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

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.

Introduction

Blood-feeding arthropods, insects, and Acari, are important vectors of human infectious diseases such as malaria, 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 essential 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 hematophagous 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 respond to stimuli produced by the host, such as carbon dioxide, 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 certain 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, 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 postattachment (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.

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

The temperature of the repellent-treated surface might be higher due to the nearby human body.

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 repellent 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 increase 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 attractants 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.

A more specialized test system suitable for ticks showing the ambush type of host seeking is the Moving Object Bioassay (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., taking 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^™ 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 individual 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 certain test protocols, volunteers are advised to perform specified 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, pathogen-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, describing the minimum data requirements necessary for registration 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. Although both assays seem similar at first sight, they can produce 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 alternative 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 fingertip 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, Falótico 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 upward 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 repelled 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 ED₅₀ or ED₉₀, describes the inherent repellency of a substance, irrespective of how long repellency lasts. The complete protection time is defined as the time from application of a given repellent until (1) the first tick is not repelled, or until (2) the first tick “confirmed” by a second tick within a certain time interval is not repelled. Ideal characteristics of a repellent are prolonged efficacy against arthropods, lack of toxicity, absence of damage to clothing and plastics, and proven resistance to washing. The US Centers for Disease Control and Prevention, and the European community (Directive 98/8) 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).

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-undecanoneBioUD^®	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.

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^™ (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 Corymbia 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 chemical 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.

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 chemical 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 considered 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, nootkatone) 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 advantage 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 essential oils to increase their repellent activity, by reducing the evaporation process on the skin. Some fixatives such as genapol (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 establish. 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 composition. 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 different 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. Although 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 Amblyomma 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 protected for 2 h whereas picaridin protected only for 1 h (Pretorius 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 moderately 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 preparations 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 dodecanoic 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 efficiency (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 ketone, 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 impregnated and not impregnated with repellent, BioUD^® provided better repellency than DEET on A. americanum and I. scapularis. 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), dihydronepetalactone, was effective against I. scapularis in laboratory testing using human subjects (Feaster et al. 2009). Similarly, the active compound isolongifolenone, a sesquiterpene isolated 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 decrease 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 Second 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. scapularis in the eastern United States. Whether applied to clothing as an aerosol spray or as an impregnant, permethrin provided excellent protection from tick bites and was significantly more effective than the extended-duration DEET formulation. The first study exploring the effect of permethrin 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 protection 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 nonimpregnated uniforms. According to the authors, the number 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,” Peripel^®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 results 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 preparation 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 compared 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 demonstrated, 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, Rossbach et al. 2010). Because permethrin is toxic for the environment, 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, carvacrol, 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 conducted with impregnated bed nets, suggests that impregnation 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, and I. scapularis. Laboratory studies were conducted with elemol, amaryllis oil, nookatone, 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 according to the amount of product (Carroll et al. 2011b). BioUD^® (2-undecanone, derived from tomato plant) tested 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 dipping 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 prevention, but it can expose people to high concentrations of the product. For safety reasons, long-lasting impregnated clothing 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-transmitted 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 attached 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 instructions 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.

Footnotes

Acknowledgments

N. Boulanger thanks the Fulbright-Région Alsace foundation and the Monahan foundation for their financial support.

Author Disclosure Statement

There are no conflicts of interest.

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