Tick Repellents for Human Use: Prevention of Tick Bites and Tick-Borne Diseases

Abstract

Abstract Ticks are arthropods and the most important vectors of major human diseases after mosquitoes. Due to their impact on public health, in vitro and in vivo assays have been developed to identify molecules with repellent activities on ticks. Repellents are useful to reduce tick bite exposure and the potential transmission of pathogens; they can be used topically or in impregnated clothing. Presently, mainly synthetic molecules are commercialized as skin repellents, e.g., N,N-diethyl-meta-toluamide (DEET), IR3535, picaridin or KBR 3023, and para-menthanediol. Permethrin is largely used for fabric impregnation. Intensive research has been conducted to identify new molecules with repellent activity and more recently, plant-derived molecules, as an alternative to synthetic molecules.

Full text

REVIEW
Tick Repellents for Human Use:
Prevention of Tick Bites
and Tick-Borne Diseases
Fre´de´ ric Pages,
1
Hans Dautel,
2
Ge´ rard Duvallet,
3
Olaf Kahl,
2
Ludovic de Gentile,
4
and Nathalie Boulanger
5
Abstract
Ticks are arthropods and the most important vectors of major human diseases after mosquitoes. Due to their
impact on public health, in vitro and in vivo assays have been developed to identify molecules with repellent
activities on ticks. Repellents are useful to reduce tick bite exposure and the potential transmission of pathogens;
they can be used topically or in impregnated clothing. Presently, mainly synthetic molecules are commercialized as
skin repellents, e.g., N,N-diethyl-meta-toluamide (DEET), IR3535, picaridin or KBR 3023, and para-menthanediol.
Permethrin is largely used for fabric impregnation. Intensive research has been conducted to identify new mole-
cules with repellent activity and more recently, plant-derived molecules, as an alternative to synthetic molecules.
Key Words: Ticks—Repellents—N,N-diethyl-meta-toluamide (DEET)—IR3535—Picaridin (KBR 3023)—para-
menthanediol—Permethrin—Plant-derived molecules.
Introduction
Blood-feeding arthropods, insects, and Acari, are im-
portantvectorsofhumaninfectiousdiseasessuchasmalaria,
dengue, Lyme borreliosis, and rickettsial diseases. Consequently
they are a major cause of morbidity and mortality (Katz et al.
2008, Debboun and Strickman 2013). Because human skin is a
key interface in the transmission of these diseases (Frischknecht
2007), strategies to prevent the contact between human and
vectors have to be considered. Arthropod repellents are an es-
sential part of these strategies. Although mainly developed
against mosquitoes, repellents are more and more considered to
prevent tick-borne diseases (Bissinger and Roe 2010). Following
an overview of the biology of hard and soft ticks and the most
important pathogens transmitted by them, we describe the main
tick bioassays used to identify molecules with anti-tick activities.
We then present the currently available data on synthetic and
plant-derived molecules and their efficacy to repel ticks.
Biology of Ticks
Ticks belong to the subphylum Chelicerata, subclass Acari,
order Acariforms, and suborder Ixodida (Mehlhorn 2001).
Argasidae (soft ticks) and Ixodidae (hard ticks) are two large
families. Their life cycle includes three postembryonic life
stages—larva, nymph, and adult. They are all obligate he-
matophagous ectoparasites, but they differ in their feeding
behavior. Hard ticks take only one blood meal per stage (from
a few days to more than 1 week), whereas soft ticks in their
nymph and adult stages may feed several times for less than
1 h ( Mehlhorn 2001, Schwan and Piesman 2002). The behavior
of ticks is highly variable depending on the species. The most
common strategy is questing behavior. Ticks that hunt re-
spond to stimuli produced by the host, such as carbon di-
oxide, lactic acid, ammonia, heat, shadows, or vibrations
(Sonenshine 1991).
Ticks transmit a large variety of pathogens to humans and
animals. They are considered to be second worldwide after
mosquitoes as vectors of human disease (Piesman and Eisen
2008). Although the risk of acquiring tick bites is high in cer-
tain areas, the risk of pathogen transmission is low if attached
ticks are removed promptly, because for most bacteria, e.g.,
Borrelia and Anaplasma, migration from the midgut to the
salivary glands of the tick must take place before transmission
occurs (Kocan et al. 2008, Piesman and Eisen 2008). However,
1
Cire OI, St. Denis Cedex 9, Re
´union, France.
2
Tick-radar GmbH, Berlin, Germany.
3
Universite
´Paul-Vale
´ry—UMR 5175 CEFE, Centre d’Ecologie fonctionnelle et e
´volutive, Montpellier Cedex 5, France.
4
Laboratoire de Parasitologie-Mycologie, Institut de biologie en sante
´, Centre Hospitalier Universitaire, Angers Cedex 9, France.
5
EA7290: Virulence bacte
´rienne pre
´coce, Groupe Borre
´liose de Lyme, Membre du Centre National de Re
´fe
´rence Borrelia, Universite
´de
Strasbourg, Strasbourg, France.
VECTOR-BORNE AND ZOONOTIC DISEASES
Volume 14, Number 2, 2014
ªMary Ann Liebert, Inc.
DOI: 10.1089/vbz.2013.1410
1

tick-borne encephalitis virus is already present in the salivary
glands of unfed vector ticks, so transmission to the host can
occur rapidly (Mansfield et al. 2009). A similar phenomenon
has been described for relapsing fever spirochetes (Schwan
and Piesman 2002), so that in most tick-borne pathogens, a
very low risk of transmission exists earlier than 12 h post-
attachment (Strickman et al. 2009). Because most tick bites
occur at the nymph stage, they can easily go unnoticed.
Repellents can be a good protection for people exposed to
tick bites.
Bioassays to Identify Molecules with Antitick Activities
There are three types of repellent tests: (1) In vitro assays
performed in the absence of any tick host- or host-associated
stimulus; (2) in vitro assays, where some chemical or physical
stimuli attractive for ticks is packaged with the repellent; or (3)
in vivo assays using living hosts (Dautel 2004).
In vitro assays
Laboratory in vitro tests are cheap and can be performed
quickly (Bissinger and Roe 2010) (Table 1). The simplest
versions consist of filter paper placed in a Petri dish, where
one-half of the filter is treated by repellent, while the other
half is untreated. The position of the ticks is recorded at
certain time intervals (Bissinger et al. 2009). Alternatively,
the tick may be placed in the untreated center of the filter
paper surrounded by a circular barrier of repellent; whether
the tick enters or crosses this barrier is recorded (Carroll et al.
2004). Such tests have the disadvantage, however, that it is
unknown whether the ticks under study are in a host-seeking
mode.
Host-seeking ticks, particularly those exhibiting ambush
behavior, such as Ixodes ricinus, typically climb a vantage point
when initiating the search for a host. Additionally, I. ricinus,
after transfer to a host, also shows a tendency to walk up on
that host (Dautel et al. 2013). Thus, ticks climbing up in a re-
pellent assay are considered more likely to be in a host-seeking
mode. A climbing assay may consist of a stick (Kaaya et al.
1995, Mwangi et al. 1995, Ndungu et al. 1995), or a vertical filter
paper strip, the upper part of which is treated with repellent
(Carroll et al. 1998, Carroll et al. 2004, Carroll et al. 2011a). A
tick is allowed to climb the stick or filter paper, and whether it
walks a certain distance into the treated zone is recorded.
Some tick attractants can be added in the assays to in-
crease the tick’s motivation to walk onto the repellent-treated
test surface. Jaenson et al. (2005, 2006) and El-Seedi et al.
(2012) used vertical test tubes with their upper opening
covered by a mesh treated with repellent. Ticks were placed
inside the tube, and the observer’s hand was placed above
the mesh. Whether the ticks climb up in response to attrac-
tants from the hand and walk onto the treated mesh is then
recorded. Dietrich et al. (2006) used a similar assay: A short
stick with a cotton tip treated with repellent was placed
vertically inside a vial, with the cotton situated in its upper
third. The upper opening of the vial was covered by a mesh,
and a human hand was placed above to induce the tick inside
the vial to climb up. I. scapularis ticks climbing up to the level
of the cotton tip were scored as not repelled. This assay is
different from the others because the ticks do not have the
opportunity to contact the repellent, but instead respond
solely to the repellent odor in the air.
Table 1. Overview of Some In Vitro Tests Published During the Past Years
Laboratory tests Field tests
Tick behavior Walking Climbing Climbing Climbing Walking/clinging Walking Clinging Clinging/walking
Type of assay Horizontal filter
paper
Vertical filter
paper;
vertical stick
Vertical tube Vertical tube with
stick inside
Moving object
bioassay
Kramer sphere Cloth dragging Volunteers walking
Test surface
temperature
Room
temperature
Room
temperature
Room
temperature
a
Room temperature
a
35C Room
temperature
Outside
temperature
Outside
temperature
a
Host stimuli? No No Human hand
(short
distance)
Human hand (short
distance)
Warmth,
movement
Olfactory
attractants
(from distance)
Movement Human body
(short distance)/
movement
Is the tick
host-seeking?
Unknown Probably yes Probably yes Probably yes Yes Most probably
yes
Yes Yes
Literature
examples
Carroll et al. 2004,
Bissinger et al.
2009
Ndungu et al.
1995, Carroll
et al. 2011
El Seedi et al.
2012, Jaenson
et al. 2005
Dietrich et al. 2006 Dautel 2004,
Dautel et al. 2013
McMahon 2003 Jaenson et al.
2006, El-Seedi
et al. 2012
Jordan et al. 2012
a
The temperature of the repellent-treated surface might be higher due to the nearby human body.
2 PAGES ET AL.

A more specialized test system suitable for ticks showing
the ambush type of host seeking is the Moving Object Bioas-
say (MOB) (Dautel et al. 1999). In this assay, the tick clings to a
heated, rotating drum, and whether the tick approaches the
drum, clings to it, and remains on the repellent-treated surface
of the drum or drops off is recorded. Thus, the ticks in this
assay show the typical behavior of ambushing ticks, i.e., tak-
ing advantage of a sudden opportunity to grasp hold. This
assay produces results that are quite close to an in vivo test
with humans (Dautel et al. 2013).
In vivo assays and field tests
In vivo tests with the repellent applied directly onto the host
should yield results that more closely reflect repellent efficacy
under real field conditions. A field test that reflects the real-life
situation best was carried out by Gardulf et al. (2004) in
Sweden. A total of 111 volunteers, all spending at least 2 h per
day outdoors in a tick habitat were involved for a period of 4
weeks. Each volunteer applied 30% Citriodiol
TM
repellent on
their lower legs before starting daily outdoor activities for a
period of 2 weeks (maximum of three applications per day),
and spent another 2 weeks outdoors without any repellent
applied. As a result, 42 tick bites were recorded during the
period, when a repellent was applied, and 112 when it was
not. However, this assay exposes volunteers to a high risk of
acquiring a tick-borne infection and can show substantial in-
dividual variations (e.g., how the product is applied by the
user, or variants in outdoor activity). Moreover, high numbers
of volunteers are required. To reduce these problems, in cer-
tain test protocols, volunteers are advised to perform speci-
fied activities, e.g., walking a certain distance or time at a
specified speed, interrupted by regular tick-check intervals.
Ticks found on a volunteer are not allowed to attach, but are
removed or observed for a certain time period before removal.
While Solberg et al. (1995) used repellent applied onto the
skin, others applied it onto clothes (Schreck et al. 1986, Lane
1989, Evans et al. 1990, Jaenson et al. 2006, Faulde et al. 2008,
Jordan et al. 2012). Unfortunately, systematic studies that
compare the efficacy of a repellent when applied on skin
versus on clothes are missing, making comparison of such
studies difficult.
In vivo studies performed in the laboratory allow control of
temperature, humidity, and light conditions. Usually, patho-
gen-free laboratory ticks of a specified age are used, the
number of ticks contacting the test person is known, and
specific behaviors such as the tick’s walking direction or the
time a given tick spends on treated skin are recorded more
precisely. For evaluation of efficacy, specific test guidelines of
the US Environmental Protection Agency ([EPA] OPPTS
810.3700, available at the EPA website) are available, de-
scribing the minimum data requirements necessary for reg-
istration in the United States. According to this protocol, ticks
are placed on an untreated skin area of a vertically held arm,
and whether the tick walks upward into a treated zone for at
least 3 cm (Carroll 2008) and/or remains there for at least
1 min is recorded. In an assay used by the Stiftung Warentest,
a German consumer care organization, ticks are delivered on
a copper plate and then placed on a vertically held arm or leg
treated with repellent. Whether the tick enters the skin and
walks a distance of at least 5 cm on treated skin within a
certain time period (Schwantes et al. 2008) is recorded. Al-
though both assays seem similar at first sight, they can pro-
duce quite different results (Dautel et al. 2013). A reason
might be that in the EPA protocol ticks have to chose between
staying on untreated skin or walking onto treated skin,
whereas in the Stiftung Warentest assay, the tick’s choice is to
stay either on a copper plate or to walk onto treated skin.
Staying on untreated skin might be a more acceptable alter-
native for a tick than staying on a copper plate, leading to a
higher motivation of the tick to walk onto the treated skin in
the latter case.
More convenient and safer for the volunteers is the fin-
gertip assay, which was developed by Schreck et al. (1995). A
finger is held vertically, touching the ground with its tip. Ticks
enter the untreated tip of the finger, and whether the ticks
walk upward for a certain distance into the repellent-treated
upper zone of the finger is recorded. A number of studies have
used this assay for repellent testing (Pretorius et al. 2003,
Carroll et al. 2005, Carroll et al. 2007, Falo
´tico et al. 2007,
Zhang et al 2009).
Although the described laboratory in vivo studies should
yield reproducible results, it is unknown whether the results
reflect the ‘‘real’’ efficacy of the repellent when used under
field conditions. In an attempt to combine field aspects with a
laboratory test, Carroll et al. (2008) developed a specific assay.
In the laboratory, volunteers stay in a tray with simulated
forest floor containing Amblyomma americanum ticks. Whether
or not the ticks enter the volunteer’s bare foot and walk up-
ward crossing 5 cm of repellent-treated skin is observed. This
test might be suited for ticks of the hunter type.
Last, because tick dragging or flagging is an effective
method to collect exophilic ticks of the ambush type, this
technique might be used for repellent evaluation. To do so, a
certain area of tick habitat is flagged with a repellent-treated
flag and another area of equal size with an untreated flag, and
the number of collected ticks is compared ( Jaenson et al. 2006,
El-Seedi et al. 2012). In this study, the resulting repellency
with I. ricinus ticks was lower than that obtained with the
vertical tube assay ( Jaenson et al. 2006). This might suggest
that a moving object like a drag is a strong stimulus for the
species to cling to, although it might eventually become re-
pelled later on, after some exposure time on the treated flag.
Again, it would be very interesting to compare the repellent
efficacy evaluated by this method with that of an in vivo test.
Repellents for Human Use, Available on the Market
A repellent is a natural or synthetic substance that causes an
arthropod to go away from its initial target. Therefore, it limits
or even prevents the human–vector contact. Repellents can be
classified into two categories—plant extracts or essential oils
and synthetic products.
The effective dose, most often expressed as the ED
50
or
ED
90
, describes the inherent repellency of a substance, irre-
spective of how long repellency lasts. The complete protection
time is defined as the time from application of a given repel-
lent until (1) the first tick is not repelled, or until (2) the first
tick ‘‘confirmed’’ by a second tick within a certain time in-
terval is not repelled. Ideal characteristics of a repellent are
prolonged efficacy against arthropods, lack of toxicity, ab-
sence of damage to clothing and plastics, and proven resis-
tance to washing. The US Centers for Disease Control and
Prevention, and the European community (Directive 98/8)
TICK REPELLENTS FOR HUMAN USE 3

recommend the same molecules as topical repellents: N,N-
diethyl-meta-toluamide (DEET), picaridin (KBR 3023),
p-menthane-3,8-diol (PMD), and IR3535 (Table 2). Indalone,
dimethyl phthalate (DMP), and ethyl hexanediol (EHD) have
been removed from the market either due to their toxicity or to
their inefficacy (Bissinger and Roe 2010, PPAV 2011).
Characteristics of synthetic molecules
DEET is the oldest repellent currently used. Marketed in
1957 in the United States, DEET is a colorless, slightly oily
solvent. It can alter plastics and synthetic fabrics. DEET is
absorbed in the superficial layers of the skin, and around 5%
of the product has systemic diffusion that can be increased
with the simultaneous use of sunscreen (Katz et al. 2008).
Microencapsulation reduces the potential toxicity of DEET
in humans (Kasting et al. 2008) and a long-lasting formula,
Ultrathon
TM
(3M), has been developed for the military (Katz
et al. 2008). The addition of cyclodextrins reduces evaporation
and increases the duration of action without increasing skin
penetration (Proniuk et al. 2002). Concentrations of 10–35%
provide an adequate protection, with a plateau at 50%. DEET is
regularly used by 30% of the people in the American market,
has been commercialized for over seven decades, and its safety
record is reliable (Katz et al., 2008). The concentration has to be
adjusted according to the age of the user (PPAV 2011).
PMD (also known as paramenthanediol) is derived from
lemon eucalyptus (Eucalyptus maculata citriodora or Cor-
ymbia citriodora). PMD is known as Quwenling in China and
in the United States as Oil of Lemon Eucalyptus through its
EPA registration. PMD is now synthesized. The full che-
mical name, 2-(2-hydroxy-2-methyl)-5-methyl-cyclohexanol
(PMDRBO) is a cis and trans mixture of p-menthane-3,8-diol.
In reports of Canadian, American, or European agencies, no
sensitization or irritation is observed, but this compound can
be irritating to the eyes. Registered in the United Kingdom by
Citrefine as Citriodiol

, it contains 64% of PMD. This product
is not as effective against ticks as DEET or picaridin.
Table 2. Most Important Natural and Synthetic Repellents Already Marketed or in Development
Molecules Development Concentration Disadvantages Advantages Other specificity
Synthetic repellents registered in US, Canadian, and European agencies
DEET 1953 10–50% Oily, alters
plastics,
irritating for
the eyes
Toxicology
well-known;
cheap, broad-
spectrum
repellent
DEET 33% =slow
release polymer =
Ultrathon(3M)
Picaridin or KBR3023
(derived
from piperidine)
BAYREPEL

1980s (Bayer) 20–30% Not so efficient
on ticks
Broad spectrum,
does not alter
plastics, low
odor
IR3535 or EBAAP 1975 (Merck) 20–35% Low repellency
at low
concentrations
Safe, good
record
Would be the
best on ticks;
structure
related to
beta-alanine
Most important
marketed plant-derived
products
p-menthane-3,8-diol
(Quwenling) Citriodiol

20–30% Contains citral
(skin irritating),
eye irritating
Eucalyptus:
Corymbia
citriodora
Permethrin (pyrethrinoids) 1979 0.5% More toxic than
repellent, should
not be applied
to skin
Clothing repellent,
polymer-coating
repellent
Most-studied tick repellent compound derived from plants
Carvacrol NA Grapefruit oil
and Alaskan
cedar
1-alpha-terpineol NA Cleome monophylla
Tanacetum vulgare
2-undecanone
BioUD

2007 7.75% Lycopersicon hirsutum,
wild tomato
Nootkatone 0.0458 (wt/vol) Chamaecyparis
nootkatensis-Alaskan
yellow cedar
Dodecanoic acid (DDA),
Contrazeck

10% Coconut and palm
kernel oil
Sources: Katz et al. 2008, Strickman et al. 2009, Bissinger and Roe 2010, Debboun and Strickman 2013.
NA, not available.
4 PAGES ET AL.

IR 3535, marketed by Merck in 1973, is also known as EBAAP
or by its chemical name 3-(N-acetyl-N-butyl)aminopropionic
acid ethyl ester. According to the criteria of the EU Directive
67/548/EC on chemicals, IR3535

is irritating to the eyes.
Picaridin or KBR 3023 was introduced on the repellent
market in Europe in the 1990s by Bayerand in 2005 in
the United States. It is derived from piperidine, and its che-
mical name is 2(2-hydroxyethyl)-1piperidinecarboxylic acid
1-methylpropyl ester. Piperidine is claimed to be as effective
as DEET. It is odorless, is not greasy, and does not damage
plastics or fabrics (Katz et al. 2008). For a short exposure,
picaridin 30% is safe for children under the age of 12 with
two daily applications. In children 13–17 years old and
adults, three daily applications of picaridin 30% is consid-
ered to be safe (PPAV 2011). A formulation of 20% picaridin
provides 8–10 h of protection (Katz et al. 2008, Strickman
et al. 2009), but skin allergy has been reported (Corazza et al.
2005).
Characteristics of plant-derived products: Essential oils
An essential oil is a fragrance obtained from a raw botanical
material. Essential oils are rapidly absorbed by the lungs, skin,
and digestive tract. These extracts are complex mixtures
containing mainly terpenoids (geraniol, citronellol, nootka-
tone) and less frequently aromatic compounds (eugenol,
vanillin) (Strickman et al. 2009). Natural products can be a
priori safer for human use and can provide an ecological ad-
vantage compared to nondegradable compounds such as
DEET. However, they can be toxic; some of them are skin
irritants and can contain carcinogens such as methyl eugenol
(Strickman et al. 2009). The majority of these natural products
active against ticks are terpenoids (Bissinger and Roe 2010).
Plants regularly mentioned in the scientific literature are
lemongrass (Cymbopogon nardus, C. excavatus martinii), cedar
(Chamaecyparis nootkatensis and Juniper virginiana), eucalyptus
(Eucalyptus maculata), geranium (Pelargonium reniforme), mint
(Mentha piperita), lavender (Lavandula augustifolia), lemon-
scented gum (Corymbia citriodora), soybeans (Neonotonia
wightii), and wild tomato (Lycopersicon hirsutum) (Choochote
et al. 2007, Strickman et al. 2009, Bissinger and Roe 2010)
(Table 2). Vanillin is often added to the formulations of es-
sential oils to increase their repellent activity, by reducing the
evaporation process on the skin. Some fixatives such as gen-
apol (10%) and polyethylene glycol (10%) are also used (Amer
and Mehlhorn 2006).
Several aspects complicate the choice of an effective plant-
derived repellent. A wide variety of products can be found
around the world, and a comprehensive list is difficult to es-
tablish. According to the geographical and botanical origin of
the plant and the extraction technique used, the composition
of the essential oil can vary greatly. Environmental factors
such as sunlight and humidity can strongly affect the com-
position. Because most of these products have not been tested
for their effectiveness in reliable assays, their efficacy should
be regarded with some skepticism.
Comparative Studies on the Efficacy of Repellents
Comparative studies have been performed either as in vitro
assays or on volunteers in laboratories or in the field in dif-
ferent areas of the world. Most of these studies were done
on mosquitoes with the aim of decreasing the incidence of
malaria. However, some of them have been conducted to
assess specifically the effectiveness of repellents on ticks. Al-
though soft ticks also transmit certain tick-borne disease
agents (for example, relapsing fever borreliae), very few data
are available to confirm the efficacy of repellents against these
ticks. An old study reports partial protection against Argas
persicus (Kumar et al. 1992). In a review of the literature,
Strickman et al. (2009) declare no protection at all of DEET
against soft ticks.
DEET is the most often tested on hard ticks. Against Am-
blyomma hebraeum, the principal vector of Rickettsia africae,
different concentrations (19.5%, 31.6%, 80%) of DEET were
tested using the human ‘‘finger tip’’ bioassay. Less than 50%
repellency was provided after 4 h for these three products
( Jensenius et al. 2005). When a topically applied 20% lotion of
DEET was compared to the efficacy of picaridin (KBR 3023) at
20% in similar conditions against Amblyomma, DEET pro-
tected for 2 h whereas picaridin protected only for 1 h (Pre-
torius et al. 2003). Comparing three repellents, 33% DEET,
20% picaridin, and 10% IR3535, applied onto the ankles of
volunteers in the laboratory, it was shown that A. americanum
can be repelled for several hours. Formulations with at least
20% ingredient were highly effective because only 10% of the
tested ticks crossed the treated area during the 12 h testing
period (Carroll et al. 2010). Working under field conditions in
Switzerland, Staub et al. (2002) evaluated the effectiveness of a
spray containing 15% of either DEET or EBAAP (IR3535

)on
forestry workers. The repellent effect on I. ricinus was mod-
erately active, with 40% effectiveness against ticks whatever
the molecule tested, when applied under everyday conditions
for a period of 5 months. Overall, IR3535 is more efficient
against ticks than DEET (Strickman et al. 2009). To improve
the efficacy of synthetic repellents, different formulations
were tested. DEET in alcoholic solution or liposomal prepa-
rations of DEET (LIPODEET) and SS220 (Morpel 220) were
applied on rabbits to repel A. americanum and Dermacentor
variabilis. The liposomal preparation of DEET was the most
efficient for repelling both tick species, with no tick binding
to rabbit ears for up to 72 h after application (Salafsky et al.
2000). SS220 also seems to be very efficient against hard
ticks (Carroll et al. 2005, Carroll et al. 2008).
Essential oils and plant extracts represent alternatives to
synthetic molecules. Schwantes et al. (2008) compared the
efficacy of different formulations containing 10% of dodeca-
noic acid (DDA) on different stages of I. ricinus. DDA is a
carboxylic acid derived from coconut oil or palm kernel oil.
Using the moving object (MO) bioassay, it showed an effi-
ciency (80–100% repellency) of 6 h with 10% DDA compared
to the reference repellent picaridin. Bissinger et al. (2009)
evaluated the effectiveness of BioUD

(11-carbon methyl ke-
tone, 2-undecanone), an active ingredient derived from wild
tomato plants, to an equivalent repellency of 98.11% DEET
against A. americanum, D. variabilis, and Ixodes scapularis.
Tested in the laboratory using filter paper surfaces impreg-
nated and not impregnated with repellent, BioUD

provided
better repellency than DEET on A. americanum and I. scapu-
laris. No difference of efficacy was observed between the
two products on D. variabilis. The active compound isolated
from the essential oil of Catmint, (Nepeta cataria), dihy-
dronepetalactone, was effective against I. scapularis in laboratory
testing using human subjects (Feaster et al. 2009). Similarly, the
active compound isolongifolenone, a sesquiterpene isolated
TICK REPELLENTS FOR HUMAN USE 5

from the pine tree, was effective against Ixodes in laboratory
bioassays.
Systemic repellents like garlic extract are ideal because of
their low cost and because their impact on the environment
would be negligible. A study was conducted with garlic as a
potential repellent against ticks. This study, conducted in the
Swedish army, shows an effect of garlic on ticks with a de-
crease of tick bites in people who consumed garlic versus
placebo (Stjernberg and Berglund 2001). However, the
methodology of this study has been criticized (Katz et al.
2008). In addition, adverse effects such as allergic reactions
and alteration of coagulation have been described in certain
patients (Borrelli et al. 2007).
Acaricide-treated clothing to avoid tick bites
The first impregnation of clothing started during the Sec-
ond World War with repellents developed by the US Army.
DMP, benzyl benzoate, and M-1960 (a cocktail of different
molecules) were tested against trombiculids (a prostigmatic
mite, vector of scrub typhus), mosquitoes, and ticks (McCain
and Leach 2007). In the 1960s, jackets impregnated with DEET
or other repellents were tested successfully. DEET resisted
washing better, lasted longer on fabrics, and seemed to be
more efficient against certain ticks, such as A. americanum,D.
variabilis, and I. scapularis (Schreck et al. 1986, Lane 1989,
Evans et al. 1990). In the 1990s, DEET was supplanted by
permethrin in clothing impregnation that was more resistant
to washing.
Permethrin is a synthetic pyrethroid first marketed in
1973. It acts as a repellent and as an insecticide and is very
active against ticks (Katz et al. 2008). Permethrin can be
applied to clothing, but it should not be applied to skin to
protect from tick bite (Bissinger and Roe 2010). Most studies
of permethrin were first conducted in the 1980s on I. scapu-
laris in the eastern United States. Whether applied to clothing
as an aerosol spray or as an impregnant, permethrin pro-
vided excellent protection from tick bites and was signifi-
cantly more effective than the extended-duration DEET
formulation. The first study exploring the effect of per-
methrin on the main European vector tick I. ricinus took
place in 1997 (Romi et al. 1997). This study, conducted in a
laboratory, confirmed the potential protection conferred by
permethrin against European ticks, but also the negative
impact of repetitive washings on impregnated fabrics. Most
studies conducted thereafter in Europe were performed with
long-lasting impregnated fabrics developed for the US
Army. A field study conducted in France assessed the pro-
tection against D. marginatus tick bites conferred by the long-
lasting permethrin-impregnated battle dress used overseas
by French forces (Ho-Pun-Cheung et al. 1999). In the group
wearing impregnated uniforms, 15% of soldiers reported at
least a tick bite against 26% in the group wearing non-
impregnated uniforms. According to the authors, the num-
ber of tick attachments was significantly lower in soldiers
with impregnated uniforms. Faulde et al. (2003) assessed the
contact toxicity and residual activity of different permethrin-
based fabric impregnation methods against wild nymphal
I. ricinus. A long-lasting polymer-coating impregnation
method was compared to two ‘‘dipping methods,’’ Peri-
pel

10 used by the UK army and IARTF used by the US
forces. Before washing treated fabrics, the knockdown effect
of the polymer-coating method was significantly higher than
the IARFT and Peripel

10 dipping methods. After 100
launderings, the knockdown activity remaining in fabrics
treated by the UTEXBEL method was comparable to the re-
sults obtained after 20 launderings with Peripel

10 and after
28 launderings with IARFT. This laboratory study on long-
lasting impregnated fabrics was followed by a field study
that confirmed the excellent efficacy of this tissue prepara-
tion in the prevention of tick-borne diseases (Faulde et al.
2008). Long-lasting impregnated clothing is also available in
the United States and in Europe for outdoor workers and
travellers. However, few studies are available to assess their
efficacy to protect against tick bites. A recent study com-
pared nontreated summer-weight clothing to summer-
weight clothing treated by different methods of permethrin
impregnation (home-made or factory-based). Whatever
clothing impregnation method used, significant protective
benefits were shown (3.4 times) compared to nontreated
outfits against laboratory-reared I. scapularis nymphs (Miller
et al. 2011). Another study was conducted with outdoor
workers in the United States and pointed out the efficiency of
factory-treated clothing with permethrin versus untreated
clothing to avoid tick bites (Vaughan et al. 2011).
The dermal absorption of permethrin has been demon-
strated, and different models have been proposed to assess it
(Hughes and Edwards 2010, Ross et al. 2011). This risk has
been evaluated (especially after the first Gulf War) for
manual and factory long-lasting impregnation as well as its
effect when combined with DEET (Appel et al. 2008, Ross-
bach et al. 2010). Because permethrin is toxic for the envi-
ronment, long-lasting factory-impregnated clothing should
be preferred.
With the progress of long-lasting impregnation techniques
and with the increase of pyrethroid resistance, alternatives to
permethrin have been studied. Studies were conducted with
DEET, KBR 3023, IR3535, or new natural compounds (plant-
derived) such as limoneme, 2-undecanone, essentials oils of
lemon, eucalyptus, geranium, lavender, nootkatone, carva-
crol, elemol, amaryllis oil, etc. ( Jaenson et al. 2006, Bissinger
et al. 2009, Zhang et al. 2009, Carroll et al. 2010, Carroll et al.
2011b, Jordan et al. 2012). New formulations of DEET (e.g.,
microencapsulation) have also been developed that reduce
the volatility of the molecule to increase the resistance to
washing while maintaining sufficient bioavailability. Fabrics
impregnated with DEET or IR3535 have been tested in the
laboratory against I. ricinus nymphs. When nymphs were
constantly exposed to impregnated fabrics, knockdown and
killing effects were observed. This work, which was con-
ducted with impregnated bed nets, suggests that impregna-
tion of clothing with synthetic repellents protects against ticks
(Faulde et al. 2010). Nevertheless, the effect of repeated
launderings remains to be tested.
Concerning natural compounds (extracts or commercial
products) in clothing impregnation against ticks, different
studies have been carried out to assess the protection against
D. variabilis,A. americanum,andI. scapularis. Laboratory
studies were conducted with elemol, amaryllis oil, nooka-
tone, carvacol, and 2-undecanone. Elemol and amaryllis oil
were as effective as DEET in repelling A. americanum and
I. scapularis, but the sensitivity of the two species varied ac-
cording to the amount of product (Carroll et al. 2011b).
BioUD

(2-undecanone, derived from tomato plant) tested
6 PAGES ET AL.

was found to be as effective as DEET on clothing in repelling
D. variabilis;BioUD

compared to commercially available
repellents was as effective as 20% DEET and more effective
than IR3535 in repelling D. variabilis and A. americanum
(Bissinger et al. 2009, Kimps et al. 2011).
Currently, only permethrin solutions for spraying or dip-
ping and some long-lasting fabrics are commercially available
to protect people from tick bites. Self-impregnation with
permethrin has clearly proven its efficacy in tick bite pre-
vention, but it can expose people to high concentrations of the
product. For safety reasons, long-lasting impregnated cloth-
ing is recommended, although most of the studies assessing
its efficacy were conducted in the army. New products and
impregnation technologies should lead to better prevention of
tick bites (Pohlit et al. 2011, Solomon et al. 2012).
Conclusions
An integrated approach to avoid tick bites and tick-trans-
mitted pathogens is necessary. This includes the use of both
protective clothing and tick repellents, checking the entire
body daily if exposed to ticks, and prompt removal of at-
tached ticks before transmission of infection may occur
(Wormser et al. 2006, Piesman and Eisen 2008, PPAV 2011).
Concerning the use of repellents, more reliable assays specific
for ticks are necessary with clear technical guidelines to avoid
high variations in results (Dautel et al. 2013). All repellents
must be applied on skin or on clothing according to the in-
structions of the manufacturers and according to official
agencies, which have fixed precise rules for their use. With the
increasing incidence of arthropod-borne diseases in different
areas of the world, new molecules are needed to prevent the
transmission of pathogens.
Acknowledgments
N. Boulanger thanks the Fulbright-Re
´gion Alsace founda-
tion and the Monahan foundation for their financial support.
Author Disclosure Statement
There are no conflicts of interest.
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Address correspondence to:
Nathalie Boulanger
Institute of Bacteriology
University of Strasbourg
3 rue Koeberle
´
Strasbourg 67 000
France
E-mail: nboulanger@unistra.fr
TICK REPELLENTS FOR HUMAN USE 9