoxide:
54–581 µg/m3) in the passenger cabin air; D-phenothrin
concentrations ranged from 127 to 280 µg/m3. The
concentrations found on individual surfaces showed a wide
range: very low concentrations were determined on vertical
surfaces (folding tables and overhead bins) (median values:
pyrethrin <1 ng/cm2; piperonyl butoxide <17 ng/cm2;
2
D-phenothrin <3 ng/cm ), while the concentrations on the seats,
in the area of the head-rests and below the seats were higher,
with median values between 24–39 ng/cm2 (pyrethrin),
144–233 ng/cm2 (piperonyl butoxide) and 219–1005 ng/cm2
(D-phenothrin). The concentrations in dust samples collected
from the seats and the floor were mostly <75 mg/kg.
More than 90% of the total amount inhaled was inhaled within
the first 5–10 minutes; the airborne concentrations 1–2 hours
after the spraying were less than 0.05 µg/m3 for pyrethrin and
less than 0.2 µg/m3 for phenothrin. The duration of the flight is
therefore of minor importance in the determination of exposure
levels.
3
Sum of cinerin I & II, jasmolin I & II and pyrethrin I & II.
39
39
It may be assumed that the surface areas exposed to pyrethroid
residues on aircraft seats are the back, thighs and back of the
head and neck. Based on the surface area data estimates reported
in the United States Environmental Protection Agency (EPA)
guidelines (EPA, 1998), the total exposed area is 2560 cm2 for
an adult male body, leading to a maximum estimated amount of
2.56 mg potentially absorbable through the skin (1.005 ng/cm2 x
2.56 cm2). Considering 10% dermal absorption, the dermal
intake for exposure consequent to a single flight in a disinsected
aircraft would be 0.0036 mg/kg, based on a body weight of
70 kg (adults). For children, based on a body weight of 10 kg
and a height of 80–100 cm, the total exposed area would be
500 cm2. Therefore, the estimated absorbed dose would be
0.005 mg/kg.
40
40
Machemer, 1998): Pauluhn suggested that in human exposure to
cyfluthrin, a type II pyrethroid, the “upper respiratory tract
sensory irritation”, may arise for 1-hour exposure at
concentrations slightly above 0.1 mg/m3 (Pauluhn, 1998). Since
Pauluhn did not address his study to type I compounds, his
findings do not necessarily apply to permethrin and D-phenotrin,
but in a risk assessment evaluation the possible onset of upper
respiratory tract sensory irritation needs to be taken into
account.
It has been roughly estimated that the threshold for the induction
of paraesthesia by pyrethroids is approximately 0.2 mg/cm2
(Ray, 1991). In the Fraunhofer experimental study,
measurements were made of the surface concentrations of
phenothrin after simulated in-flight spraying. The highest
concentration measured on the body surface of the sprayer was
4 µg/cm2, most values being less than 1 µg/cm2. On the
passenger seats, the concentrations did not exceed 2 µg/cm2
(Berger-Preiss, 2003).
41
After residual spraying with permethrin, Sutton et al. (2003)
reported a mean concentration for all wipe samples of arm rests,
walls and floor runners, of 18 µg/cm2, with a variation between
0.002–418 µg/cm2 and a mean concentration for fabric (pieces
cut out of seat covers of 4 µg/cm2 (0.3–11 µg/cm2)).
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filled tank. Occupants are advised to stay outside until the spray
is dry and to sweep or mop the floor before children or pets are
allowed to re-enter. Sprayed surfaces must not be cleaned.
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43
reduction of the volatilization over time and the natural
degradation of the applied compound are not taken into account.
These estimates are about 1000 times lower than the lowest ADI
established for the pyrethroids recommended by WHO for
indoor residual application.
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44
Pyrethroid metabolite concentrations in urine were in the same
range as those reported for the general population without
specific pyrethroid exposure. These data suggest the absence of
a significant indoor exposure to pyrethroids (Berger-Preiss et al.,
2002; Schettgen et al., 2002).
7 CONCLUSIONS
The data made available after 1990 refine and improve the
knowledge on pyrethroid toxicity, but the whole body of new
data does not reveal hazards not known at the time of WHO
recommendations.
45
45
Some neurobehavioural effects have been observed in
experimental animals, with NOAELs no different from those
used previously in WHO hazard characterization. Neuro-
developmental effects have been observed at dose levels at
which other effects have not been reported. The following
arguments should be considered in the interpretation of the
neurotoxic effects observed in neonatal mice, consisting of
changes in the density of muscarinic receptors at low doses:
46
46
Table 4 summarizes the NOAELs and respective ADIs,
calculated on the basis of a safety factor (SF) of 100, for the
pyrethroids currently recommended by WHO for use in public
health applications under review in this document.4
NOTE: The ADI, expressed as mg/kg bw, is the level of daily exposure to
pesticides that, after an entire lifetime of humans, appears to be unable to
cause any appreciable risk, on the basis of all the facts known at a given time.
It has been calculated from the relevant NOAEL, with the application of a
safety factor.
a
The Joint FAO/WHO Expert Committee on Food Additives has given
an ADI of 0–0.002mg/kg for cyhalothrin, from a lowest-observed-adverse-
effect level of 1 mg/kg bw/day, and a “safety factor of 500” (IPCS, 2004a).
4
As the NOAELs and ADIs are from studies using oral exposure, they
apparently give very limited information vis-à-vis local effects such as
dermal effects and respiratory tract sensory irritation.
47
47
possibility of collecting exposure data on subjects exposed to
pyrethroids as a consequence of public health uses. However,
such data do not reflect the pattern of exposure: short-term
(minutes) high-level exposure and long-term low-level exposure
give similar results.
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particular type of psychosomatic reaction. Since among the
application modalities proposed for aircraft disinsection by
WHO, the highest concentrations are anticipated with the blocks
away and top-of-descent methods, particular attention should be
paid to ensure that this kind of application is made strictly
according to the directions for use of the involved compound.
5
See http://www.who/int/whopes/quality
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