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Travel medicine (6) Bite avoidance

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The Pharmaceutical Journal Vol 265 No 7111p298-304
August 26, 2000 Continuing education

Travel medicine (6) Bite avoidance

By Larry Goodyer, PhD, MRPharmS

Insect bite avoidance is an important method of reducing the risk of contracting many of the tropical diseases covered in previous articles in this series. This article focuses on methods of bite avoidance

Travel medicine article index

All travellers to the tropics should be made aware of the importance of bite avoidance. A large survey of over 100,000 European tourists to east Africa indicated that the risks of malaria are significantly reduced if adequate bite avoidance measures are taken.1
Repellents are widely available through pharmacies, making the pharmacy an important source of advice for travellers. Therefore, pharmacists should be in a position to assess and recommend insect repellents and insecticides, as well as offering advice on how they are best used.
Biting insects also have a nuisance value and can make life unpleasant for a trekker or walker in many situations. A good example is the infamous Scottish midge that seems to be resistant to most repellents.
This article will focus on methods of avoiding mosquito bites, which are responsible for transmitting a variety of tropical diseases, including malaria. There are a number of broad strategies that can be used to reduce insect bites and these will be considered in some detail. They are to:

  • Reduce general exposure to insects through knowledge of their behaviour and how they are attracted to bite
  • Use repellent applied to the skin
  • Use insecticides which are impregnated into materials such as clothing, mosquito nets or tents
  • Remove insects from the environment using contact insecticides, eg, knock-down sprays or burners/mats

A variety of other methods, such as the use of electronic buzzers and vitamin B tablets, will also be discussed.
It is important that travellers are aware that such measures are designed to avoid biting insects rather than stinging insects like wasps and bees.

Reducing exposure to bites from mosquitoes

The key to successful methods of avoiding mosquito bites is to understand the ways in which mosquitoes are attracted to feed from humans. This is a complex area which is not completely understood.
The bite of the female Anopheles mosquito is responsible for transmitting malaria. The male of the species is much more benign, feeding exclusively on plant nectar. The female's blood meal is important for the development of mosquito eggs before they are laid. Therefore the tendency to bite is closely related to the reproductive cycle of the mosquito.
There are a number of factors that attract the mosquito to its human prey:2

  • Chemoreceptors on the insect antenna can detect minute quantities of substances released by human skin. The two most important substances are believed to be lactic acid and carbon dioxide. The quantity produced may be important. Mosquitoes can detect carbon dioxide from quite a long range
  • Mosquitoes rely on body heat and moisture to determine where to bite once they are within close range of an individual
  • Some perfumes or other strong smelling substances can act as attractants
  • Mosquitoes can find a human by sight or by detecting movement. They are more attracted by dark clothing, which validates the wearing of "tropical whites"

Other useful facts which may be of help in avoiding mosquito bites include:

  • Anopheles mosquitoes bite at night, with the most intense outdoor activity being in the early evening
  • Aedes mosquitoes, which can transmit dengue, are daytime feeders and are most active in the afternoon
  • Environmental conditions, such as a cold temperature, may reduce the tendency of insects to bite. Therefore, insects are less likely to bite in a cooler air-conditioned room. A sealed air-conditioned room would be safe to sleep in without a mosquito net, provided no insects had gained entry during the day. Air turbulance from air conditioning systems or strong fans also reduces the chances of being bitten
  • Prevailing wind conditions can influence the number of mosquitoes found in a particular locality
  • There appears to be a gender difference in attracting mosquitoes, with females getting significantly more bites in trials.3 In addition, children tend to be bitten less than adults. Larger people tend to be bitten more than smaller individuals
  • Mosquitoes find it more difficult to bite through loose than tight fitting clothes. It is particularly important to wear long-sleeved clothing and trousers after dusk

The bite of the tsetse fly can be quite painful. Tsetse flies appear to be attracted by the colour blue and moving objects. They have a tendency to enter through the windows of moving vehicles. Therefore, it is best to keep windows closed when tsetse flies are about. Tsetse flies are less susceptible than mosquitoes to insect repellents.
The sandfly is quite difficult to avoid, apart from by using a mosquito net treated with insecticide. The insecticide is essential because sandflies are small enough to pass through holes in the net. They tend to bite at night or in the early hours of the morning. Sandflies are quite poor flyers, so if sleeping in the open, it may best to sleep higher up, for instance on the roof of a building.
Of the other biting insects, ticks and fleas can be found in undergrowth in both tropical and temperate climates. Therefore, to prevent bites, ramblers and trekkers should keep trousers tucked into socks.
The key features for avoiding bites are summarised in Table 1.

Table 1 Methods of avoiding insect bites
InsectMethods
MosquitoRepellents applied to skin
Insecticide applied to clothing
Use of knockdown spray or insecticide-impregnated mats to clear room of mosquitoes
Avoid night time exposure (Anopheles)
Cover up arms and legs
Sleep under insecticide-impregnated mosquito net
Wear light coloured clothing
TicksTreat socks with DEET or permethrin
Tuck trousers into socks
Tsetse flyUse DEET repellent
Avoid the colour blue
Close windows of vehicles
SandflySleep under insecticide-impregnated mosquito net
Sleep above ground level and avoid moving around outside in the early hours of the morning.

Insect repellents

Insect repellents are the mainstay of bite avoidance strategies. It is important for pharmacists to understand their mode of action and their limitations in order to advise on correct use. The mechanism of action of repellents applied to the skin is not well understood, but undoubtedly they interfere with the chemical stimuli which attract mosquitoes. Repellents can be thought of as having a vaporising effect: molecules of repellent evaporate from the skin and interfere with the "homing mechanism" that mosquitoes use.
Whether or not a person is bitten while wearing a repellent depends on a large number of variables, partly because of the range of stimuli that attract mosquitoes. It is a common observation that some people claim a particular repellent does not work while it is of great benefit for other individuals. Therefore, it is worth examining the general factors that affect repellent efficacy.
Duration of action is the single most important factor influencing efficacy, in that repellents are rarely applied with sufficient frequency. It must be remembered that within a short time of applying a repellent, its efficacy will reduce. When a repellent is advertised as having "a duration of up to 12 hours" it does not necessarily mean that 100 per cent effectiveness is maintained over the full time period. In fact, one standard for expressing length of activity is the time taken for the level of protection to fall by one half. In situations of high insect density, and where a large number of insects may be carrying malaria, such a fall in efficacy could be unacceptable.
There are a number of factors that determine duration of activity:

  • The formulation of a product may influence the length of action. Simple liquid or gel formulations evaporate from the skin relatively quickly but there is little evidence that cream formulations last any longer. There are sustained release formulations which give a longer duration of action. However, the only sustained release products that have been developed are based on diethyltoluamide (DEET) and none is currently available in the UK, except through specialist stores
  • Sweat from the skin which removes the repellent is an important factor, particularly in the humid tropics. Repellents may also be removed through abrasion or washing
  • A certain proportion of the repellent is absorbed by the skin and consequently removed
  • The amount of product applied is probably the most critical factor in terms of duration of action. Put simply, the higher the concentration and the greater the amount applied, the longer it will last (with the exception of sustained release formulations). In the case of DEET, this has led to a debate concerning the most effective minimum concentration of repellent to be used, which will be discussed later
  • As ambient temperature increases, protection time is reduced, probably due to increased evaporation of repellent. Protection time may also be reduced in windy conditions4

An important factor explaining the occasional observation by travellers that a repellent works in one locality but not in another, is that there is an enormous range of species of mosquito with varying sensitivity to repellents. This variation is even present within species. For instance, DEET is highly effective against Anopheles stephensi but much less active against Anopheles albimnus.5 A useful reference species is Anopheles gambiae, against which DEET has a reasonable activity. Aedes are generally more sensitive than Anopheles to repellent.
The individual characteristics of a person may determine the efficacy of a repellent, although this has not been well studied. However, as previously mentioned, female sex and high sweat and lactic acid production would reduce repellent efficacy.
Those who claim to obtain unsatisfactory protection from repellents should be advised to apply them more frequently.6 Mosquitoes would always prefer to bite a person with no repellent on their skin than one wearing a repellent, even if the repellent is not very effective and/or is present in quite low concentrations. Therefore, when travelling in a group, an individual may well be in a better position to avoid bites if others in the group are not using repellents!
It should be emphasised that repellents cannot be used as a means of protection overnight, mainly because the length of action gives insufficient protection. Mosquito nets should be used unless sleeping in a sealed air-conditioned room.
Compliance is an important factor in determining repellent efficacy. If an insect repellent has to be reapplied every couple of hours throughout the night, just as with any therapeutic regime, it is highly likely that doses will be missed. In addition, if the repellent is cosmetically unacceptable to individuals, they are unlikely to use it properly. Fears of adverse effects from the repellent may also reduce compliance. This area of insect repellent use has not been well studied, but it is known that compliance with bite avoidance measures is in general lower than compliance with malaria chemoprophylaxis.1 A postal questionnaire to tourists visiting the Kruger national park in South Africa indicated that, while 80 per cent were using repellents, less than half were following other advice, such as wearing long-sleeved clothing and socks.7 A survey conducted among servicemen from Singapore found that only half used an army-issued repellent while on exercise.8
The most pragmatic answer is a take a concordance approach: any repellent the person is happy to use regularly is better than one they find unacceptable, however efficacious it may be.

Mosquito net
Mosquito nets should be treated with insecticides

Assessment of repellent activity

Before considering the relative merits of the repellents currently available in the UK, it is worth examining the way in which they are assessed. This is important from an evidence-based perspective when considering data from manufacturers.
The most convenient methods for assessment in the laboratory are the so-called cage tests. In these, a volunteer is required to place an arm into a cage containing mosquitoes and the number of bites received in a particular time is noted. In a free flight test, an individual will stand in a large cage containing mosquitoes. Cage test methods are used to calculate the minimum effective dose, ie, potency, of a repellent.
The cage test value of greatest use is the longevity of repellent at a particular dose. However, there is little standardisation of the test. One method is to compare two treated arms placed in separate cages. Some tests use the time taken for the first bite, whereas others use the time for repellent activity to fall by 50 per cent.
Cage tests do not take into account many of the variables described in the previous section, so the most realistic data is obtained from field tests. Again, there are no standardised methods for performing such tests. Field tests are carried out at destinations where mosquitoes are breeding. A count is taken of the number of bites received by volunteers, with and without repellents, in a particular time. Larger-scale trials are carried out by the military and these can usually be viewed as impartial.
There are therefore a number of factors which should be considered by the pharmacist when presented with data by manufacturers on insect repellent efficacy. In most studies, data are given as a comparison to the "gold standard" DEET. Indeed, a useful marketing strategy is to present a repellent as "an alternative to DEET-based products". Panel 1 shows a list of the factors to be considered. In practice it can be difficult to ascertain whether, in terms of efficacy, a product is superior, particularly if different dosages are used to those available commercially. Some of the deficiencies in evaluating data will be discussed later when considering individual products on the UK market. It is also of interest to note that, unlike in some countries (including the US), there is no requirement in the UK to present efficacy or toxicity data to licensing authorities before marketing a topically-applied insect repellent.

Panel 1: Some factors to consider when assessing efficacy data for insect repellents
Mosquito speciesThere is great variation in sensitivity to different repellents
Location of controlsControl and treated subjects should have adequate distance between them so that controls do not attract insects prefer-entially. In cage tests, treated and untreated limbs should not be in same cage
Concentration andapplication of productConcentration applied should reflect actual normal application rate of the commercially available product
Comparison with DEETLength of action compared with DEET is particularly important. Comparison should be made with both high and low concentrations of DEET

Advice points on the correct use of insect repellents are given in Panel 2.

Panel 2: Correct use of insect repellents

  • Apply only to exposed skin
  • For use on the face, dispense repellent into the palms of the hands, rub together and then carefully apply to the face, avoiding the eyes and mouth
  • Do not apply to broken or inflamed skin
  • Wash repellent off hands after application to avoid contact with eyes, mouth or genitals. Also, wash off repellent before going to bed
  • If the effects seem to be wearing off, reapply more frequently than the time interval stated on the label
  • Apply carefully to children and do not apply to their hands
  • If using a repellent for the first time, test the product on a small area of skin in case of allergy

Diethyltoluamide (DEET)

DEET has been used worldwide as a repellent for over 40 years so it is not surprising that more research has been performed on this repellent than any other. There is evidence to suggest that its main mode of action may be through inhibiting lactic acid receptors on the mosquito antennae.9 It has been proposed that lactic acid is an important attractant which orientates mosquitoes to human skin. As it is still regarded as a "gold standard" repellent, DEET will be discussed in some detail.

Formulation differences The length of action is a central factor when considering the usefulness of a repellent, and has been the matter of some debate. It has been suggested that, for most mosquito repellents, the protection given is proportional to the logarithm of the concentration applied.10 For DEET, a plateau of protection is reached when a concentration of 50 per cent is used, although this depends on the actual quantity of solution applied to the skin. In the case of alcoholic solutions of DEET, the alcohol evaporates quickly leaving essentially pure DEET on the skin although the applied total dosage is lower than if a 100 per cent solution had been applied. In normal use there is a general consensus that 50 per cent DEET will provide acceptable levels of protection for three to four hours. Using 100 per cent DEET may extend this range by a further hour. Therefore, DEET insect repellents must be reapplied at least every four hours. In practical terms, this would mean applying the repellent in the early evening and at least once before retiring (although repellent should not be worn overnight). If there is a high mosquito density and malaria is a risk, it may be prudent to reapply more frequently to achieve better protection.
An attractive alternative to reapplying repellents is to use a sustained release DEET product, based on microencapsulated hydrogel, emulsion or lipospheres.11 The 3M sustained release product Ultrathon is no longer widely available in the UK, although other sustained release brands are made in the US and will probably be introduced in the UK in the near future. There are no slow release products currently marketed in the UK. As less of the DEET is absorbed through the skin from these formulations, there are theoretical advantages concerning adverse reactions (see below). They are also formulated with a lower percentage of DEET, at around 20 to 30 per cent. In cage tests, the length of action was the same as a high strength DEET preparation. In the field, some studies have shown better activity than for simple high concentration DEET, possibly due to resistance to other factors such as wash-off by sweat or water. Nonetheless, claims by manufacturers of lengths of action of six hours or more should be taken with caution and more frequent application may be needed in areas of high mosquito activity.
Insect repellents should generally be applied after suncreen, as the sunscreen may occlude evaporation of DEET. However, there is evidence of a breakdown in suncreen efficacy.12 There are formulations that combine both sunscreen and repellent but these have not been widely tested and should not be relied upon in malaria-endemic areas.
Clothing can be treated with DEET, although this tends to be a somewhat messy procedure. DEET (100 per cent) is diluted one in four with water, with which it is not misible so the solution must be stirred vigorously to disperse the DEET. Clothing is dipped into the solution. The treated clothing can be expected to retain repellent properties for up to one week, providing it is stored in an airtight plastic bag between uses.
An alternative way of using DEET is to apply approximately 5ml of 100 per cent solution to a cotton wrist or leg band. Bands can be worn to give some protection to the areas where mosquitoes might bite. They last some weeks after treatment. Ready treated bands are commercially available, as are kits to make them.
In a similar manner, high concentrations of DEET can be applied to the edges of clothes. However, evidence suggests that the repellent action of DEET is observed only 3-4cm outside the area of application and that different species tend to prefer feeding from various parts of the body.2 Unfortunately little work has been performed to define the efficacy of such uses of DEET.

Adverse effects and contraindications The use of DEET has been the subject of controversy because of perceived disadvantages involving adverse reactions and contraindications in both pregnancy and young children. To a large extent, such fears have been unfounded13 and the risk of adverse effects in normal use is low.14 When comparing the benefits of DEET in repellent activity with the risk of adverse events, many experts have concluded that it should still be considered the agent of first choice where there is a risk of malaria. However, the potential adverse events to DEET should be examined.
As for any topically applied agent, allergic skin reactions are occasionally reported. More serious skin reactions have been reported when DEET is left on overnight. It was noticed that soldiers who used high concentrations of DEET on a regular basis just before they went to bed developed a serious skin reaction in the antecubital fossa (the flexure at the elbows),15 probably related to occlusion of the skin. DEET or indeed any other insect repellent should not be applied at bedtime. DEET is irritant to the eyes and mucous membranes and care should be taken when applying it to the face.
A potential drawback in the use of DEET is that it is a plasticising agent, which means that it tends to damage any plastic objects with which it comes into contact. Particular care should be taken regarding plastic glasses and watch faces. In addition, some people find the smell of DEET to be objectionable.
Reported adverse systemic reactions to DEET have resulted in some branded repellents changing formulation to become DEET-free. However, the incidence of systemic reactions must be put into perspective. DEET has been used since the 1950s and it has been estimated that in the US around 30 per cent of the population use DEET-containing products at least once a year. Until recently, this figure was about 25 per cent for the UK population. With such large numbers of users, the incidence of adverse reactions and toxicity is remarkably low. The low incidence is also attested to by a US survey of reports to poison centres.16 Unlike in the UK, US reports can be made directly by the public as well as by health workers. The survey found that of the 3,098 adverse reactions to DEET reported between 1985 and 1990, only 44 resulted in a hospital admission and just five were classified as serious adverse reactions. Most of the adverse reactions were due to the inappropriate use of DEET, such as inhalation or ocular contact. The reactions were unrelated to the concentration of DEET in the product. Accidental oral ingestion of large volumes of DEET has led to toxicity of the cardiovascular, respiratory and central nervous systems. Some of the toxicity may be due to the industrial methylated spirits with which DEET is formulated. Toxicity from topically applied DEET products in adults, even in high concentrations, is extremely rare.
One of the biggest concerns in recent years has been the safety of DEET in children. This is based on 12 reports of encephalopathy since the introduction of DEET17 although, in some of these cases, the reaction cannot be positively attributed to the use of DEET. It has been argued that the larger surface area:weight ratio in children compared with adults might allow an increased dermal absorption for the same dose if high concentrations are applied. However, studies do not show a high dermal absorption or systemic accumulation of topically applied DEET in humans. One of the most recent studies showed that just 8 per cent of topically applied DEET was absorbed and that it was completely eliminated within four hours.18 Whether or not this kinetic profile would present a risk to children has not been studied. It has been suggested that sustained release formulations, which have lower dermal absorption, would be a better alternative for children and for pregnant women.11 The use of DEET in pregnancy is discouraged although there has only been one documented case of harm to a foetus through the use of DEET.19
There have also been concerns that DEET may have been responsible for Gulf war syndrome (a group of symptoms reported by soldiers who had served in the Gulf war).20 Again, there is little direct evidence for this hypothesis and no similar symptoms have ever been reported in normal use by travellers.
In summary, DEET is much maligned in terms of toxicity. It would be wise to use it carefully in children and in pregnancy, using a lower strength sustained release action formulation if possible.

Bayrepel (Autan)

Autan contained DEET until last year when it was reformulated to contain Bayrepel, a novel compound. There is only a limited amount of independent published data available on this product. Cage tests have only been reported by the manufacturer for two Anopheles species and did not include Anopheles gambiae, the most usually studied species. In addition, there have been no studies published which compared the product with concentrations of DEET higher than 20 per cent or with sustained release formulations. Data from field tests are also quite limited. However, the product seems acceptable to users and does not possess the plasticising effects of DEET.

Lemon eucalyptus extract (Mosiguard)

Lemon eucalyptus has been used for some years in China as an insect repellent. A particularly effective extract of lemon eucalyptus has been marketed as Mosiguard over the past few years. Published laboratory data indicate equivalence to 20 per cent DEET,21 but field tests are fewer in number and scale22 than those that have been carried out with DEET. There are limited data or direct studies comparing the product with higher concentrations of DEET or with long-acting preparations. However, of all the natural-based products, lemon eucalyptus is probably among the most effective.

Merck RS3535

The manufacturer of Jungle Formula has recently changed the formulation of its range. All products, except the 50 per cent lotion, have been changed from containing DEET to contain a substance developed by Merck called RS3535 (ethyl butylacetylaminopropionate). Other than the data on file,23 it is difficult to obtain independent evidence which confirms the efficacy or toxicity profile of RS3535. The manufacturer of Jungle Formula suggests that its DEET-based lotion is used when visiting malaria endemic areas and that the RS3535-based range is reserved for use in areas without insect-borne diseases.

Natural products

There are a number of products based on natural products which usually contain a blend of volatile oils as active ingredients. Published literature is only available to any significant extent for citronella which, while effective, has an extremely short length of action, often under one hour.2
It must also be made clear that just because the product is natural it is not necessarily safe.

Insect repellents - what to advise

It seems a reasonable conclusion that most insect repellents on the market are effective. As regularity of application is one of the most important factors, customer preference is of the highest priority. If the user finds a product cosmetically acceptable and it has worked for them in the past, then in non-malaria endemic areas there is little reason to discourage its use. The real debate concerns what to advise as a first-line agent for use in areas where there is a high risk of contracting diseases from biting insects.
Most manufacturers would claim that their product can be used for this purpose but undoubtedly DEET has the backing of the largest body of evidence because of extensive research carried out over the past 30 years. In adults, at least, toxicity of DEET is not an important consideration. Pharmacists should encourage correct use of repellents as covered in Panel 2.
The most helpful study on products available in the UK was probably a cage test comparison carried out at the London School of Hygiene and Tropical Medicine for Which? magazine in which all available repellents were tested and ranked on a star system. Only those products containing concentrations of DEET greater than 30 per cent were recommended as suitable for areas where there was a risk of insect-borne disease (Table 2 [29KB approx 8 sec download time]). A similar outcome was found in a study on US products.24
My own feeling is that adults visiting high risk tropical areas should be offered a high strength DEET product as a first choice. However, if they are unhappy about the cosmetic properties of DEET or its perceived toxicity, then they should be offered an alternative agent.

Insecticides

Insecticides - products which kill insects - also have an important role in bite avoidance. The organophosphate insecticides are no longer used in products for personal protection and the public should be reassured of this fact. Almost universally, pyrethroids are now used, the most common of which is permethrin.
The pyrethroids have a very low mammalian toxicity and permethrin has the additional advantage of a high residue effect on materials, ie, it has a long persistence on certain fabrics after treatment.
One of the principal uses of permethrin-related compounds is in the treatment of mosquito netting. It is important that netting should be treated for two reasons - to deter insects from biting through the net should a person accidentally touch the side while asleep and to deter insects from entering through a tear in the net. In addition, it helps to prevent the entry of small insects such as sandflies. There are a number of studies that have demonstrated the effectiveness of such nets, and they provide a useful strategy in preventing malaria in the local population.25 Nets can be purchased ready-treated with insecticides and with treatment kits which can used to re-treat the net every one to three months.
It is claimed that the very highest level of protection can be obtained by using a repellent on the skin and permethrin on clothing,2 eg, Bug Proof. Clothing treated with permethrin affords relatively low levels of protection,5 but when an insect repellent is additionally used on the skin, added protection is obtained.26,27 Re-treatment is only required every couple of weeks even if the clothes are washed. There is evidence that use of an insecticide on clothes will also reduce biting of unprotected individuals when close to the wearer.
Treating socks and trousers with permethrin is particularly useful for protection against ticks which may be picked up from the undergrowth.
Insecticides can be used to clear a room of insects before going to bed. There are three ways that this can be performed:

  • A simple knock-down aerosol spray
  • A small mat inserted into an electronic heating element in the wall socket that will slowly vaporise the insecticide
  • Coils to burn and release vapour of the insecticide

Coils and mats should be used with care in people with asthma. Manufacturers recommend that coils are only used outdoors.

Some other methods of bite of avoidance

There is some anecdotal, but little research-based, evidence that thiamine tablets taken at a dose of 50mg per day can offer protection against mosquito bites. The tablets need to be taken regularly and this method of bite avoidance should not be advised for those visiting malaria endemic areas.
Citronella candles give a pleasant odour and may offer a degree of protection in their immediate vicinity,28 although burning ordinary candles may also be effective. One of the strangest methods reported for avoiding mosquito bites is using Limburger29 cheese. When the cheese is placed in a room at night, mosquitoes appear to ignore humans in preference for the cheese. However, this is not really a practicable method of bite avoidance for most travellers. Finally, pharmacists should be wary of electronic products claiming to deter mosquitoes by emitting an ultrasonic noise. The evidence supporting these devices is weak or non-existent.

Dr Goodyer is director of pharmacy practice research at King's College London, and superintendent of Nomad Travel Pharmacy

References

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12.Montemarano A, Gupta RK, Burge JR, Klien K. Insect repellents and the efficacy of sunscreens. Lancet 1997;349:1670-1.
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14.Osimitz TG, Murphy JV. Neurological effects associated with the use of insect repellent N,N-diethyl-m-toluamide (DEET). J Toxicol Clinical Toxicol 1997;35:442-5.
15.Reuveni H, Yagupsky P. Diethyltoluamide-containing insect repellents: adverse effects in worldwide use. Arch Dermatol 1982;118:582-3.
16.Veltri JC, Osimitiz TG, Bradford DL, Page PC. Retrospective analysis of calls to poison control centres resulting from exposure to the insect repellent DEET from 1985-1989. J Toxicol Clin Toxicol 1994;32:1-16.
17.Osimitz TG, Grothaus RH. The present safety assessment of DEET. J Am Mosquito Control Assoc 1995;11:274-8.
18.Selim S, Ralph E, Hartnagel TG, Osimitz TG, Gabriel KL, Schoenig GD. Absorption and metabolism of DEET following dermal application to human volunteers. Fundam Appl Toxicol 1995;25:95-100.
19.Schaefer C, Peters PW. Intrauterine diethyltoluamide exposure and foetal outcome. Reprod Toxicol 1992;6:175-6.
20.Baynes RE, Halling KB, Riviere JE. The influence of diethyl-m-toluamide (DEET) on the percutaneous absorption of permethrin and carbaryl. Toxicol Appl Pharmacol 1997;144:3332-9.
21.Trigg JK, Hill N. Laboratory evaluation of a eucalyptus-based repellent against four biting arthropods. Phytother Res 1996;10:313-6.
22.Trigg JK. Evaluation of a eucalyptus-based repellent against Anopheles spp in Tanzania. J Am Mosquito Control Assoc 1996:12:243-6.
23.Marchia F. Insect repellent 3535. SOEW Journal 1996;22:478-85.
24.Chou JT, Rossignol PA, Ayres JW. Evaluation of commercial insect repellents on human skin against Aedes aegypti. J Med Entomology 1997;34:624-30.
25.Alonso PL, Lindsay SW, Armstrong JRM, Conteh M, Hill AG, David PH et al. The effect of insecticide-treated bed nets on the mortality of Gambian children. Lancet 1991;337:1499-502.
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Citation: The Pharmaceutical JournalURI: 20002630

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