Article

The Insect repellents: A silent environmental chemical toxicant to the health

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Abstract

In recent years, a large number of insect repellents have been developed with the idea of consumer benefits. In addition to already known advantageous application of insect repellents, there is increasing concern about the potential toxicity in environment leading to health caused by random use of these compounds. An increasing number of evidence suggests that insect repellents may trigger undesirable hazardous interactions with biological systems with a potential to generate harmful effects including intermediate metabolites. Biotransformation followed by bioaccumulation (vice e versa) may be an important phenomenon for toxic response of this chemicals. In this review, we have summarized the current state of knowledge on the insect repellent toxicity, including biochemical pathway alteration under in vitro and in vivo conditions considering different classes of organisms, from lower to higher vertebrate. Furthermore, we have tried to incorporate the effects of insect repellent in light of some clinical reports. We hope this review would provide useful information on potential side effects of uncontrolled use of insect repellents.

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... For the past decade, studies are being conducted on plant extracts to determine their efficacy as natural insect repellent. They discovered a plant which contain citronellal chemotypes that can be effectively used as insects repellent, for example, Lemon myrtle (Roy et al., 2017) and Lemongrass (Shah et al., 2011). ...
... In this study, the essential oil used as natural insect repellent is the Lemon myrtle (Backhousia citriodora), which is an Australian native rainforest tree. The aroma and taste of Lemon myrtle are similar to a blend of lemon, lemongrass and lime, which contained 90-98% (w/w) citral (Roy et al., 2017). Lemon myrtle has several health benefits, such as for stress and insomnia, sore throat, pimples and acne, odor fighting properties, insect bites, excellent cleaning, etc (Horn et al., 2012). ...
Conference Paper
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Microemulsions are typically isotropic (clear) solutions with very small droplets (~10 to 100 nm), possess low viscosity and are thermodynamically stable. These properties have attracted much interest in producing high value-added products. In addition, there are growing interests in replacing petrochemical-based ingredients with naturally-derived materials, such as palm methyl esters and palm-based surfactants in the microemulsion system. There are numerous applications of microemulsion, for example in multipurpose liquid cleaners. The most significant properties of microemulsion for liquid cleaner applications are the improved solubilisation capacity for both polar and non-polar soil compounds due to very low values of interfacial tension achieved between aqueous and oil phases and their spontaneous formation. Other examples of microemulsion products are multipurpose liquid cleaners consisting of natural insect repellent for hard surfaces of household and industrial applications, microemulsion-spray natural insects repellent, and microemulsion-aerosol insecticides. This paper highlights the research and development of palm-based microemulsion system consisting of natural insect repellent for multipurpose liquid cleaners.
... contact, inhalation, and at times, ingestion (Dimitroulopoulou et al., 2015). Insect repellants which are usually directly applied to the skin contain picaridin in its formulation that may contribute to skin diseases such as acanthosis and hyperkeratosis (Roy et al., 2017). A further example in a report by Awodele et al. (2014) regarding workers at a paint manufacturing company exposed to significant concentrations of heavy metals in the pigments of paint such as lead, cadmium, arsenic as well as chromium, show that the workers suffered headaches, skin irritation, and eye irritation due to inhalation, dermal absorption, and eye exposure. ...
... Consumers may unintentionally ingest the chemical substances in products; for instance, a person eats, prepares food or smokes after applying insect repellent cream or lotion without washing his hands. One of the chemical ingredients contained in insect repellent such as N, N-diethyl-3methylbenzamide (DEET), upon ingestion, might cause symptoms of nausea, vomiting, hypotension and coma (Roy et al., 2017). Besides that, young children are more susceptible to ingest any chemical substance released from a product as they tend to put everything in their mouth. ...
Article
The numerous formulated products which are introduced to the market consist of chemical ingredients that may cause various safety and health hazards to the consumers. Therefore, it is extremely important to practice a systematic methodology to formulate products with acceptable safety and health performances. This work presents an index-based methodology to assess the safety and health hazards of the ingredients during the early formulation stage of product design. Hence, new inherent safety and health sub-indexes are introduced to improve the current safety and health hazards that are needed in formulated product design. The inherent safety and health sub-indexes are assigned with scores based on the degree of potential hazards. A higher score indicates a higher safety risk or severe health effect, and vice versa. The proposed methodology will greatly assist the users to identify the adverse safety and health effects caused by the ingredients. Hence, it is pivotal to eliminate or reduce the safety and health impacts from product usage. A case study on common ingredients used in the formulation of paint is presented on this study to describe the proposed method.
... The use of mosquito repellents is an obvious, practical and economical way of preventing the transmission of severe mosquito-borne diseases (Tawatsin et al., 2001). However, the continued use of synthetic and natural repellents has resulted in mammalian toxicity, residue contamination of human food, environmental pollution and resistance among the insect vectors (Bharati and Saha, 2017;Qualls et al., 2012;Roy et al., 2017). Therefore, in view of growing concern on the application of existing repellents, eco-friendly alternatives of synthetic and natural counterparts have gained tremendous importance in vectors management in the recent years. ...
Article
Growing concern on the application of synthetic mosquito repellents in the recent years has instigated the identification and development of better alternatives to control different mosquito-borne diseases. In view of above, present investigation evaluates the repellent activity of ethyl anthranilate (EA), a non-toxic, FDA approved volatile food additive against three known mosquito vectors namely, Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus under laboratory conditions following standard protocols. Three concentration levels (2%, 5% and 10% w/v) of EA were tested against all the three selected mosquito species employing K & D module and arm-in-cage method to determine the effective dose (ED50) and complete protection time (CPT), respectively. The repellent activity of EA was further investigated by modified arm-in-cage method to determine the protection over extended spatial ranges against all mosquito species. All behavioural situations were compared with the well-documented repellent N,N-diethylphenyl acetamide (DEPA) as a positive control. The findings demonstrated that EA exhibited significant repellent activity against all the three mosquitoes species. The ED50 values of EA, against Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus were found to be 0.96%, 5.4% and 3.6% w/v, respectively. At the concentration of 10% w/v, it provided CPTs of 60, 60 and 30 min, respectively, against Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus mosquitoes. Again in spatial repellency evaluation, EA was found to be extremely effective in repelling all the three tested species of mosquitoes. Ethyl anthranilate provided comparable results to standard repellent DEPA during the study. Results have concluded that the currently evaluated chemical, EA has potential repellent activity against some well established mosquito vectors. The study emphasizes that repellent activity of EA could be exploited for developing effective, eco-friendly, acceptable and safer alternative to the existing harmful repellents for personal protection against different hematophagous mosquito species.
... Age ( Various scientific studies have shown the adverse impact of insect repellent and incense smoke exposure through animal and epidemiological studies [93][94][95]. Liu et al. found that a large concentration of volatile organic compounds (VOCs), PAHs, aldehydes and fine particles, which pose an acute and chronic health risk, could be generated by mosquito coils [96]. Besides, mosquito coils are the most toxic insect repellents than mat and liquid repellents [93] due to a higher lipid peroxidation response and increased freeradical substances that can alter the cell membrane and cause damage to DNA [95]. ...
Article
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This study aimed to assess the association of exposure to particle-bound (PM2.5) polycyclic aromatic hydrocarbons (PAHs) with potential genotoxicity and cancer risk among children living near the petrochemical industry and comparative populations in Malaysia. PM2.5 samples were collected using a low-volume sampler for 24 h at three primary schools located within 5 km of the industrial area and three comparative schools more than 20 km away from any industrial activity. A gas chromatography–mass spectrometer was used to determine the analysis of 16 United States Environmental Protection Agency (USEPA) priority PAHs. A total of 205 children were randomly selected to assess the DNA damage in buccal cells, employing the comet assay. Total PAHs measured in exposed and comparative schools varied, respectively, from 61.60 to 64.64 ng m−3 and from 5.93 to 35.06 ng m−3. The PAH emission in exposed schools was contributed mainly by traffic and industrial emissions, dependent on the source apportionment. The 95th percentiles of the incremental lifetime cancer risk estimated using Monte Carlo simulation revealed that the inhalation risk for the exposed children and comparative populations was 2.22 × 10−6 and 2.95 × 10−7, respectively. The degree of DNA injury was substantially more severe among the exposed children relative to the comparative community. This study reveals that higher exposure to PAHs increases the risk of genotoxic effects and cancer among children.
... Therefore, it can be suggested that the reason for its toxicity might be something else. Chemicals generally used in the composition of mosquito repellents like N-diethyl-3-methylbenzamide (DEET), picardin and pyrethroids have been known to cause severe toxicity (Diaz 2016;Li et al. 2016, Roy et al. 2017), but in sample studied, ethyl butylaminopropionate (EBAAP) has been used as main ingredient. This chemical is not known to cause any toxicity according to WHO (2006). ...
Article
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Specialized cosmetic products for infant use are gaining a lot of popularity in the Indian as well as global market, as these products have become an inseparable part of modern urban lifestyle. Baby cosmetics are available in a wide range. They claim to be milder than similar products meant for adult use. However, these products need to be checked for their safety through a battery of assays based on biological systems, along with the ones based on chemical and physical protocols. This study attempts to test different baby cosmetic products using one prokaryotic and one eukaryotic assay system. Chemical protocols prescribed by cosmetic product controlling organizations of India are also used to estimate the quantity of harmful heavy metals like arsenic, lead and cadmium if present in the samples. Few of the products tested have shown significant toxicity as well as heavy metal content. The results hold a lot of importance keeping in mind the extra sensitivity of an infant body. It is further suggested that studies using cell based and in vivo test systems should be done to confirm the findings.
... Toxicity studies have been usually oriented to characterise the potential harmful effects that IRs may pose to humans, resulting in low usage risk despite the reported adverse effects observed in children [13,22]. No-observedadverse-effects concentrations (NOEC) were used when available, and predicted no-effect concentrations (PNEC) were calculated using the available half maximal effective concentration (EC 50 ) and LC 50 data taken from the literature [12,38,44,45]. Despite the lack of data regarding chronic toxicity for these compounds; estimates exist for generic green algae and fish [38]. ...
Article
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Insect repellents (IRs) are a group of organic chemicals whose function is to prevent the ability of insects of landing in a surface. These compounds have been found in the environment and may pose a risk to non-target organisms. In this study, an on-line solid phase extraction – high performance liquid chromatography-tandem mass spectrometry multiresidue method was developed using an atmospheric photoionization source (SPE-HPLC-(APPI)-MS/MS). The use of the APPI as an alternative ionization technique to electrospray (ESI) and atmospheric pressure chemical ionization (APCI) allowed expanding the range of analytical techniques suitable for the analysis of IRs, so far relied in gas chromatography. High sensitivity and precision was reached with method limits of quantification between 0.2 and 4.6 ng l⁻¹ and interday and intraday precision equal or below 15%. The validated method was applied to the study of surface water samples from three European river basins with different flow regime (Adige River in Italy, Sava River in the Balkans, and Evrotas River in Greece). The results showed that two IRs (DEET and Bayrepel) were ubiquitous in the Sava and Evrotas basins, reaching concentrations as high as 105 μg l⁻¹ of Bayrepel in the Sava River, and 5 μg l⁻¹ of DEET in the Evrotas River. Densely populated areas and effluent waste waters are pointed out as the responsible for this pollution. In the alpine river Adige, only three samples showed low levels of IRs (6.01–37.8 ng l⁻¹). The concentrations measured were used to perform an environmental risk assessment based on the hazard quotients (HQs) estimation approach by using the chronic and acute eco-toxicity data available. The results revealed that despite the high frequency and eventually high concentrations of these IRs determined in the three basins, only few sites were at risk, with 1 < HQs < 3.3.
... Therefore, it can be suggested that the reason for its toxicity might be something else. Chemicals generally used in the composition of mosquito repellents like N-diethyl-3-methylbenzamide (DEET), picardin and pyrethroids have been known to cause severe toxicity (Diaz 2016;Li et al. 2016, Roy et al. 2017), but in sample studied, ethyl butylaminopropionate (EBAAP) has been used as main ingredient. This chemical is not known to cause any toxicity according to WHO (2006). ...
... Synthetic contact insecticides, fumigation, and insect repellents, such as pyrethroids-cyfluthrin and deltamethrin-phosphine, methyl bromide, and DEET (N,N-diethyl-3-methyl-benzamide) have been applied to protect stored crops and products over long periods. However, random use of these conventional insecticides and repellents has triggered severe environmental and health problems [7][8][9][10]. Botanical insecticides have long been thought to be attractive alternatives for pest control because of their safety and eco-friendly properties [11][12][13]. ...
Article
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Toxic and repellent effects of the essential oil from Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag. were evaluated against Lasioderma serricorne and Liposcelis bostrychophila. The essential oils (EOs) from roots (ER) and leaves (EL) of A. heterotropoides were obtained separately by hydrodistillation and characterized by gas chromatography-mass spectrometry (GC-MS) analysis. Major components of ER and EL included methyleugenol, safrole, and 3,5-dimethoxytoluene. Both ER and EL of A. heterotropoides showed certain toxicity and repellency against L. serricorne and L. bostrychophila. 3,5-Dimethoxytoluene, methyleugenol, and safrole were strongly toxic via fumigation to L. serricorne (LC50 = 4.99, 10.82, and 18.93 mg/L air, respectively). Safrole and 3,5-dimethoxytoluene possessed significant fumigant toxicity against L. bostrychophila (LC50 = 0.83 and 0.91 mg/L air, respectively). The three compounds all exhibited potent contact toxicity against the two insect species. Here, the EL of A. heterotropoides was confirmed to have certain toxicity and repellency against stored product insects, providing a novel idea for the comprehensive use of plant resources.
... DEET, DEPA, IR3535, and Picaridin) are commonly used as active ingredient in insect repellent products 22 . However, an increasing number of evidences suggest that such synthetic repellents may trigger undesirable hazardous interactions with biological systems, with a potential to generate harmful effects 7,22,23 . As an alternative, over the last 50 years, many plant species have been screened as potential sources of repellents and insecticides. ...
Article
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Abstract Repellents are a main tool to prevent the outbreak of mosquito-borne diseases that represents a threat for millions of people worldwide. Plant-based products are very promising, low-toxic and eco-friendly alternative to synthetic repellents. Here, we performed an olfactory screening of the essential oils (EOs) of Artemisia verlotiorum Lamotte (Asteraceae), Lavandula dentata L. (Lamiaceae), and Ruta chalepensis L. (Rutaceae) for their possible use as ingredients in topical repellents. The EOs smell profiles were then matched with their repellence against the mosquito Aedes albopictus (Skuse) (Diptera Culicidae). To obtain a more complete bioactivity description, we also tested the EOs oviposition deterrence and the larvicidal activity. The best smell profile was associated with A. verlotiorum EO, while R. chalepensis EO showed the lowest overall pleasantness. All the EOs had a significant activity as skin repellent against Ae. albopictus, deterred the oviposition in the field, and exerted a clear larvicidal activity. Beside the best smell profile, A. verlotiorum EO showed also the longest lasting repellent effect, assuring the complete protection of the treated skin against Ae. albopictus for a time 60% longer than the synthetic repellent DEET.
... In the Po lagoons, we have also identified icaridin (or picaridin), i.e. another insect repellent (Table 3). Developed more recently than DEET, icaridin represents with the previous compound the two most common synthetic substances of this group of consumer products (Roy et al., 2017). It is characterized by moderate hydrophobicity (log K ow 2.57) and toxicity to aquatic organisms (Liu et al., 2018). ...
Article
A comprehensive analytical screening has been applied for the first time to surficial sediment samples collected from seven lagoons of the Po River Delta. This screening has been used to gain further insights into the exposure conditions potentially present in the Po lagoons. Despite a certain degree of variability was observable within the lagoons, this study confirmed the general tendency that the northernmost Caleri lagoon is less contaminated than the other lagoons of the delta, which conversely are more exposed to river waters and particularly to the Po River. This screening identified 23 suspect and 8 target contaminants in the investigated lagoons. The target contaminants were quantified by means of authentic analytical standards, and showed concentration values ranging from 0.01 ng/g for irbesartan, to 80 ng/g for DEET, respectively. The surveyed molecules included pharmaceuticals, industrial chemicals, personal care products, pesticides as well as illicit substances mainly originating from inland waters and the anthropic activities of their (sub)basins. Notably, many of these chemicals, such as flame retardants (TPhP, TCEP, TCPP), phthalates (DnBP, DiBP, DnOP), synthetic hormones (norethisterone, trenbolone) and several parabens (methyl-, ethyl-, butylparaben) are endocrine disruptors and have been detected in all Po Delta lagoons. This study showed that the lagoons of the Po Delta are exposed to a multitude of chemicals substances whose multiple interactions are very likely. As suggested by other studies conducted in this area, the disrupting activities of chemicals capable to interfere with the endocrine system of aquatic organisms should be thoroughly investigated.
... (Hemiptera: Micronectidae) in Vietnam (Nam et al. 2000), and water scavenger beetle Hydrochara affinis (Coleoptera: Hydrophilidae) in Korea (Baek et al. 2014). Despite the limitations in application, environment-friendly mosquito control programs, including biological control, are encouraged by some mosquito control agencies or academic societies such as Society for Vector Ecology, in order to circumvent the harm caused by insecticide application to natural ecosystems and humans (Yanola et al. 2015, Roy et al. 2017. ...
Article
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In order to elucidate the poorly understood relationships between mosquito larvae and their predatory aquatic insects in urban and suburban areas of tropical Southeast Asia, where vector‐borne diseases are prevalent, aquatic insects were sampled from 14 aquatic habitats in residential areas of Chiang Mai, northern Thailand, during the rainy season (July to November) in 2016. Correlations among biological variables, densities of major predatory aquatic insect groups (i.e., Odonata, Coleoptera, and Hemiptera: OCH group) in wetlands and artificial lentic habitats, and the density of mosquito larvae were analyzed. Among the sampled mosquito larvae, Culex spp. were the most abundant, and both OCH density and water quality were major determinants of Culex spp. density (rs = −0.302 and −0.396, respectively). Logistic regression analyses indicated that the probability of Culex spp. occurrence was significantly and negatively correlated with OCH density. Furthermore, high macrophyte abundance was associated with higher predator density, potentially reducing mosquito density. Hemipteran predators were most negatively correlated with Culex spp. density, regardless of whether macrophyte abundance was high or low (rs = −0.547 and −0.533, respectively). Therefore, hemipteran predators were the most important aquatic insect predators in the urban and suburban residential areas of Chiang Mai, Thailand, and OCH species, such as the hemipteran Micronecta scutellaris, could be used as biological control agents against mosquitoes in the region.
... Although synthetic insecticides such as organophosphate, pyrethroid, etc. have reduced the Aedes mosquito population successfully, the continuous increase in the use of the synthetic insecticides has led to mosquito resistance [6], and more importantly, potential toxicity in the environment and adverse effects on human health [7,8]. Besides, repellents are often used to protect against mosquito bites by applying on human skin. ...
Article
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Dengue is one of the most dangerous vector-borne diseases transmitted by Aedes mosquitoes. The use of mosquito repellents to protect human hosts and insecticides to reduce the mosquito population is a crucial strategy to prevent the disease. Here, we reported larvicidal and repellent activities of Mentha arvensis L. essential oil against Aedes aegypti, the main vector of the disease. The essential oil was extracted by hydro-distillation from the aromatic plant grown in Vietnam. The yield was 0.67% based on the weight of fresh leaves. The essential oil was analyzed by gas chromatography-mass spectrometry (GC-MS). The main components were menthol (66.04%), menthyl acetate (22.19%), menthone (2.51%), and limonene (2.04%). Toxicity test on Aedes aegypti larvae showed that the median lethal concentrations, LC50 and LC90 were 78.1 ppm (part per million) and 125.7 ppm, respectively. Besides, the essential oil showed excellent repellency on Aedes aegypti mosquitoes. At 25%, 50%, and 100% concentration, the respective complete protection times (CPTs) were 45 min, 90 min, and 165 min. When adding 5% vanillin to the essential oil (25%), the complete protection time of the essential oil increased up to 120 min. In conclusion, the EO from Mentha arvensis L. has been shown to be a promising natural larvicide and repellent against Aedes aegypti mosquitoes.
... Since the transmission of these viruses depends on the presence of the competent mosquito vectors Aedes aegypti and Aedes albopictus [3][4][5], measures such as repellent-or insecticide-treated nets, indoor spraying, or personal protection measures are needed to protect people from mosquito-borne infections [6]. To date, mosquitoes are mainly controlled by synthetic insecticides and repellents, but besides the quick development of resistance by insect pests, their use is often prohibitively expensive, unsustainable, and it poses relevant risks to humans and environmental health [7]. ...
Article
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Mosquito-borne arboviruses diseases cause a substantial public health burden within their expanding range. To date, their control relies on synthetic insecticides and repellents aimed to control the competent mosquito vectors. However, their use is hampered by their high economic, environmental, and human health impacts. Natural products may represent a valid eco-friendly alternative to chemical pesticides to control mosquitoes, and mosquito-borne parasitic diseases. The aim of this work was to combine the chemical and sensorial profiles with the bioactivity data of Salvia spp. essential oils (EOs) to select the most suitable EO to be used as a repellent and insecticide against the invasive mosquito Aedes albopictus (Diptera: Culicidae), vector of pathogens and parasites, and to describe the EOs smell profile. To do this, the EOs of four Salvia species, namely S. dolomitica, S. dorisiana, S. sclarea, and S. somalensis were extracted, chemically analyzed and tested for their bioactivity as larvicides and repellents against Ae. albopictus. Then, the smell profiles of the EOs were described by a panel of assessors. The LC50 of the EOs ranged from 71.08 to 559.77 μL L−1 for S. dorisiana and S. sclarea, respectively. S. sclarea EO showed the highest repellence among the tested EOs against Ae. albopictus females (RD95 = 12.65 nL cm−2), while the most long-lasting, at the dose of 20 nL cm−2, was S. dorisiana (Complete Protection Time = 43.28 ± 3.43 min). S. sclarea EO showed the best smell profile, while S. dolomitica EO the worst one with a high number of off-flavors. Overall, all the EOs, with the exception of the S. dolomitica one, were indicated as suitable for “environmental protection”, while S. dorisiana and S. sclarea were indicated as suitable also for “Body care”.
... Furthermore, the long-term exposure of DEET and some other pesticides produced mood and cognitive changes in animal experiments that had consistency with neuro-inflammatory changes in hippocampal brain areas experienced by GW veterans [13,14]. Even, some neurotoxicity signs and genotoxic effects were reported to be received by DEET in a few pieces of research [15]. Although, the environmental risk assessment results of DEET indicate that is unlikely to produce an adverse biological effect in aquatic systems [16]. ...
... Citronellal gets a lot of attention for its repellency efficiency against mosquito 20,21,32,59,60 , although its exact mode of action is still unknown. This lack of knowledge regarding the mechanism involved in its activity can be attributed to the inconsistency of the diverse methods used to determine the repellency of volatiles in insects [60][61][62][63][64][65][66][67][68] . In this study, we used a Y-tube olfactory meter which included in its design, most of the critical elements necessary for determining the mosquito-repellent activity of citronellal in vitro. ...
Article
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Anopheles gambiae s.s. is a key vector of Plasmodium parasites. Repellents, which may be a promising alternative to pesticides used to control malaria mosquitoes. Although citronellal is a known mosquito repellent, its repellency characteristics are largely unknown. Determining the specific odorant-binding proteins (OBPs) and odorant receptors (ORs) that detect and transfer the citronellal molecule in A. gambiae s.s. will help to define the mode of action of this compound. In this research, we assessed the repellent activity of citronellal in A. gambiae s.s. using a Y-tube olfactory meter, screened candidate citronellal-binding OBPs and ORs using reverse molecular docking, clarified the binding properties of predicted proteins for citronellal using fluorescence competition binding assay. Results showed that citronellal had a dosage effect on repelling A. gambiae s.s.. The 50% repellent rate was determined to be 4.02 nmol. Results of simulated molecular docking showed that the only proteins that bound tightly with citronellal were AgamOBP4 and AgamORC7. Fluorescence competitive binding assays confirmed the simulations. This research determined that citronellal was captured by AgamOBP4 and transmitted to AgamORC7 in A. gambiae s.s.. Our study will be beneficial in the further understanding the repellent mechanism of citronellal against A. gambiae s.s..
... Insect repellents are PCPs that, through their application on the skin, clothing or other surfaces have the ability to deter insects from approaching and resting (Fink et al., 2017). These compounds play an important role to prevent mosquito bites (Roy et al., 2017). One of the most common uses is on human skin, particularly in tropical environments and in temperate zones during the summer season where mosquitoes are particularly abundant. ...
Article
Personal care products (PCPs) are part of the large and growing family of emerging contaminants (ECs). Many daily products such as sunscreens, toothpaste, make-up products, perfume, and others, fall under this definition, and their use is increasing exponentially. Furthermore, the degradation of some components of these products is limited. Indeed, they are able to easily reach and accumulate in aquatic systems, representing a new class of contaminants. Moreover, due to their chemical properties, they can interfere at different biological levels, and for this reason, they need to be thoroughly investigated. We have reviewed the literature on PCPs, with a special focus on the adverse effects on the freshwater zebrafish (Danio rerio). The aim of this work is to provide a careful assessment of the toxicity of these compounds, in order to raise awareness for more conscious and responsible use.
... Furthermore, synthetic repellents' application to exposed skin to protect from mosquito bites is a common approach for reducing the transmission of mosquito-borne diseases and irritating bites [16]. However, there are concerns about their toxicity and safety [17,18]. These limitations have necessitated researchers to develop new compounds to combating mosquitos and preventing mosquito bites. ...
Article
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It is estimated that one million deaths per year are caused by mosquito-borne diseases worldwide. While preventing such diseases is possible and, of course, more manageable than attended to treat patients. Prevention of these diseases is based on improving the environment (e.g., decreased stagnant water) and controlling mosquitoes in immature and adult forms. Resistances among mosquitoes, environmental pollution, and adverse effects on non-target species, such as humans, are some of the major disadvantages of using chemical insecticides. Essential oils (EO)s with a wide range of activities on mosquitoes, including ovicide effect, larvicide effect, pupicide effect, adulticide effects, and repellent effect, are proper alternatives for synthetic ones. However, their practical usage is questioned due to their volatility and lower efficiency than synthetic samples. In recent years, researchers have attended to overcome these challenges by formulating EOs into nanoformulations. In this study, existing reports on exploiting EO-based nanoformulations in mosquito control have been categorized as larvicides, repellents, and adulticides. Moreover, by discussing the reported results, the appropriate nanoformulations for each purpose have been suggested; polymeric nanoparticles are more suitable for larvicides, lipid nanocarriers are more suitable for repellents nanoemulsions are more suitable for adulticide.
... The widespread utilization of synthetic pesticides poses hazards for both the environment and human health due to their toxicity and poor biodegradability [1,2]. In addition, the use of some chemical pesticides or their residues may be hazardous for non-target organisms, including humans and beneficial organisms [3,4]. ...
Article
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Chemical insecticides have many harmful effects, including as foodborne residues and environmental contaminants, as well as side effects on natural enemies and serious risks for human health. The use of plant-derived essential oils (EOs) as effective bio-agents has become an essential component of integrated pest management. In this study, the contact toxicity, deterrent, and repellent activities were evaluated for essential oils obtained from Mentha piperita, Mentha longifolia, Salvia officinalis, and Salvia rosmarinus, grown at high altitudes in the Taif region, KSA, on Aphis punicae. Furthermore, the toxicity of these EOs against the predator Coccinella undecimpunctata was estimated. A total of 17, 14, 16, and 26 compounds were identified in the EOs of M. piperita, M. longifolia, S. officinalis, and S. rosmarinus, respectively. They showed a variation in the major compounds: M. piperita (Carvone, 61.16%), M. longifolia (Pulegone, 48.6%), S. officinalis (Eucalyptol, 33.52%), and S. rosmarinus (α-pinene, 36.65%). A contact toxicity test on A. punicae imago and C. undecimpunctata larvae showed that LC50 were approximately four-fold greater for all tested EOs towards aphids compared to towards the predator, while the two species of Salvia sp. were more effective than the other two species of Mentha sp. The LC50 values on A. punicae ranged from 1.57 to 2.97 µg/mL, while on C. undecimpunctata larvae, they ranged from 5.96 to 10.33 µg/mL. Furthermore, the EOs of two species of Salvia sp. showed excellent repellence and deterrence against A. punicae. In conclusion, the tested EOs, especially those from Salvia sp., have been shown to be promising natural aphicides, repellent, and deterrent against A. punicae, and they are safe for important insect predators
... The most widely marketed insect repellent worldwide is n,n-diethyl-meta-toluamide (DEET) because it is a broadspectrum repellent that is effective against various mosquito species and ticks. However, since treatment with synthetic chemicals such as DEET is associated with human health risks [14], most people hesitate to apply DEET products to their skin or clothing and deliberately look for other DEET-free repellent products. For these reasons, alternative natural repellents are now very appreciated by consumers, and essential oils of aromatic plants are considered the most promising candidates [15,16]. ...
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Arthropod-borne infectious diseases cause many deaths and a major economic burden worldwide. Repellents play an important role in protecting people from infectious biting arthropods. The repellency of veratraldehyde, a known food additive, and the WJ-1041 formulation containing 10% veratraldehyde was tested against Aedes albopictus and Culex pipiens pallens females and Haemaphysalis longicornis nymphs using arm-in-cage, indoor or filter paper tests. Veratraldehyde exhibited repellency similar to or lower than that of n,n-diethyl-meta-toluamide (DEET) against A. albopictus, but in H. longicornis, the activity of veratraldehyde was better than that of DEET. The repellency of the 10% veratraldehyde solution was comparable to that of 20% DEET against the two mosquitoes. When comparing repellency between the WJ-1041 formulation (10% veratraldehyde) and 10% DEET against C. pipiens pallens, A. Albopictus and H. longicornis, the two showed similar repellency and complete protection time (CPT) values. However, there was a small difference depending on the tested insects. The absorption of veratraldehyde via skin was minimal, if at all. The pharmacokinetic parameters (Cmax and Tmax) of veratraldehyde in blood samples of rats were not different from those of the control group. Based on these results, veratraldehyde has high potential to be commercialized as a repellent agent against infectious disease-borne pests in the near future.
... 9 Therefore, the uncontrolled consumption of synthetic repellents in general and DEET as a special case has risen many warnings about their safety on personal basis in addition to their probable effect on environmental pollution. 10 Thiamine hydrochloride (TH) or vitamin B1 is essential for aerobic metabolism, cell growth, transmission of nerve impulses and acetylcholine synthesis. Its deficiency causes disorders like beriberi, Wernicke-Korsakoff syndrome, optic neuropathy, Leigh's disease, African Seasonal Ataxia, and central pontine myelinolysis. ...
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Thiamine hydrochloride (TH) was thought to exert a good insect repellent activity. The purpose of this work was to develop a formulation that releases TH in sustained regimen on human skin. Long lasting protection against mosquito bites was achieved. Pullulan acetate (PA) was used to prepare TH nanospheres. Optimal system was incorporated in Pluronic® hydrogel. Formulae were tested for in-vitro release and ex-vivo permeation. Complete protection time (CPT) was done adopting Kaplan-Meier survival function for the synthetic repellent (DEET), TH solution and nanospheres in hydrogel. Release profile of TH solution, nanospheres and nanosphere-loaded hydrogel (DG) demonstrated an added effect of DG, where t 1/2 was 11.2±1.4 h. SEM for DG showed homogenous dispersion of nanospheres inside the matrix of the gel. Ex-vivo permeation showed only 0.761±0.04% of TH in hydrogel permeated the skin after 12h, while 44.98±3.2% permeated when TH solution was applied. Clinical study revealed a significant difference in CPT between TH solution with either DEET or (DG) (p<0.05), and no significant difference between DEET and DG with CPT 400±31 and 360±18 min, respectively (P > 0.05). The high efficacy of TH-loaded hydrogel rendered it a successful alternative for DEET, offering long protection against mosquito bites.
... Synthetic pesticides are used for public health sprays as chemicals with insecticidal properties such as organochlorines, organophosphorus, carbamates, pyrethroids, synthetic pyrethroid pyrroles, and phenyl pyrazole (Schofield, 1993;Pal, 1994). The excessive, unlimited, uninterrupted, indiscriminate, and continuous application of synthetic insecticides as principal agents results in the unwarranted toxic or lethal effects on non-target organisms, the development of resistance in mosquitoes, and more importantly, potential toxicity in the environment and adverse effects on human health, posing a great threat to life and the environment (Shrivastava et al., 2002;Kawada et al., 2009;Koures et al., 2012;Raveen et al., 2014;Rathy et al., 2014;Hemlatha et al., 2015;Roy et al., 2017). So, there is an urgent need for an alternative source to synthetic insecticides across the globe. ...
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Mosquitoes are counted as the oldest human enemy; play a significant role in the health hazardous of the community. It has endemic conditions for Malaria, Japanese encephalitis (JE), Dengue, Yellow fever, Chikungunya, and Filariasis, etc. However, JE cases are recently declined, it showed 44,000 new cases and 6000 fatalities from between 2008 to 2014 in Uttar Pradesh and Bihar. The prolonged use of synthetic insecticides raises the risk of unintended harmful or fatal consequences such as biological amplification, mosquito resistance development, and negative impacts on environmental quality and non-target species, including human health. Phytochemicals are botanicals that are naturally occurring pesticides produced from oral resources, and they are a viable alternative to synthetic insecticides in Integrated Mosquito Management. Plant-based insecticides are less toxic, delay the development of resistance because of their structure, and easily biodegradable. Secondary metabolites derived from botanicals act as both a larvicidal agent and a defense mechanism in and of themselves. In this article, we have summarized the recent studies on the effectiveness of phytochemical compounds such as Saponine, steroids, isoavonoids, essential oils, alkaloids and tannins have strong potential especially against mosquito's larva. We also focused on their mode of action on the target population, variance in larvicidal efficacy among Culex, Aedes, and Anopheles mosquitoes, the polarity of solvents employed during extraction, active component nature, and prospective improvements in biological control. This review will reveal the idea of natural plant sources that are cost-effective and eco-friendly than synthetic chemicals against the mosquito and it will help reduce the risk of vector-borne diseases.
... IR3535 is a transparent, colorless, odorless liquid mixture that has proven to be safe, as demonstrated by acute toxicity, local tolerability, phototoxicity and repeated-dose toxicity assays. 15 Further, IR3535 is non-genotoxic and has thus been considered a safe insect repellent ingredient by the US Environmental Protection Agency since 1999. Moreover, this compound is classified as a hypoallergenic substance based on skin irritation tests. ...
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BACKGROUND IR3535 is among the most widely used synthetic insect repellents, particularly for the mitigation of mosquito-borne diseases such as malaria, yellow fever, dengue, and Zika, as well as to control flies, ticks, fleas, lice, and mites. These insects are well-known vectors of deadly diseases that affect humans, livestock, and crops. Moreover, global warming could increase the populations of these vectors. RESULTS Here, we performed IR3535 dose-response analyses on Drosophila melanogaster, a well-known insect model organism, using electrophysiology and binary food choice assays. Our findings indicated that bitter-sensing gustatory receptor neurons (GRNs) are indispensable to detect IR3535. Further, potential candidate gustatory receptors were screened, among which GR47a was identified as a key molecular sensor. 0.1%–0.4% ranges of IR3535 affected larval development and mortality. Additionally, DEET (i.e., another commonly used insecticide) was found to exert synergistic effects when co-administered with IR3535. CONCLUSION Our findings confirmed that IR3535 directly activates bitter-sensing GRNs, which are mediated by GR47a. This relatively safe and highly potent insecticide can be largely used in combination with DEET to increase its efficiency to protect livestock and crops. Collectively, our findings suggest that the molecular sensors elucidated herein could be used as targets for the development of alternative insecticides. This article is protected by copyright. All rights reserved.
... In the absence of vaccines, repellents could be an option to minimise the risk of contracting different mosquito-borne diseases (Islam et al. 2017). Synthetic repellents and insecticides are used to control Ae. aegypti; however, the frequent use of this substance results in vector resistance and environmental contamination (Roy et al. 2017). Currently, DEET (N,N-diethyl-meta-toluamide), the most frequently used mosquito repellent, represents an important tool for mosquito control (Zhu et al. 2018;Dennis et al. 2019). ...
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Essential oils have been tested as insect repellents with moderate results. The most important characteristics of these oils are that they possess a high chemical diversity of compounds, are cheap, and are easily accessible. Recently, mixtures of essential oils have shown a higher repellent activity than a single essential oil, probably by increasing the effectiveness with the number of chemicals in the mixture. The repellent effect of essential oils from citronella (Cymbopogon nardus), mint (Mentha arvensis), rosemary (Rosmarinus officinalis L.), clove (Eugenia caryophyllata), and their mixture was evaluated against Aedes aegypti. The mixture of citronella, mint, and clove essential oils (1:1:1) was also evaluated in an adulticidal bioassay. Additionally, chemical identification was performed using these commercial essential oils. The 1:1:1 mixture of citronella, mint, and clove essential oils was as effective as the commercial repellent DEET at lower doses (5%), and it is a good candidate for an adulticide at higher doses (20–25%). The chemical constituents of the essential oils were mostly terpenes and oxygenated terpenoids. These findings were discussed in terms of economic and environmental frameworks.
... Synthetic pesticides are used for public health sprays as chemicals with insecticidal properties such as organochlorines, organophosphorus, carbamates, pyrethroids, synthetic pyrethroid pyrroles, and phenyl pyrazole (Schofield, 1993;Pal, 1994). The excessive, unlimited, uninterrupted, indiscriminate, and continuous application of synthetic insecticides as principal agents results in the unwarranted toxic or lethal effects on non-target organisms, the development of resistance in mosquitoes, and more importantly, potential toxicity in the environment and adverse effects on human health, posing a great threat to life and the environment (Shrivastava et al., 2002;Kawada et al., 2009;Koures et al., 2012;Raveen et al., 2014;Rathy et al., 2014;Hemlatha et al., 2015;Roy et al., 2017). So, there is an urgent need for an alternative source to synthetic insecticides across the globe. ...
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Mosquitoes are considered a most common human enemy; causes mortality, morbidity, monetary and social disruption. It plays a significant role in endemic conditions for Malaria, Japanese encephalitis (JE), Dengue, Yellow fever, Chikungunya, and Filariasis etc. The prolonged use of synthetic insecticides raises the risk of unintended harmful or fatal consequences such as biological amplification, mosquito resistance development, and negative impacts on environmental quality and non-target species, including human health. So that there is urgent need to find natural and environmentally safe phytochemicals as an alternative to synthetic pesticides from indigenous plant sources that are accessible to the whole local community. Phytochemicals are botanicals that are naturally occurring pesticides produced from floral resources, and they are a viable alternative to synthetic insecticides in Integrated Mosquito Management (IMM). Plant based insecticides are less toxic, delay the development of resistance because of its structure and easily biodegradable. In this article, we have summarized the recent studies published in 2020 and 2021 on the biopesticide effect of botanicals with their suitable solvents which possess strong potential against mosquitoes larva. We also focused on their mode of action on the target population, variance in larvicidal efficacy among Culex, Aedes, and Anopheles mosquitoes, polarity of solvents employed during extraction, active component, and prospective improvements in biological control.
... Most of the popular commercial tick repellents and acaricidal products are based on synthetic chemicals (Bissinger and Roe 2010). Previous studies have investigated potential issues using synthetic chemicals, due to their potential to pollute and persist in the environment, causing bioaccumulation, which results in toxicity towards humans and other animals (Roy et al. 2017). ...
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Repellent and acaricidal activity of essential oils extracted from three varieties of basil (Ocimum basilicum L.) were evaluated on blacklegged ticks (Ixodes scapularis Say) and American dog ticks (Dermacentor variabilis Say) in laboratory conditions. Essential oils were extracted and characterized through gas chromatography-mass spectrometry, and tested at different concentrations for long-term repellent activity using horizontal bioassays. In addition, basil essential oils were combined with an inert material (i.e., granite rock dust) with known insecticidal and miticidal properties to assess acaricidal activities against adult ticks. Among the tested basil varieties, var. Jolina essential oil at 15% vol/vol concentration repelled 96% of tested ticks up to 2 h post-treatment. The EC50 for I. scapularis nymphs was 4.65% vol/vol (95% confidence interval: 4.73–4.57). In acaricidal tests, the combination of essential oil from var. Aroma 2 at 10% wt/wt with rock dust resulted in 100% tick mortality after only 24 h post-exposure, with a LD50 of 3.48% wt/wt (95% CI 4.05–2.91) for freshly prepared treatment tested on I. scapularis adults. The most common compounds detected in basil essential oils by GC–MS were linalool (52.2% in var. Nu Far, 48.2% in Aroma 2, 43.9% in Jolina), sabinene (6.71% in Nu Far, 8.99% in Aroma 2, 8.11% in Jolina), eugenol (11.2% in Jolina, 8.71% in Aroma 2), and estragole (18.2% in Nu Far). The use of essential oils alone and in combination with rock dust provides an innovative and environmentally friendly approach for managing ticks and inhibiting vector-borne disease transmission.
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Studies have reported the presence of ethyl butylacetylaminopropionate (IR3535) in waters, and the content of this repellent is expected to rise significantly in the future. There are extremely scarce data in the literature regarding the behavior of IR3535 and its derivatives in water. The present work reports the results obtained from experiments conducted under controlled conditions aiming at investigating the transformation of IR3535 in chlorinated water, in addition to an attempt to identify its disinfection by-products (DBPs). The work also reports the findings of analyses conducted in swimming pool water samples which sought to investigate the presence and content of IR3535 and its targeted DBPs in these samples. The results obtained in the controlled experiments show that IR3535 is not completely degraded under the chlorinated conditions evaluated and 9 DBPs were tentatively identified. The presence of IR3535 was detected in both adults and children’s pool water samples at concentrations ranging from 62 ng L⁻¹ to 114 ng L⁻¹. Some of the DBPs identified in the controlled experiments were also detected in the pool water samples. The toxicity of the 9 DBPs identified was evaluated using the QSAR model, where some by-products presented mutagenic and carcinogenic properties.
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Mosquitoes have already developed resistance toward most of the commercial synthetic repellents. Therefore, searching for new potential alternatives is the need of the hour. In the study, we evaluated the repellency of six citrus-derived essential oils against Aedes aegypti using the arm-in-cage method. The results showed more than 50 percent repellency up to 4 h exposure time at 1 mg/cm2 area for three Citrus spp. with maximum repellency of 81 percent for C. aurantifolia. Therefore, two of the major constituents of C. aurantifolia EO, namely citral and limonene, were chosen further for the repellency test. The results showed higher efficacy of compounds than crude oil. EC50 for commercial standard repellent DEET was determined for comparison under the same experimental conditions. To understand the possible mode of action of citral, limonene and DEET, in-silico interactions of these compounds with odorant-binding proteins (OBP1 and OBP22) and acetylcholinesterase (AChE) enzymes were studied. The findings revealed positive docking of all of these compounds having affinity values in the range of − 6.0 to − 6.9 kcal/mol. Overall, the study demonstrated that limonene and essential oils of Citrus aurantifolia could be the best potential alternative for synthetic repellents.
Chapter
Pharmaceuticals and personal care products (PPCPs) are chemicals of anthropogenic origin. With the developing technology, the intensive use and unconscious disposal of PPCPs, whose varieties, numbers, and spread around the world have increased rapidly, have been a serious concern in recent years. Medical and personal wastes, sewage, and industrial and agricultural activities are the main sources of PPCPs. Not only drugs used by people, but also medicines, fertilizers, and similar substances used in agricultural activities can leak into the soil and mix with groundwater and drinking water and cause serious pollution. Although PPCPs are not classified as persistent organic pollutants, many of them exhibit properties similar to persistent organic pollutants. Because PPCPs are continuously discharged into the environment, they are included in the so-called pseudo-persistent class. This review summarizes current information on the classification of PPCPs, their occurrence in the environment, their impact on the functioning of the ecosystem, their transport to soil and water, their infiltration, and environmental exposure to PPCPs.
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Microencapsulation is a promising method for controlling and prolonging the release of safer, bio-based insect repellents, which can be used for protection against many vector-borne endemic diseases. Geraniol is an effective insect repellent; however, its encapsulation in gelatin/gum Arabic, and its long-term retention have not been studied to date. In this study, complex coacervation was used to obtain novel geraniol-containing microcapsules using gelatin/gum Arabic. The effect of processing conditions on the size and morphology of the microcapsules and the subsequent release properties was investigated. Optimal conditions included a coacervation pH of 4.45 and a crosslinking pH of 6.0. Lower mixing rates produced single core capsules with larger particle size (93 µm). Higher mixing rates resulted in multi-core capsules with smaller average particle sizes (34 µm). The geraniol contents of microcapsules were found to be 90%, 68%, and 73% for mixing rates of 700 RPM, 1000 RPM, and 1300 RPM, respectively. Microcapsule formulations showed excellent release profiles into humid air without any burst release, with retentions of 80%, 74%, and 76% at 26 days for mixing rates 700 RPM, 1000 RPM, and 1300 RPM, respectively. Encapsulation of geraniol results in longer-lasting retention compared to similar systems; hence it can be used as textile coatings for use in insect repellent clothing or incorporated into various carrier solutions for application as an area treatment. Our research highlights the possibility of tuning diffusion characteristics based on microcapsule morphology opening new applications for this technique.
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Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.
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Metabolic resistance-associated enzymes primarily detoxify xenobiotics and endogenous substances. Insecticides that could inhibit these enzymes may potentiate their toxic effect on the targeted pest by hampering the metabolic detoxification pathways. In a recent investigation, we identified eugenol as a potential larvicide against Aedes aegypti. Therefore, the goal of this work was the in-silico study of eugenol with metabolic detoxification enzymes while using the organophosphate temephos as a control. Temephos is said to inhibit acetylcholinesterase (AChE), an important enzyme of the central nervous system. So, AChE was also used for docking study. Modeller9.21 software was used to create models of the said enzymes. Ligands were eugenol and temephos, and the receptors were detoxifying enzymes and AChE. Docking was performed using autodock vina software, and their binding interactions are presented using UCSF Chimera and ligplot. Results revealed good docking of both the compounds, with binding affinity values ranging from –5.4 to –6.9 kcal/mol for detoxifying enzymes, which appeared to be in a comparable range. Again, both the ligands docked well with the AChE enzyme with binding affinity value of –6.5 kcal/mol for eugenol and –7.9 kcal/mol for temephos. Since, ligands act by binding to receptors, it is thought that eugenol and temephos work in a similar way and might block metabolic detoxification enzymes. In light of the negative environmental consequences and side effects of temephos, eugenol, which has a comparable binding affinity for the metabolic enzymes studied, might be recommended as a viable alternative to temephos for use as a mosquito larvicide.
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Due to the extensive use and incomplete removal, pharmaceutical and personal care products (PPCPs) are introduced into the water continuously. It has been proved that the unique properties of PPCPs are influential to organisms and the environment, and gradually affect human health. In this paper, the toxicological effects of typical PPCPs, and the environmental behavior of PPCPs in aquatic are reviewed. The risk assessments of PPCPs in the water are summarized. The research directions of environmental toxicology research of PPCPs in the future are proposed. Many PPCPs were found to be toxic or even highly toxic toward aquatic organisms, and have the potential for bioaccumulation. It is essential to study the acute and long-term toxicity of PPCPs and their metabolites, evaluate the environmental behaviors and make a reasonable assessment of ecotoxicology and human health risks of PPCPs.
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The ubiquity of lizard in homes and has caused huge problem to human. They are one of the very important agents to transmit Salmonella that cause food poisoning towards human being. Through this research the potential of Kaffir lime peel toward lizard was reported. The process to produce Kaffir lime extract is hydrodistillation extraction method. The repellency test of essential oil will be assess at different concentration (0%, 25%, 50%, 75% and 100%). The duration of observation will be test from 3 to 6 hour duration. The results has shown that the concentration up to 50% and above of essential oil from Kaffir lime peel extraction may reflect the lizards in a state of discomfort.
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Background N’,N’-diethyl-m-toluamide (DEET) is the most widely used repellent substance worldwide. It is formulated as aerosol, solution, lotion, gel and patches. However, the official compendia report monographs to analyze only DEET drug substance and solution. Objective In this study an isocratic HPLC method was validated to assay DEET in lotion, gel and solution, under the same analytical conditions. Method The method was validated according to ICH requirements and DEET detection was achieved at around 11 min, using C-18 column, a mobile phase composed by methanol, acetonitrile and water pH 4.5 (45:10:45), flow rate at 1 mL min-1 and detection at 270 nm. Results A linear relationship was observed in the range of 2.5 to 100 µg mL-1, the method was precise (relative standard deviation < 2%) and accuracy was demonstrated by DEET recovery values ranging from 99.5 to 100.2%. The specificity was studied by a forced degradation test, where degradation products were observed after alkaline degradation and ultraviolet radiation. Appropriate resolution between DEET, degradation products and excipient peaks indicated the method specificity. Robustness was evaluated by a full factorial design, and no effect on DEET assay was observed under simultaneous variation in analytical parameters. The method was applied to assay nine marketed formulations, demonstrating its good applicability. Conclusion The validated HPLC method was successfully applied to the quantitative analysis of DEET in lotion, gel and solution, contributing to improve the quality control and the efficacy of these formulations.
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Despite the ubiquitous occurrence of N,N-diethyl-m-toluamide (DEET) in aquatic systems, assessments evaluating the toxicity of DEET on phytoplankton species are summed to a single study on a unicellular green alga. In particular, the toxicological effects of DEET in dinoflagellates are unknown. In this study, we employed the mixotrophic dinoflagellate Gymnodinium instriatum as a study system to evaluate acute effects of DEET on the oxygen flux of laboratory cultures. This study reports an inhibitory reaction model of DEET described by the equation y = 4.99x(0.54), where y represents the percent inhibition of oxygen flux and x represents DEET concentration in mg L(-1) (r(2) = 0.98). Based on this model, the effective concentration of DEET needed to reduce O2 flux by 50 % (EC50) for this species was found to be at 72.9 mg L(-1). The reported EC50 is more than five times lower than the EC50 reported previously for the unicellular green algae Chlorella protothecoides. This study raises the question of the potential toxicological effects of DEET in dinoflagellates, in particular those populations inhabiting systems characterized by low water circulation such as enclosed bays and lagoons.
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N,N-diethyl-m-toluamide (DEET) has been registered for commercial use as an insect repellent for over five decades, and is used widely across the world. Concerns over the safety of DEET first emerged during the 1980s after reports of encephalopathy following DEET exposure, particularly in children. However, the role of DEET in either the illness or deaths was and remains purely speculative. In response to these cases a number of reviews and investigations of DEET safety were carried out. Here we examine the methods used and information available to determine the safety of DEET in humans. Animal testing, observational studies and intervention trials have found no evidence of severe adverse events associated with recommended DEET use. Minor adverse effects noted in animal trials were associated with very large doses and were not replicated between different test species. The safety surveillance from extensive humans use reveals no association with severe adverse events. This review compares the toxicity assessment using three different models to define the risk assessment and safety threshold for DEET use in humans and discusses the clinical consequences of the thresholds derived from the models. The theoretical risks associated with wearing an insect repellent should be weighed against the reduction or prevention of the risk of fatal or debilitating diseases including malaria, dengue, yellow fever and filariasis. With over 48 million European residents travelling to regions where vector borne diseases are a threat in 2009, restricting the concentration of DEET containing repellents to 15% or less, as modelled in the 2010 EU directive, is likely to result in extensive sub-therapeutic activity where repellents are infrequently applied. Future European travellers, as a consequence of inadequate personal protection, could potentially be at increased risk of vector borne diseases. Risk assessments of repellents should take these factors into account when setting safe limits.
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Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.
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Preservatives and fragrances are important and frequent skin sensitizers, found in a wide range of products intended for personal and occupational use. To examine the use of preservatives and fragrances in certain cosmetics and detergents on the market. The product types studied were shampoos, hair conditioners, liquid soaps, wet tissues, washing-up liquids, and multi-purpose cleaners. Ingredient labels of 204 cosmetic products and ingredient data sheets of 97 detergents, available on company websites, were examined. The preservatives most frequently identified were phenoxyethanol, methylparaben, sodium benzoate, propylparaben, and methylchloroisothiazolinone/methylisothiazolinone. Parabens were found in 44% of cosmetics and 9% of detergents; formaldehyde-releasers in 25% of cosmetics and 8% of detergents; and isothiazolinones in 23% of cosmetics and 28% of detergents. The fragrances most frequently identified were linalool, limonene, hexyl cinnamal, butylphenyl methylpropional, and citronellol. Eighty-eight per cent of the products contained fragrances, and any of the 26 fragrances requiring labelling were found in half of the cosmetics and one-third of the detergents. Several preservatives and fragrances with well-known skin-sensitizing potential were common in the examined product types. Such products may be used several times a day by consumers and workers.
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Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are capable of enhancing skin permeation of each other when applied simultaneously. We carried out a cellular study in rat astrocytes and neurons to assess cell toxicity of DEET and oxybenzone and a 30-day study in Sprague-Dawley rats to characterize skin permeation and tissue disposition of the compounds. Cellular toxicity occurred at 1 µg/mL for neurons and 7-day treatment for astrocytes and neurons. DEET and oxybenzone permeated across the skin to accumulate in blood, liver, and brain after repeated topical applications. DEET disappeared from the application site faster than oxybenzone. Combined application enhanced the disposition of DEET in liver. No overt sign of behavioral toxicity was observed from several behavioral testing protocols. It was concluded that despite measurable disposition of the study compounds in vivo, there was no evidence of neurotoxicological deficits from repeated topical applications of DEET, oxybenzone, or both.
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This study investigated the stereoselective biotransformation and resulting estrogenic activity of the pyrethroid insecticide, permethrin (PM). Results of both in vivo (male Japanese medaka, vitellogenin (VTG) protein in plasma) and in vitro (primary rainbow trout hepatocyte VTG-mRNA expression) assays indicated stereoselective estrogenic activity of PM. 1S-cis-PM was observed to have significantly higher activity (P ≤ 0.05) than the 1R-cis enantiomer in both in vivo and in vitro evaluations. All enantiomers of PM were oxidized to a 4'-hydoxy PM (4OH PM) metabolite and underwent esterase cleavage to 3-phenoxybenzyl alcohol (3-PBOH) and 3-(4'-hydroxyphenoxy)-benzyl alcohol) (3,4'-PBOH). Racemic 4OH PM as well as 3-PBOH, and 3,4'-PBOH possessed significant (P ≤ 0.05) estrogenicity. 1S-trans-PM underwent esterase cleavage more extensively than the corresponding 1R-trans-PM. Inhibition studies with ketoconazole confirmed cytochrome P450-catalyzed hydroxylation as well as esterase cleavage of PM for all stereoisomers. These studies indicated stereoselectivity in the estrogenic activity of PM resulting from stereoselective biotransformation of the parent compound to more estrogenic metabolites.
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Comparative inhalation toxicity studies of aerosols of insect repellents N,N-diethylbenzamide (DEB), N,N-diethylphenylacetamide (DEPA), and N,N-diethyl-3-methylbenzamide (DEET) were carried out in mice. The respiratory pattern was monitored using a computer program that recognizes the modifications of the breathing pattern. Exposure to the aerosols caused a dose-dependent decrease in normal breath, with an increase in airway obstruction. All the three insect "sensilla irritants" showed no significant mammalian sensory irritation. The acute LC(50) value for a 4-h exposure of DEB, DEPA, and DEET aerosols in male mice was found to be >2.5 g/m(3), 1714 mg/m(3), and 1369 mg/m(3), respectively. Irreversible depression in respiratory frequency was observed after exposure to DEB aerosol at a concentration of 277 mg/m(3) and above, which did not revert back to normal level even after aerosol exposure was stopped. At a concentration of 156 mg/m(3) of DEB, no respiratory depression was observed. DEPA and DEET caused no depression in respiratory frequency up to a concentration 1292 and 950 mg/m(3), respectively. Hence the two insect repellents DEET and DEPA do not cause any harmful effect to the respiratory parameters in acute exposure, showing that they are more suitable chemicals to be used as insect repellents as compared to DEB.
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Species differences in the intrinsic clearance (CL(int)) and the enzymes involved in the metabolism of pyrethroid pesticides were examined in rat and human hepatic microsomes. The pyrethroids bifenthrin, S-bioallethrin, bioresmethrin, beta-cyfluthrin, cypermethrin, cis-permethrin, and trans-permethrin were incubated in rat and human hepatic microsomes in the presence or absence of NADPH. Metabolism was measured using a parent depletion approach. The CL(int) of the pyrethroids was 5- to 15-fold greater in rat relative to human microsomes except for trans-permethrin, which was approximately 45% greater in human microsomes. The metabolism of bifenthrin, S-bioallethrin, and cis-permethrin in rat and human hepatic microsomes was solely the result of oxidative processes. The metabolism of bioresmethrin and cypermethrin in human hepatic microsomes was solely the result of hydrolytic processes. Bioresmethrin and cypermethrin in rat hepatic microsomes and beta-cyfluthrin and trans-permethrin in microsomes from both species were metabolized by both oxidative and hydrolytic pathways. The metabolism of trans-permethrin was reduced when incubated with its diastereomer, cis-permethrin, in both rat and human hepatic microsomes. Rat cytochrome P450 (P450) isoforms that showed activity toward several pyrethroids included CYP1A1, CYP1A2, CYP2C6, CYP2C11, CYP3A1, and CYP3A2. Human P450 isoforms that showed activity toward multiple pyrethroids were CYP2C8, CYP2C9, CYP2C19, and CYP3A4. Species-specific differences in metabolism may result in variable detoxification of pyrethroids, which may in turn result in divergent neurotoxic outcomes. These species differences and isomer interactions in metabolism of pyrethroids should be considered when assessing the potential adverse health effects of pyrethroid pesticides.
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The tissue distribution of 14C-labelled N,N-diethyl-m-toluamide (DEET), a widely used mosquito repellent, was studied by means of whole-body autoradiography after cutaneous application to mice. The early picture was very similar to that previously observed after intravenous injection of the substance, with high concentration of radioactivity mainly in the lacrimal gland, liver, bile, intestinal contents, kidney, urine, and nasal mucosa. Urinary excretion in mice was highest early after application whereas in a human volunteer maximal excretion appeared only after several hours. In mice a low but significant excretion persisted throughout the observation time of one month, probably emanating from the considerable amount of radioactivity remaining in the smeared skin area, as observed both autoradiographically and by means of quantitative measurements.
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Groups of 15 male and 15 female rats were given diets containing 0 (control), 0·2, 1·0 or 5·O% diethyl phthalate (DEP) for 16 wk. Consumption of diet containing 5% DEP was associated with a reduction in food intake and in the rate of body-weight gain, and similar effects were seen in the females given 1% DEP. No statistically significant effects on water intake or on the results of the haematological examinations, serum-enzyme levels, urinary cell-excretion rate, renal concentration tests or histological examination were seen in the treated animals. However, there were increases at wk 16 in the relative liver weight of females at all treatment levels and of males fed the highest level. There were also increases in the absolute and relative weights of stomach and small intestine in rats of both sexes; in the females these were statistically significant at all dietary levels at wk 16.
Article
The pyrethroid insecticide permethrin was tested for its ability to induce sister chromatid exchanges (SCE), micronuclei (MN) and structural chromosome aberrations (CA) in cultured human peripheral blood lymphocytes. Permethrin was tested in the range of 5-500 micrograms/ml in the absence and in the presence of a rat liver activation system (S9 mix). Small elevations in the SCE frequencies were found and even though statistically significant may have no biological meaning, the more so since there was no dose-effect relationship. Permethrin induced both MN and CA when it was evaluated in the absence of a metabolic activation system. Nevertheless, it cannot be said that S9 mix suppressed the activity in itself. The effect of permethrin seemed to be time of exposure dependent. Permethrin could be characterized as a S-phase independent agent with greater potential for inducing chromosomal damage than sister chromatid exchanges.
Article
1. The pharmacokinetics and metabolism of (1R, cis)- and (1R, trans)-isomers of tetramethrin (i.v. 0.25 mg/kg) were studied in rats. 2. The experimental data for the time course of the concentration of tetramethrin isomers in plasma fit a pharmacokinetic two-compartmental open model. Plasma levels of both isomers were similar. The terminal half-life of the trans-isomer in plasma was greater (125 min) than the cis-isomer (72 min). 3. The concentrations of the two metabolites, 3,4,5,6-tetrahydrophthalimide (TPI) and N-(hydroxymethyl)-3,4,5,6-tetrahydrophthalimide (MTI), were consistently higher in the plasma of rats treated with the trans-isomer than in those treated with the cis-isomer. 4. In rats treated with the trans-isomer, the majority of radioactivity excreted after 96 h was found in urine. The faeces was the major excretory route for rats treated with the cis-isomer (26% urine, 69% faeces with cis-isomer; 64% urine, 29% faeces with trans-isomer). 5. Metabolism of each isomer was rapid and complete. Parent chemical was not detected in urine and only small quantities of the intact cis-isomer were found in the faeces. MTI, TPI, and cyclohexane-1,2-dicarboximide (HPI) were detected in both urine and faeces. 6. The amount of radioactivity excreted into the bile was similar for both isomers. However, levels of the intact parent compound and TPI were higher in the bile isolated from rats treated with the trans-isomer. The trans-isomer was found to undergo enterohepatic circulation.
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This article reviews 573 cases of acute pyrethroid poisoning reported in the Chinese medical literatures during 1983-1988. There were 325 cases of acute deltamethrin poisoning (occupational 158, accidental 167), 196 patients of acute fenvalerate poisoning (occupational 63, accidental 133, including 2 cases of ingestive fenvalerate-organophosphate mixture poisoning), 45 cases of acute cypermethrin poisoning (occupational 6, accidental 39) and 7 cases of other pyrethroid poisoning (occupational 2, accidental 5). The clinical manifestations have been reviewed and analysed. The diagnosis, gradation and differential diagnosis of occupational acute pyrethroid poisoning have been discussed.
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1. The toxicokinetics of cis- and trans-tetramethrin isomers were investigated using the isolated perfused rat liver preparation. 2. The concentration of cis- and trans-tetramethrin decreased rapidly in the plasma perfusate and was initially replaced by N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide (MTI) and then by 3,4,5,6-tetrahydrophthalimide (TPI). Plasma perfusate concentrations of the intact cis-isomer were higher than those of the trans-isomer. Concentrations of MTI and TPI were higher in livers treated with the trans-isomer. 3. Tetramethrin and its metabolites were rapidly excreted in the bile. Bile from livers perfused with trans-isomer contained higher concentrations of parent isomer and metabolites MTI and TPI, than did bile from livers treated with the cis-isomer.
Article
This study examined the extent of dermal absorption of a series of phthalate diesters in the rat. Those tested were dimethyl, diethyl, dibutyl, diisobutyl, dihexyl, di(2-ethylhexyl), diisodecyl, and benzyl butyl phthalate. Hair from a skin area (1.3 cm in diameter) on the back of male F344 rats was clipped, the [14C]phthalate diester was applied in a dose of 157 mumol/kg, and the area of application was covered with a perforated cap. The rat was restrained and housed for 7 days in a metabolic cage that allowed separate collection of urine and feces. Urine and feces were collected every 24 hr, and the amount of 14C excreted was taken as an index of the percutaneous absorption. At 24 hr, diethyl phthalate showed the greatest excretion (26%). As the length of the alkyl side chain increased, the amount of 14C excreted in the first 24 hr decreased significantly. The cumulative percentage dose excreted in 7 days was greatest for diethyl, dibutyl, and diisobutyl phthalate, about 50-60% of the applied 14C; and intermediate (20-40%) for dimethyl, benzyl butyl, and dihexyl phthalate. Urine was the major route of excretion of all phthalate diesters except for diisodecyl phthalate. This compound was poorly absorbed and showed almost no urinary excretion. After 7 days, the percentage dose for each phthalate that remained in the body was minimal and showed no specific tissue distribution. Most of the unexcreted dose remained in the area of application. These data show that the structure of the phthalate diester determines the degree of dermal absorption. Absorption maximized with diethyl phthalate and then decreased significantly as the alkyl side chain length increased.
Article
Certain types of plastic materials require the addition of appreciable quantities of plasticizers to impart specific physical-chemical properties to the final item. Presently, many vinyl devices used with drug products may contain plasticizers of the phthalate type. For this reason, a series of phthalic acid esters were evaluated for parenteral toxicity including LD50 values and hexobarbital narcosis. Experiments utilized in the study also included i.p. injections in mice for acute toxicity profiles, i.v. administration in rabbits for blood pressure and respiration effects, and intradermal injections into rabbits for irritation effects. A further study was conducted to note what effects repeated i.p. doses of the phthalates would have on mice over a period of time, examining the effects on organs, weight gain, and the blood. Finally, tissue culture experiments were conducted to attempt to correlate certain of the toxicity manifestations. The most salient feature of the toxicity of these compounds was the central depression on the animals and the rather low order of toxicity by the parenteral route of administration.
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Di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) were mixed with diet at graded levels of 0.05, 0.1, 0.2. 0.4 and 1.0 wt-% and given to pregnant ICR mice throughout gestation. Maternal weight gain was suppressed and fetal resorption increased at 0.2, 0.4 and 1.0% levels of DEHP and 1.0% level of DBP. All the implanted ova died early in rats fed 0.4 and 1.0% levels of DEHP. External malformations increased significantly by 0.2% DEHP, and 1.0% DBP showed borderline significance. The major malformations in treated groups were neural tube defects (exencephaly and myeloschisis), suggesting that the phthalic acid esters (PAEs) affect neural tube closure in developing embryos. Treatment with the compounds caused intrauterine growth retardation and delayed ossification with an apparently dose-related response pattern. These results indicate that a high dose of DEHP and DBP might be embryotoxic and teratogenic in mice. The maximum nonembryotoxic doses of PAEs in mice were more than 2000 times the estimated level of human intake through the food chain. Thus it is assumed that the current "normal" exposure level of PAEs dose not pose an imminent threat to human fetal development.
Article
The absorption, metabolism, and excretion of N,N-diethyl-m-toluamide (DEET) in male human volunteers following dermal application of [14C]DEET was studied. DEET was applied to two groups of six volunteers either as the undiluted technical grade material or as a 15% solution in ethanol. The material was applied over a 4 x 6-cm area on the volar surface of the forearm and was left in contact with the skin for 8 hr, then rinsed off the skin. Application sites also were tape stripped at 1, 23, and 45 hr after rinsing. Serial blood samples and all urine and feces were collected for 5 days after application. Aliquots of these materials were analyzed for total radioactivity in order to define absorption and excretion patterns. Urine samples also were analyzed by HPLC to characterize the metabolic profile and/or to identify metabolites. Absorption of DEET as evidenced by plasma radioactivity occurred within 2 hr after dose application. Elimination of radioactivity from plasma was rapid and quantifiable levels of radioactivity were observed in plasma for only 4 hr after the end of the 8-hr exposure period. Urine was the principal route of excretion of radioactivity and accounted for an average of 5.61 and 8.33% of the applied dose in the undiluted DEET and 15% DEET in ethanol groups, respectively. Excretion of radioactivity in the feces was less than 0.08% of the applied dose in both groups. DEET did not accumulate in the superficial layers of the skin as evidenced by low amounts of radioactivity in the tape strippings.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
1. Urinary and faecal metabolites in rat treated with 14C-labelled (1RS, trans)-tetramethrin [3,4,5,6-tetrahydrophthalimidomethyl (1RS, trans)-chrysanthemate] were identified using chromatographic techniques and spectroanalyses (nmr and ms). 2. 3-Hydroxy-cyclohexane-1,2-dicarboximide was found to be a major and unique urinary metabolite, reduced at the 1,2-double bond of the 3,4,5,6-tetrahydrophthalimide moiety. 3. The major faecal metabolites were sulphonic acid conjugates, having a sulphonic acid group incorporated into the double bond of the 3,4,5,6-tetrahydrophthalimide moiety. 4. On the basis of the metabolites identified here, the major biotransformation reactions of trans-tetramethrin in rats are: (1) cleavage of the ester linkage; (2) cleavage of the imide linkage; (3) hydroxylation of the cyclohexene or cyclohexane ring of the 3,4,5,6-tetrahydrophthalimide moiety; (4) oxidation at the methyl group of the isobutenyl moiety; (5) reduction at the 1,2-double bond of the 3,4,5,6-tetrahydrophthalimide moiety; and (6) incorporation of a sulphonic acid group into the 1,2-double bond of the 3,4,5,6-tetrahydrophthalimide moiety.
Article
The optimal management of arthropod bites is prevention, and many over-the-counter insect repellents are available. Since first marketed in 1956, deet has remained the most effective repellent against mosquitoes, biting fleas, gnats, and chiggers. Permethrin is applied to clothing rather than to skin, and it is a better repellent against ticks than deet. The risk of serious side effects with the use of deet is slight; nevertheless, the lowest effective concentration should be used. The current, popular repellent agents (for adults and children) and their active ingredients are discussed. In addition, the Environmental Protection Agency guidelines for the safe use of insect repellents are supplied.
Article
N,N-Diethyl-m-toluamide (DEET), the active ingredient in many commercial mosquito repellents, is thought to be responsible for a wide range of local and systemic adverse reactions following its use. Many investigators have studied the dermal absorption of pure DEET; however, there is only one report in the literature on the absorption of DEET from commercial mosquito repellents and the effect of concentration of DEET on its absorption through skin. The first objective of the present study was to evaluate the permeation characteristics of DEET from four commercial products, Everglades (95%), Repel Deerhunters (52.25%), Off Skintastic (6.65%), and Skedaddle (6.2%), as compared to pure DEET (approximately 100%). The second objective was to study the effects of ethanol, the solvent for DEET, on the permeation of DEET and investigate its potential for enhancing the dermal absorption of DEET. Permeation studies of DEET from commercial mosquito repellents and from solutions containing various percentages of ethanol were conducted across human skin using an infinite dose technique with a Franz diffusion cell. Permeation parameters such as steady-state flux (Jss), lag time (tL), diffusion coefficient (D), permeability (P), and skin/ vehicle partition coefficient (K) were obtained from the permeation profiles in each case. The cumulative amount of DEET permeated can be ranked according to the following order: neat DEET (100%) = Everglades (95%) > Repel (52.25%) > Skedaddle (6.2%) = Off Skintastic (6.65%). Pure DEET exhibited the highest flux value of 63.20 +/- 24.52 micrograms/cm2-h, while Off Skintastic had the lowest value of 21.12 +/- 14.75 micrograms/cm2-h. The tL and D values for each of the products were similar to that of pure DEET. The total amount of DEET permeated from 30-45% ethanolic solutions at the end of 36 h was significantly higher than that from pure DEET and from the 60-90% ethanolic solutions. The Jss, P, and K values of DEET from the 30-45% ethanolic solutions were significantly higher than those from the 75-90% ethanolic solutions, while the tL and D values were similar for each solution. Therefore, there is potential for significant absorption of DEET after the dermal application of commercial mosquito repellents, and ethanol, used as a solvent, may enhance the permeation of DEET.
Article
KBR 3023, 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)-piperidine, a prospective insect repellent being developed by the Bayer Corporation, was evaluated for reproductive toxicity in the Sprague-Dawley rat. As the intended human use of the test compound is topical, the test system was also exposed to the compound via the dermal route. Specifically, the adult rats (P generation) were fitted with Elizabethan collars, to reduce the likelihood of oral ingestion, and dermally administered either 0, 50, 100, or 200 mg KBR 3023/kg body weight throughout the study (5 d/week) beginning at the onset of the 10-week premating period and continuing through the mating, gestation, and lactation phases. Clinical signs and changes in body weight and food consumption were assessed throughout the study. All adults and neonates underwent a gross necropsy examination. Tissues retained for microscopic examination from all adult animals included the kidney, liver, pituitary, reproductive organs, and samples of skin from the shaved dose site. In addition to the parameters noted above, the animals were evaluated for the effect of the test compound on estrous cycling, mating, fertility, gestation length, litter size, pup sex ratio, and pup viability. There were no test compound-related clinical signs or effects on body weight or food consumption observed in either the adults or the pups during any phase of the study. There were no compound-related effects on any reproductive or litter parameters. Dermal findings at the dose site (acanthosis and hyperkeratosis) were noted in both generations. Other than the dermal findings, no compound-related necropsy findings were seen in either the adults or the pups. No compound-related histopathologic findings were noted in the reproductive tissues of either the males or females. Based on these results, KBR 3023, administered as described in this study at dose levels as high as 200 mg/kg body weight (the physical limit of dermal application for this compound), did not demonstrate any reproductive toxicity.
Article
Drug interactions have been suggested as a cause of Gulf War Syndrome. Pyridostigmine bromide (PB), a prophylactic treatment against potential nerve gas attack, the insect repellent DEET, and permethrin (PERM) impregnated in soldiers' uniforms may have interacted and caused greater than expected toxicity. We tested those 3 drugs singly and in combinations on male and female Sprague-Dawley rats in open field arenas to find the effects on rate of locomotion and thigmotaxis. Administration rates were 10 mg PB/kg; 50, 200, or 500 mg DEET/kg; 15, 30, or 60 mg PERM/kg; 5 mg PB/kg + 100 mg DEET/kg; 5 mg PB/kg + 15 mg PERM/kg; 100 mg DEET/kg + 15 mg PERM/kg; or vehicle by gavage and i.p. injection. Locomotor behavior was quantified by video-computer analysis for 2 h post-treatment. Female rats were tested in either pro- or metestrus. Drug interactions were determined by the isobolographic method. Blood serum drug concentrations were estimated by high performance liquid chromatography or gas chromatography-mass spectrometry. Single drug effects were very limited within the ranges tested. Double-drug administrations at half the single-drug rates resulted in statistically significant interactions in male rats for both locomotion rate and thigmotaxis. Combination of PB + PERM and DEET + PERM significantly affected speed, whereas only the combination of DEET + PERM significantly affected thigmotaxis. Female rats did not show significant interactions. Our data suggest that serum concentrations of PB and DEET may have been higher in females than males. Administration of PB + DEET may have reduced the serum concentration of DEET, and administration of PB + PERM may have increased the serum concentration of PERM.
Article
Diethyl phthalate (DEP; CAS No. 84-66-2) has many industrial uses, as a solvent and vehicle for fragrance and cosmetic ingredients and subsequent skin contact. This review focuses on its safety in use as a solvent and vehicle for fragrance and cosmetic ingredients. Available data are reviewed for acute toxicity, eye irritation, dermal irritation, dermal sensitization, phototoxicity, photoallergenicity, percutaneous absorption, kinetics, metabolism, subchronic toxicity, teratogenicity, reproductive toxicity, estrogenic potential, genetic toxicity, chronic toxicity, carcinogenicity, in vitro toxicity, ecotoxicity, environmental fate and potential human exposure. No toxicological endpoints of concern have been identified. Comparison of estimated exposure (0.73 mg/kg/day) from dermal applications of fragrances and cosmetic products with other accepted industrial (5 mg/m(3) in air) and consumer exposures (350 mg/l in water; 0.75 mg/kg/day oral exposure) indicates no significant toxic liability for the use of DEP in fragrances and cosmetic products.
Article
N,N-Diethyl m-toluamide (DEET) and permethrin have been implicated as potential neurotoxic agents that may have played an important role in the development of illnesses in some veterans of the Persian Gulf War. To determine the effect of subchronic dermal application of these chemicals on the adult brain, we evaluated histopathological alterations in the brain of adult male rats following a daily dermal dose of DEET (40 mg/kg in 70% ethanol) or permethrin (0.13 mg/kg in 70% ethanol) or a combination of the two for 60 days. Control rats received a daily dermal dose of 70% ethanol for 60 days. Animals were perfused and brains were processed for morphological and histopathological analyses following the above regimen. Quantification of the density of healthy (or surviving) neurons in the motor cerebral cortex, the dentate gyrus, the CA1 and CA3 subfields of the hippocampus, and the cerebellum revealed significant reductions in all three treated groups compared with the control group. Further, animals receiving either DEET or permethrin exhibited a significant number of degenerating (eosinophilic) neurons in the above brain regions. However, degenerating neurons were infrequent in animals receiving both DEET and permethrin, suggesting that neuronal cell death occurs earlier in animals receiving combined DEET and permethrin than in animals receiving either DEET or permethrin alone. The extent of neuron loss in different brain regions was similar among the three treatment groups except the dentate gyrus, where neurodegeneration was significantly greater with exposure to DEET alone. The neuron loss in the motor cerebral cortex and the CA1 subfield of all treated groups was also corroborated by a significant decrease in microtubule associated protein 2-immunoreactive elements (15-52% reduction), with maximal reductions occurring in rats receiving DEET alone; further, the surviving neurons in animals receiving both DEET and permethrin exhibited wavy and beaded dendrites. Analysis of glial fibrillary acidic protein immunoreactivity revealed significant hypertrophy of astrocytes in the hippocampus and the cerebellum of all treated groups (24-106% increase). Thus, subchronic dermal application of DEET and permethrin to adult rats, alone or in combination, leads to a diffuse neuronal cell death in the cerebral cortex, the hippocampal formation, and the cerebellum. Collectively, the above alterations can lead to many physiological, pharmacological, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction.
Article
Possible genotoxic effects exerted by three widely used pesticides, permethrin, N,N-diethyl-m-toluamide (DEET) and diazinon, in primary human nasal mucosal cells were investigated. Primary nasal mucosa cells were prepared from tissue biopsies taken from 21 patients who underwent nasal surgery. Cells were exposed to 0.5-1.0 mM concentrations of permethrin, DEET and diazinon for 60 min. Genotoxic effects were detected by the alkaline microgel electrophoresis assay ("comet assay"). Within the concentration range, no significant cytotoxic effects were observed, but all three tested pesticides showed a significant genotoxic response that was concentration dependent. More pronounced genotoxic effects were observed in mucosal cells from the middle turbinate than in the inferior turbinate. The results provide some evidence for the potential carcinogenicity of these agents to human nasal mucosal cells. This should be further investigated.
Article
Field trials to compare repellent formulations containing either picaridin or deet against rainforest mosquitoes in northern Queensland, Australia, were conducted. Three repellents were compared at night: 9.3% picaridin and 19.2% picaridin (Autan Repel and Autan Repel Army 20, respectively, Bayer, Sydney, Australia) and 35% deet in a gel (Australian Defense Force [ADF]). During the day, the following three repellents were compared: 19.2% picaridin, 20% deet in a controlled release formulation (Sawyer Controlled Release Deet), and 33% deet in a polymer formulation (U.S. Army Extended Duration Topical Insect and Arthropod Repellent [EDTIAR]). The predominant mosquito species collected was Verrallina lineata (Taylor), with smaller numbers of Ochlerotatus kochi (Donitz), Anopheles farauti s.s. Laveran, Ochlerotatus notoscriptus (Skuse), and Coquilletidia xanthogaster (Edwards). In nighttime tests, 19.2% picaridin provided >94.7% protection for at least 9 h, and ADF deet provided >95% protection for 7 h. The 9.3% picaridin formulation provided >95% protection for only 2 h, and provided 60% protection at 9 h. In daytime tests, Sawyer 20% deet provided >95% protection for 6 h, and both 19.2% picaridin and U.S. Army EDTIAR provided >95% protection for 8 h. In both nighttime and daytime tests 19.2% picaridin provided similar or better protection than deet formulations.
Article
The acute lethal interaction that occurs in rodents when high doses of a peripherally restricted cholinesterase inhibitor, pyridostigmine bromide (PB), and the insect repellent N, N-diethyl-m-toluamide (DEET) are combined was first described during studies of chemical mixtures that were targeted as potential causative agents of Gulf War illnesses. This study was intended to provide insight into possible mechanisms of that lethal interaction. Following a single intraperitoneal injection of PB (2 mg/kg) and/or DEET (300 or 500 mg/kg), respiratory activity was measured in conscious freely moving rats using whole-body plethysmography. Cardiovascular function was also monitored simultaneously through an arterial catheter. PB (2 mg/kg) given alone stimulated respiration and increased blood pressure. Arterial pH levels were decreased, whereas pO(2) and pCO(2) remained at control levels. Administration of DEET (300 mg/kg) alone increased tidal volume and decreased blood pressure. Blood gases and pH levels were unaltered. A higher dose of DEET (500 mg/kg) also decreased respiratory and heart rate. Coadministration of PB (2 mg/kg) and DEET (300 mg/kg) increased tidal volume, decreased arterial pH, and elevated pCO(2). Heart rate and blood pressure declined progressively after drug coadministration. Pretreatment with atropine methyl nitrate (AMN), a peripherally selective competitive antagonist at nicotinic and muscarinic receptor sites, reduced the individual effects of PB or DEET, and significantly increased survival after coexposure to these agents. Although changes in respiratory function may have contributed to the lethal interaction, it was concluded that the primary cause of death was circulatory failure.
Article
Reducing the risk of mosquito bites is currently the only way to reduce the risk of West Nile virus infection. Methods for avoiding mosquito bites include limiting the time spent outdoors at dawn and dusk, wearing protective clothing and using an insect repellent. Repellents containing DEET (N,N-diethyl-m-toluamide, also known as N,N-diethyl-3-methylbenzamide) are the most effective and most widely used. However, concerns have been raised over the risk of adverse toxic effects, especially in young children and pregnant and lactating women. In this article, we review the available evidence on the effectiveness and safety of DEET-based products. The evidence does not support increased risk in young children.
Article
Military personnel deployed in the Persian Gulf War (PGW) were exposed to a combination of chemicals, including pyridostigmine bromide (PB), DEET, and permethrin. We investigated the dose-response effects of these chemicals, alone or in combination, on the sensorimotor performance and cholinergic system of male Sprague-Dawley rats. Animals were treated with a daily dermal dose of DEET and/or permethrin for 60 days and/or PB (gavage) during the last 15 days. Neurobehavioral performance was assessed on day 60 following the beginning of the treatment with DEET and permethrin. The rats were sacrificed 24 h after the last treatment for biochemical evaluations. PB alone, or in combination with DEET, or DEET and permethrin resulted in deficits in beam-walk score and longer beam-walk times compared to controls. PB alone, or in combination with DEET, permethrin, or DEET and permethrin caused impairment in incline plane performance and forepaw grip strength. PB alone at all doses slightly inhibited plasma butyrylcholinesterase activity, whereas combination of PB with DEET or permethrin increased its activity. Brainstem acetylcholinesterase (AChE) activity significantly increased following treatment with combinations of either DEET or permethrin at all doses, whereas the cerebellum showed a significant increase in AChE activity following treatment with a combination of PB/DEET/permethrin. Co-exposure to PB, DEET, and permethrin resulted in significant inhibition in AChE in midbrain. PB alone or in combination with DEET and permethrin at all doses increased ligand binding for m2 muscarinic acetylcholine receptor in the cortex. In addition, PB and DEET together or a combination of PB, DEET, and permethrin significantly increased ligand binding for nicotinic acetylcholine receptor. These results suggest that exposure to various doses of PB, alone and in combination with DEET and permethrin, leads to sensorimotor deficits and differential alterations of the cholinergic system in the CNS.
Article
Synthetic insect repellents, IR3535 and KBR 3023 (also known as picaridin, or by the trade name Bayrepel®), were tested in Burkina Faso against mosquito vectors of disease to compare their relative efficacy and persistence profiles to those of the ‘gold standard’ DEET. Collection of >49 000 mosquitoes (∼95% belonging to the Anopheles gambiae complex) showed that after an exposure of 10 h, KBR 3023 produced the highest protection against anophelines, followed by DEET, then IR3535. The response of aedines was more variable. By fitting a logistic plane model we estimated 95% effective dosages (ED95) for An. gambiae s.l., as well as a decay constant characterizing the exponential loss of repellent from the skin, with time. The ED95 values for DEET, IR3535, and KBR 3023 were 94.3, 212.4, and 81.8 μg/cm2 respectively. The decay constants were estimated at −0.241, −0.240, and −0.170 h−1 respectively. The corresponding estimates of half-life were 2.9, 2.9, and 4.1 h. Immunoenzymatic detection of the circumsporozoite protein (CSP) of Plasmodium falciparum in 842 An. gambiae s.l. showed that CSP-positive mosquitoes were equally frequent in treated and control subjects, indicating that the repellents could produce a reduction in the number of malaria infectious bites.
Article
Amongst twenty-three workers exposed to synthetic pyrethroids, ninteen had experienced one or more episodes of abnormal facial sensation, developing between thirty min and three hr after exposure and persisting for thirty min to eight hr. There were no abnormal neurological signs and electrophysiological studies were normal in the arms and legs. It is concluded that the symptoms are most likely to be due to transient lowering of the threshold of sensory nerve fibres or sensory nerve endings following exposure of the facial skin to pyrethroids, similar to the phenomena that have been described following exposure of animal nerves to pyrethroids.
Article
Various compounds were tested for effects on the toxicity of the insect repellent N, N-diethyl-m-toluamide (DEET) in German cockroaches, Blattella germanica (L.). Organophosphate and carbamate acetylcholinesterase inhibitors carbaryl, DEF, eserine (physostigmine, malathion and pyridostigmine bromide synergized DEET toxicity also synergized the toxicity of the formamidine pesticides. Amitraz and chlordimeform. Results suggest that DEET may have some toxic actions that are similar to those of formamidine pesticides. DEET synergized the toxicity of some acetylcholinesterase inhibitors but not others. Results further suggest that some mechanism other than acetylcholinesterase inhibition was responsible for the toxic interactions observed between DEET and the acetylcholinesterase inhibitors.
Article
Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies.
Article
Arthropod bites remain a major cause of patient morbidity. These bites can cause local or systemic effects that may be infectious or inflammatory in nature. Arthropods, notably insects and arachnids, are vectors of potentially serious ailments including malaria, West Nile virus, dengue, and Lyme disease. Measures to curtail the impact of insect bites are important in the worldwide public health effort to safely protect patients and prevent the spread of disease. The history of insect repellent (IR) lends insight into some of the current scientific strategies behind newer products. Active ingredients of currently available IRs include N,N-diethyl-3-methylbenzamide (DEET), botanicals, citronella, and, the newest agent, picaridin. Currently, the Environmental Protection Agency's registered IR ingredients approved for application to the skin include DEET, picaridin, MGK-326, MGK-264, IR3535, oil of citronella, and oil of lemon eucalyptus. DEET has reigned as the most efficacious and broadly used IR for the last 6 decades, with a strong safety record and excellent protection against ticks, mosquitoes, and other arthropods. Newer agents, like picaridin and natural products such as oil of lemon eucalyptus are becoming increasingly popular because of their low toxicity, comparable efficacy, and customer approval. Various characteristics and individual product advantages may lead physicians to recommend one agent over another.