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PubMed1999

Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m-toluamide (DEET).

Chronic toxicity and/or oncogenicity studies were conducted in rats, mice, and dogs with the insect repellent DEET. DEET was mixed in the diet and administered to CD rats for two years at concentrations that corresponded to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400 mg/kg/day for females; to CD-1 mice for 18 months at dosage levels of 250, 500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each group consisted of 60 animals of each sex, and two concurrent independent control groups, each containing 60 animals/sex were included in each study. Each group in the dog study consisted of four male and four female dogs and one control group was included in the study. Treatment-related effects were observed at the highest dose level in all three studies. For rats, the effects included decreases in body weight and food consumption and an increase in serum cholesterol in females only. In mice, the effects observed were decreases in body weight and food consumption in both sexes. The effects observed in dogs included increased incidences of emesis and ptyalism, and levels of transient reduction in hemoglobin and hematocrit, increased alkaline phosphatase (males only), decreased cholesterol, and increased potassium. One male dog in the high-dose group also exhibited ataxia, tremors, abnormal head movements, and/or convulsions on several occasions during the study. The highest no-observed-effect levels (NO-ELs) for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day, respectively. No specific target organ toxicity or oncogenicity was observed in any of the studies.

Animals↗
PubMed2001

Evaluation of immunotoxicity induced by single or concurrent exposure to N,N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel.

Approximately 5,000 to 80,000 of the US service personnel involved in the Persian Gulf War have complained of a variety of nonspecific symptoms since their return in 1991. These symptoms have been collectively labeled Gulf War Illness and include muscle fatigue, general malaise, myalgia, impaired cognition, ataxia, headaches, fever, joint pain, skin rash, gastrointestinal disturbances, sleep disturbances, and respiratory difficulties. Exposures of military and service personnel were diverse and included the prescribed anti-nerve gas agent pyridostigmine bromide (PYR), N.N-diethyl-m-toluamide (DEET) insect repellent, and environmental exposures to jet fuel. Thus, studies in our laboratory were undertaken to determine if concurrent exposure to these agents, singly or in combination, would contribute to significant alterations in immunological function and disease susceptibility. To assess immune status, eight-week old B6C3F1 female mice were exposed for 14 days to single compounds or tertiary mixtures of 15.5 mg/kg DEET, 2 mg/kg PYR, and 500 mg/kg JP-8 (termed low dose), or 31 mg/kg DEET, 5 mg/kg PYR, and 1,000 mg/kg JP-8 (termed high dose). Immunosuppression was assessed 24 h after the last exposure. No remarkable alterations were evident in hematological parameters, spleen and thymus organ weight and total cellularity, natural killer (NK) cell activity, cytotoxic T-cell activity, or mitogen-induced lymphocyte proliferation after exposure to either single or tertiary mixtures at low or high doses. A few changes in CD4/CD8 flow cytometric lymphocyte subpopulations were detected after exposure to the tertiary mixture at the high dose. Delayed type hypersensitivity (DTH) was decreased by 88% after exposure to the high-dose mixture, and suppression of antibody-specific IgM immune responses (plaque-forming cell, PFC) occurred after exposure to all single and tertiary mixtures at both dose levels. In the PFC response, antagonism was apparent in the mixture, while coexposure to these agents resulted in a synergistic effect in the DTH response. Susceptibility to B16F10 tumor or Listeria monocytogenes challenge was not affected after single or tertiary exposures. These data suggest that combined exposure to DEET, PYR, and JP-8 does not profoundly alter many immunological endpoints, but does selectively target functional endpoints such as the PFC and DTH response. This should be considered when assessing human health risks in the military environment.

Animals↗
PubMed1996

Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos.

The operating environment of the service personnel during the Persian Gulf War involved psychological, biological, and chemical elements including exposure to pesticides such as the insect repellent DEET (N,N-diethyl-m-toluamide) and the insecticide chlorpyrifos (O,O-diethyl O-3,5,6-trichloropyridinyl phosphorothioate) and to pyridostigmine bromide (PB,3-dimethylaminocarbonyloxy-N-methylpyridinium bromide) that was administered as a prophylactic agent against possible nerve gas attack. The present study was designed to determine the toxicity produced by individual or coexposure of hens 5 days/week for 2 months to 5 mg PB/kg/day in water, by gavage; 500 mg DEET/kg/day, neat, sc; and 10 mg chlorpyrifos kg/day in corn oil, sc. Coexposure to various binary treatments produced greater neurotoxicity than that caused by individual exposures and was characterized by severe neurologic deficit and neuropathological alterations. Also, neurotoxicity was further enhanced following concurrent administration of the three chemicals. Severe inhibition of plasma butyrylcholinesterase (BuChE) activity was produced in hens treated with PB (activity 17% of control) compared to those treated with chlorpyrifos (activity 51% of control) or DEET (activity 83% of control). BuChE inhibition was further increased in binary and tertiary treatment groups compared to individual treatment groups. In contrast, a significant inhibition of brain acetylcholinesterase (AChE) was produced in hens administered chlorpyrifos alone (activity 67% of control), while those given chlorpyrifos in combination with other compounds exhibited a significant inhibition of brain AChE activity ranging from 43 to 76%. Brain neurotoxicity target esterase (NTE) was not inhibited in any of the individual treatment groups or PB/DEET, but was significantly inhibited and had activity expressed as a percentage of control in groups administered combined chlorpyrifos with PB of 73% or DEET of 74% and in the tertiary treatment group of 71%. We hypothesize that test compounds may compete for xenobiotic metabolizing enzymes in the liver and blood and may also compromise the integrity of the blood-brain barrier, leading to an increase in their "effective concentrations" in the nervous system to levels equivalent to the toxic doses of individual compounds. This is consistent with the present observation of increases in (1) the inhibition of brain AChE and NTE, (2) the extent of neurologic dysfunction, and (3) the severity and frequency of neuropathologic lesions in the combined treatment groups compared to those administered individual compounds.

Animals↗
PubMed1991

Mutagenicity and metabolism of dimethyl phthalate and its binding to epidermal and hepatic macromolecules.

As an active ingredient in insect repellents, dimethyl phthalate (DMP) had previously been shown to produce chromosomal aberrations in the livers of rats following subchronic application of the phthalate to skin. When we tested DMP in the Ames mutagenesis assay, it produced in bacterial tester strain TA100 (but not TA98) a dose-related mutagenic response that was abolished by NAD- and NADP-independent metabolism associated with rat liver microsomal preparations (S9). In a host-mediated mutagenesis assay, rats were injected ip with DMP (2 g/kg body weight); urine was collected for 24 h, extracted, and analyzed for mutagenic activity and phthalic acid-containing derivatives. The extracted urine was not mutagenic to TA100 and contained an equivalent of 1.96 mg phthalate/ml urine. More than 97% of the phthalic acid-containing derivatives present in the extracted urine consisted of the nonmutagenic metabolite of DMP, monomethyl phthalate (MMP). In vitro experiments showed that rat liver homogenates hydrolyzed 93% of carbonyl-labeled 14C-DMP (7.7 mM) to MMP in 2 h and bound 0.07 nmol of [14C]phthalate/mg liver macromolecules. By contrast, rat epidermal homogenates metabolized only 5% and bound 38-fold higher levels of carbonyl-labeled 14C-DMP (2.66 nmol/mg of macromolecules), with no detectable binding to nucleic acids. Compared to epidermis and plasma, liver had a fivefold higher rate of DMP monoesterase activity (1240 nmol/h/mg protein), which, when inhibited by 67%, resulted in a 4.4-fold increase in phthalate-bound hepatic macromolecules (0.31 vs. 0.07 nmol of carbonyl-labeled 14C-DMP/mg macromolecules). In addition to MMP, formaldehyde was produced during the metabolism of DMP by liver. When ethanol was used to inhibit the oxidation of DMP-derived methanol by hepatic homogenates, there resulted a 74% reduction in the accumulation of formaldehyde and similar reductions of 71 and 73% in the binding of methyl-labeled 14C-DMP to nucleic acids and macromolecules. (Methyl-labeled, unlike carbonyl-labeled, 14C-DMP yields a 14C-labeled methanol when hydrolyzed.) These results indicate that the DMP diester is a weak bacterial mutagen, which binds to epidermal and hepatic macromolecules other than nucleic acids, and that although the rapid hepatic metabolism of DMP to its monoester (MMP) and methanol affords protection against higher levels of phthalate binding as well as against DMP-induced bacterial mutagenesis, it also oxidizes DMP-derived methanol to formaldehyde, a metabolite that binds macromolecules, including nucleic acids.

Animals↗
PubMed1996

Absorption, distribution, metabolism, and excretion of N,N-diethyl-M-toluamide in the rat.

This study was conducted to evaluate the pharmacokinetic parameters of absorption, distribution, metabolism, and excretion (ADME) of the personal insect repellent N,N-diethyl-m-toluamide (DEET) after oral or dermal administration of [14C]DEET in the rat. Six experiments were conducted using separate groups, each consisting of five male and five female rats. Three experiments involved the determination of ADME patterns after oral administration of [14C]DEET as: 1) a single low dose (100 mg DEET/kg body weight); 2) a single high dose (500 mg DEET/kg body weight); and 3) a repeated low dose (100 mg DEET/kg body weight daily for 14 days). A fourth experiment involved the determination of ADME patterns after dermal administration of [14C]DEET at a single low dose of 100 mg DEET/kg body weight. In these four experiments, urine and feces were collected over a 7-day posttreatment period, after which time the animals were euthanized and selected tissues and organs were harvested. Urine, feces, and tissues were analyzed for total 14C content. The major urinary metabolites were identified, and the urinary metabolic profile for each dosage regimen was determined. The remaining two experiments examined the distribution of radioactivity in tissues of animals euthanized at peak 14C blood levels after receiving a single oral low dose or a dermal low dose. In the three experiments designed to determine the ADME patterns of DEET after oral administration, 85-91% of the administered radioactivity was found in the urine and 3-5% was found in the feces. The overall quantitative pattern of excretion of radioactivity into the urine and feces was similar for males and females in the three groups; however, the rate at which the radioactivity was excreted into the urine differed noticeably between individual oral dosing regimens. The fastest rate was observed in the repeated oral low-dose group, followed by the single oral low-dose and the single oral high-dose groups. In the group of rats that received the dermal low dose, 74-78% of the administered dose was found in the urine and 4-7% was found in the feces. An additional 6.5% was found on the surface of the skin at the application site or in association with the occlusive enclosure. The rate of absorption and subsequent excretion of administered radioactivity into the urine and feces was much slower after dermal administration than after all oral dosing regimens. Total tissue residues of 14C activity at 7 days ranged from 0.15 to 0.67% of the administered dose for all dosage regimens. At peak 14C blood levels, the percentages of administered dose reaching the systemic circulation and total 14C tissue residues were significantly higher in the group of animals administered [14C]DEET orally vs. the animals administered [14C]DEET by the dermal route of administration. In both cases, the only tissues with 14C residues consistently higher than that of plasma were the liver, kidney, and fat. HPLC analysis of urine from rats in the ADME phase of the study showed that DEET was metabolized completely in all treatment groups, with little or no parent compound excreted in the urine. Two major urinary metabolites were identified by mass spectroscopy. In both metabolites, the aromatic methyl substituent in the DEET molecule was oxidized to a carboxylic acid moiety. One of the metabolites also had undergone N-dealkylation of an ethyl substituent on the amide moiety.

Administration, Cutaneous↗
PubMed1994

Remedies for common family ailments: 4. Insect bites and stings.

For going abroad, taking the correct anti-malarial medication should have high priority. Insect-repellents are a useful preventative. Products to treat insect bites and stings include astringents local anaesthetics antihistamines corticosteroids and crotamiton.

Humans↗
PubMed2001

An evidence-based vector control strategy for military deployments: the British Army experience.

We describe the British Army's current strategy for controlling arthropod vectors of disease during overseas deployments. Military commanders and medical officers have different, but complementary responsibilities in achieving vector control. In this paper we define a hierarchy of evidence-based vector control guidelines. Field guidelines must be based on the best available research evidence, preferably that derived from pragmatic randomised controlled trials (RCTs), and from systematic reviews of trials. Assessing the effectiveness of different vector control measures involves a trade-off between the relative benefits and harm of different technology options. There is compelling scientific evidence that bed nets and screens treated with a pyrethroid insecticide are highly effective in protecting against nocturnally active, anthropophilic arthropods (including ectoparasites), and will reduce the incidence of malaria, leishmaniasis, lymphatic filariasis and Chagas' disease. Etofenprox and deltamethrin are the safest pyrethroids, and permethrin the least safe. Vector control strategies of probable effectiveness are the use of insecticide-treated clothing, the wearing of protective clothing, and the correct use of DEET-based topical insect repellents. Aerosol insecticides are of debatable effectiveness. Other effective vector control measures, of limited usefulness during deployments, include electric fans, mosquito coils/vaporising mats, and smoke. "Biological" vector control measures, and insect buzzers/electrocuters are ineffective. Practical insect avoidance measures, based on an understanding of vector biology, complete the military vector-control arsenal. We conclude that practical insect avoidance measures, combined with pyrethroid-treated nets and clothing, and DEET-based topical repellents, can achieve almost 100% protection against biting arthropods.

Animals↗
PubMed1992

Effect of the repellent deet on the antennal chemoreceptors for oviposition in Aedes aegypti (Diptera: Culicidae).

The insect repellent, N,N-diethyl-m-toluamide (deet), interferes with detection of the host attractant, lactic acid (LA), by LA-excited neurons on the antennae of female Aedes aegypti (L.) mosquitoes. In the current laboratory behavioral experiment, the attraction of gravid female mosquitoes to a source of ethyl propionate, an oviposition attractant, was reduced by a factor of two when deet was present. Similarly, when deet was presented together with ethyl propionate in electrophysiological experiments, sensitivity of the neural response to ethyl propionate was depressed in a transient, dose-dependent manner that could account for the reduction in behavioral attraction of gravid females to ethyl propionate. Electrophysiologically, the sensitivity of oviposition attractant receptors to ethyl propionate on gravid females was not different from that on nongravid host-seeking females. The similarity between the depression of sensitivity of the oviposition attractant-sensitive neurons induced by deet and that observed in the host attractant-sensitive neurons suggest a common mode of action of deet on peripheral chemoreceptor neurons that mediate these behaviors.

Aedes↗
PubMed2000

The repellant and antifeedant properties of Cyperus articulatus against Tribolium casteneum Hbst.

Cyperus articulatus is an insect repellant plant commonly found in Northern Nigeria and used traditionally in pest control. The light petroleum and methanol extracts of the plant's rhizome were evaluated against Tribolium casteneum Hbst (the red flour beetle) using standard techniques. The methanol extract showed more antifeedant property than the light petroleum extract, while both the extracts were observed to have similar repellant actions.

Animals↗
PubMed2006

Atypical membrane topology and heteromeric function of Drosophila odorant receptors in vivo.

Drosophila olfactory sensory neurons (OSNs) each express two odorant receptors (ORs): a divergent member of the OR family and the highly conserved, broadly expressed receptor OR83b. OR83b is essential for olfaction in vivo and enhances OR function in vitro, but the molecular mechanism by which it acts is unknown. Here we demonstrate that OR83b heterodimerizes with conventional ORs early in the endomembrane system in OSNs, couples these complexes to the conserved ciliary trafficking pathway, and is essential to maintain the OR/OR83b complex within the sensory cilia, where odor signal transduction occurs. The OR/OR83b complex is necessary and sufficient to promote functional reconstitution of odor-evoked signaling in sensory neurons that normally respond only to carbon dioxide. Unexpectedly, unlike all known vertebrate and nematode chemosensory receptors, we find that Drosophila ORs and OR83b adopt a novel membrane topology with their N-termini and the most conserved loops in the cytoplasm. These loops mediate direct association of ORs with OR83b. Our results reveal that OR83b is a universal and integral part of the functional OR in Drosophila. This atypical heteromeric and topological design appears to be an insect-specific solution for odor recognition, making the OR/OR83b complex an attractive target for the development of highly selective insect repellents to disrupt olfactory-mediated host-seeking behaviors of insect disease vectors.

Animals↗
PubMed1990

Attraction of mosquitoes to diethyl methylbenzamide and ethyl hexanediol.

Studies by prior workers have shown that insect repellents can act as attractants when present as low concentrations, deposits or residues. In the present study deet and ethyl hexanediol were tested in 2-fold serial doses from 1.9 X 10(-9) to 1.6 X 10(-2) mg/cm2 on the forearms of volunteers against colonized Anopheles albimanus, Aedes aegypti and Ae. taeniorhynchus. Both compounds were significantly repellent at the high end of the dose range, as expected. Neither was significantly attractant to An. albimanus in low doses. However, deet was significantly attractant to Ae. aegypti in the dose range 7.6 X 10(-9) to 1.2 X 10(-4) mg/cm2 and to Ae. taeniorhynchus in the dose ranges 1.9 X 10(-9) to 3.1 X 10(-8) mg/cm2 and 2.0 X 10(-6) to 2.5 X 10(-4) mg/cm2. Ethyl hexanediol was significantly attractant to Ae. taeniorhynchus in the dose range 1.9 X 10(-9) to 6.2 X 10(-5) mg/cm2. Based on these results and prior work of V.G. Dethier and C.N.E. Ruscoe, a model sequence of the effects of chemicals on insects with increasing dose was developed. It was concluded that the labels of commercial repellents should be amended to include instructions to wash off or reapply the repellent when it is no longer effective.

Administration, Cutaneous↗
PubMed1962

Entomological aspects of African onchocerciasis and observations on Simulium in the Sudan.

Following a review of the literature on Simuliidae, relevant to the African scene, since 1955, the authors present observations made on Simulium damnosum at Mvolo, Equatoria, and along the Damer reach of the Nile, in the Sudan and consider these in relation to the economic importance of this species and the possibilities for control of the fly and of onchocerciasis transmitted by it.Meta-diethyltoluamide has been shown to be an effective repellent against this species, and the authors suggest that this or some other modern insect repellent might usefully be made available locally.It is suggested that the full life-cycle of S. damnosum in this area needs to be worked out, and a study made of the long-term effects of DDT larviciding on the flora and fauna of a typical river. A procedure for larviciding is recommended. Attention is drawn to the possibility of achieving natural control.

Animals↗
PubMed1998

Travel medicine: helping patients prepare for trips abroad.

One third of persons who travel abroad experience a travel-related illness, usually diarrhea or an upper respiratory infection. The risk of travelers' diarrhea can be reduced by eating only freshly prepared, hot foods. Combination therapy with a single dose of ofloxacin plus loperamide usually provides relief from travelers' diarrhea within 24 hours. Using a diethyltoluamide (deet)-containing insect repellent and wearing permethrin-coated clothing can reduce the risk of malaria, yellow fever and other diseases contracted from insects. Routine immunizations such as tetanus, measles, mumps and rubella, and influenza should be updated if necessary before the patient embarks on the trip. Hepatitis A immunization should be administered to persons traveling to places other than Canada, Australia, New Zealand, Japan and western European countries. Typhoid vaccination should be considered for travelers going to developing countries. Yellow fever immunization is indicated for travelers going to endemic areas of South America and Africa. Malaria prophylaxis with chloroquine is indicated for travelers going to Mexico and Central America. Mefloquine is recommended for those traveling to areas where malaria is resistant to prophylactic treatment with chloroquine. Medical advice for patients planning trips abroad must be individualized and based on the most current expert recommendations.

Humans↗
PubMed2003

[Arthralgia and rash from Australia caused by Ross river virus].

A 58-year-old entomologist presented with disabling arthralgia after a recent visit to the Northern Territory of Australia. A faint maculopapular rash was noticed on the trunk and limbs. The presumptive diagnosis of RRV disease was confirmed by the finding of IgM and IgG antibodies against RRV in serum. RRV, a mosquito-transmitted alpha virus, is the most common cause of arboviral disease in Australia. This disease, initially referred to as epidemic polyarthritis, is characterised by joint pain, rash and constitutional manifestations. The reservoir of RRV are marsupials, other mammals and birds, but mosquitoes may also transmit the disease between humans. The diagnosis is mainly based on RRV-specific serology. In case of arthritis viral RNA sometimes can be detected in synovium biopsies by PCR. No specific therapy is available; the prognosis is favourable. Prevention is based on protection against mosquito bites by wearing clothes to protect the skin, and by using insect repellents.

Alphavirus Infections↗
PubMed1996

Fungicidal and insect controlling properties of Proteus strain RRLJ 16, isolated from tea, Camellia sinensis (L) O Kuntze, plantations.

A strain of Proteus RRLJ 16, isolated from acid (pH 4.5-5.5) iron rich tea (Camellia sinensis) plantation soil, produced siderophores with single absorption peak at 370 nm when cultured in iron free medium. Extracted crude fraction of siderophores and live cultures showed in vitro antibiosis against five species of pathogenic fungi. When the strain was cultured in a normal bacteriological medium without iron stress, it produced an insect repellent compound. The culture filtrate sprayed (dilution of 1:100 in water) on tea plants infected with pink mites or green flies, the insect populations disappeared from the plants. Termite galleries sprayed similarly showed no termite activity after 24 hr of spraying. No reinfestation by insects was observed on treated plants for more than one year.

Animals↗
PubMed1993

Tendency to being bitten by insects among patients with eczema and with other dermatoses.

In order to ascertain whether patients with eczema are more prone to being bitten by insects than those with other dermatoses, data were collected by interview and questionnaire from 496 patients attending the outpatient department of a hospital in Sydney and a general dermatological practice in Geelong, Australia. Of the 93 patients with eczema 65% claimed they were prone to insect bite and that they were bitten in preference to other people when in a group, compared with 17% of the 403 patients with other chronic dermatoses. Similar proportions of both groups (approximately 50%) had used insect repellents. Excluding those with eczema 30% of the 149 patients with a family history of atopy claimed they were prone to being bitten by insects compared with 8% of the 254 patients without a family history of atopy. There was no difference in the prevalence of eczema or family history of atopy between men and women, but more women felt themselves to be susceptible to insect bites than men. There is evidence that patients with eczema and those with a family history of atopy are prone to being bitten by insects. Further confirmatory work, perhaps using volunteers and mosquitoes, is indicated. However, patients with severe eczema or a family history of atopy should take care when travelling to areas where disease-carrying insects are prevalent.

Adolescent↗