\r\n\tBook, “Mites, Ticks and Humans", is written by keeping in vision non-availability of any standard text dealing in different aspects of acarology at one place. Separate chapters in this book are devoted to medical importance of mites and ticks; ectoparasites, endoparasites and disease transmitting mites; classification, biology and epidemiology of dust mites; manifestations, diagnostics and preventions of dust mites allergy; ticks transmission of disease causing pathogens; and measures to mitigate mites and ticks. Book will stimulate interest in the readers for more information about different mites and ticks affecting publics. The knowledge contained in the book may prove as best material for graduate and post-graduate level courses, teachers and researchers in entomology, pestss control advisors, professional entomologists, pesticide industry managers, policy planners, and other experts having interest in mites and ticks.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"1ab684433f948520e8e90a2e74e2801a",bookSignature:"Dr. Muhammad Sarwar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8964.jpg",keywords:"Basic biology, Diversity of lifestyles, Scabies, Mange, Ecosystem, Soil mite, Dust mites allergy, Asthma, Vectors, Dispersal or spreading modes, Pest management, Detection and survey",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 28th 2019",dateEndSecondStepPublish:"September 16th 2019",dateEndThirdStepPublish:"November 15th 2019",dateEndFourthStepPublish:"February 3rd 2020",dateEndFifthStepPublish:"April 3rd 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"272992",title:"Dr.",name:"Muhammad",middleName:null,surname:"Sarwar",slug:"muhammad-sarwar",fullName:"Muhammad Sarwar",profilePictureURL:"https://mts.intechopen.com/storage/users/272992/images/system/272992.jpeg",biography:"Dr. Muhammad Sarwar, Principal Scientist, is in his thirtieth year of service with the Department of Agriculture, Government of Punjab. He is also currently working for the Pakistan Atomic Energy Commission. He completed his post doctorate in 2008, funded by the Higher Education Commission of Pakistan from the Institute of Plant Protection in the Chinese Academy of Agricultural Sciences, Beijing, China. He has several hundred published papers to his credit and is recipient of the Shield award, letters of appreciation, and certificates of performance from faculty members of the Chinese Academy of Agricultural Sciences, Beijing, China. In 2010, the Zoological Society of Pakistan presented him with the Prof. Dr. Mirza Azhar Beg Gold Medal. In 2011, the Pakistan Council for Science and Technology awarded him a Research Productivity Award.\n\nHis research activities focus on integrated pest management for rice, cotton, chickpea, and Brassica crops; predatory mites, ladybird beetles, Chrysoperla, Trichogramma, and parasitoids of fruit flies culturing as bio-control agents; integrated management of fruit flies and mosquitos; and other arthropod pest control methodologies. He has also researched vertebrate pest control, especially controls of rodents in field crops and storage. He was the first to explore thirty-six new species of stored grain mites belonging to eight genera, including Forcellinia, Lackerbaueria, Acotyledon, Caloglyphus, and Troupeauia in the Acaridae family; and Capronomoia, Histiostoma, and Glyphanoetus in the Histiostomatidae family. He also planned and designed research trials on the integrated management of cotton leaf curl virus (CLCV), pest scouting, pest monitoring, and forecasting. He conducted training of progressive farmers and field staff, and provided advisory services to the farmers regarding plant protection practices. He also trained pesticide dealers on the proper handling, distribution, and storing of pesticides.\n\nUnder a coordinated research program, Dr. Sarwar collaborated with other institutes to trace resistance sources for cotton, rice, gram, rapeseed, mustard plants, and stored cereals and pulses. He has supervised post-graduate research and is an external examiner for post-graduate studies. He has also organized various workshops, served as a reviewer for scientific journals, and is a member of various working committees. He is responsible for opening up a new avenue on rearing of predatory mites as bio-control agents of insects and mites pests in greenhouse and field crops.\n\t\nDr. Sarwar is an approved supervisor with the Higher Education Commission (HEC) of Pakistan. He completed a course in Basic Management organized by the Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, in 2011. He has also completed trainings in Beijing, Bangkok, Havana, and Vienna. 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1. Introduction
The three mainstays for cancer treatment include surgical removal of tumors, radiation therapy and chemotherapy, which have led to improved patient survival for certain types of cancer, but there is still much room for improvement. Cancer is one of the leading causes of death worldwide and accounted for 7.6 million deaths (13% of all deaths) in 2008 (World Health Organization, 2012). The 2012 Report to the Nation on the Status of Cancer indicated that there was a decrease in overall cancer mortality and incidence in the U.S.A. from 1999 to 2008, particularly for the four major cancer sites: lung, colorectum, breast and prostate [1]. However, there were increases in the incidence of other types of cancer, including those of the pancreas, kidney, thyroid and liver, as well as melanoma and adenocarcinoma of the esophagus, from 1999 to 2008.
Over the past decades, the struggle against cancer has led to the discovery of new strategies to fight this disease and to bring hope to patients. These new strategies include hyperthermia (also commonly known as thermal therapy or thermotherapy), biological therapies (e.g. immunotherapy), photodynamic therapy, laser treatment, gene therapy, and inhibitors of angiogenesis. Most of these strategies still need optimization, and in some cases (e.g. hyperthermia, photodynamic therapy), improved equipment is required. Moreover, a better understanding of the biological mechanisms involved in their anticancer action would certainly be beneficial. Hyperthermia is one of the few strategies to be adopted as a promising therapy among the alternative methods to treat cancer.
Hyperthermia is defined as moderate elevation in temperature. Hyperthermia can either have a pathological origin, resulting from the fever response of the organism to viral or bacterial infections, or may occur during exposure to high temperatures as during heat stroke. It is relatively recent as a clinical procedure, in which body tissues are exposed to elevated temperatures in the range of 39°C to 45°C. These high temperatures can damage and kill cancer cells with minimal injury to normal tissues [2]. During the last two decades, hyperthermia has been used as an efficient complement to standard cancer treatments such as radiation therapy and chemotherapy [2,3] (Figure 1). A further advantage is that hyperthermia can eliminate drug-resistant and radio-resistant tumour cells. Another form of hyperthermia involves very high temperatures (> 60°C), which can destroy or «cook» tumours by a technique known as thermal ablation (see review, [4]). The present review will address the therapeutic potential of moderate hyperthermia (39°C to 45°C).
Figure 1.
Hyperthermia complements standard cancer treatments such as chemotherapy and radiation therapy in destroying tumour cells.
2. Hyperthermia
2.1. Scientific history
The use of heat to treat disease, including cancer, is a concept that dates back to early Egyptian times, over 5000 years ago (see review, [5]). Indeed, the Egyptian medical papyrus recounts an attempt to treat breast cancer with a "heated stick" [6]. Likewise, many Greek doctors, among them Hippocrates, suggested cauterizing superficial tumours by using heated metal. Many ancient cultures, including the Roman, Chinese, Indian and Japanese cultures have used this concept for the treatment of a variety of diseases. During the late 1800s, there were numerous observations by astute clinicians of spontaneous remissions of cancer in patients suffering from a variety of infections [7]. Dr. William B. Coley found 47 case reports in which simultaneous infection seemed to have caused the remission of an incurable neoplastic malignancy (see review, [8]). In the late 1800s, he used “Coley’s Mixed Toxins” (bacterial pyrogenic toxins) as a deliberate fever-inducing treatment to control tumor growth [9]. Despite promising observations during several decades, these cancer treatments were difficult to administer in a controlled manner, and responses were unpredictable [10]. Using a different approach, Westermark reported the use of localized, non-fever producing heat treatments (42-44°C) by means of water-circulating cisterns that resulted in the long-term remission of inoperable cancer of the cervix [11]. As different techniques were developed, such as surgery, radiation therapy and chemotherapy, further development of hyperthermia for cancer treatment was put on the back burner. There was a resurgence of interest in the use of hyperthermia in cancer treatment based on scientific studies initiated in the 1960s and 1970s. A turning point was a study conducted in transplanted mouse tumors that illustrated novel biological phenomena: cytotoxicity of hyperthermia was dependent on time and temperature; increased sensitivity of large versus small tumors to hyperthermia (later attributed to vascular events); heat-induced thermotolerance of normal and tumor tissue; and hyperthermia-induced sensitization to radiation [12]. These promising observations led to quantitative experimental studies and a rapid increase in our understanding of the biological effects of hyperthermia. Furthermore, they frame the rationale for the clinical use of hyperthermia, and the development of more effective technologies for the precise application of heat to tumors and for the measurement of heat distribution in tumors by thermometry.
2.2. Cellular changes
Temperatures in the range of moderate hyperthermia can be non-lethal (39 to 42°C) or lethal (>42°C). Temperatures above 42°C were shown to kill cancer cells in a time- and temperature-dependent manner that was measured by the clonogenic cell survival assay [13]. However, despite numerous studies during at least three decades, which have improved our understanding of hyperthermia biology, the mechanisms involved in heat-induced cytotoxicity are still ill-defined [14]. Hyperthermia causes many changes in cells and leads to a loss of cellular homeostasis [15-17]. A key event appears to be protein denaturation and aggregation, which results in cell cycle arrest, inactivation of protein synthesis, and inhibition of DNA repair processes [18]. Other cellular effects of hyperthermia include: (1) the inhibition of DNA synthesis, transcription, RNA processing and translation; (2) increased degradation of aggregated/misfolded proteins through the proteasomal and lysosomal pathways; (3) disruption of the membrane cytoskeleton; (4) metabolic changes (e.g. uncoupling of oxidative phosphorylation) that lead to decreased levels of ATP; and (5) alterations in membrane permeability that cause increases in intracellular levels of Na+, H+ and Ca2+ (see reviews, [19,20].
Hyperthermia can cause changes in lipids but these appear to be reversible [21]. The viscosity of the plasma membrane decreases with increasing temperature [22], and this may be associated with altered transport functions of the membrane. Changes in membrane viscosity were linked to an elevation in the activity of the ATP-dependent sodium-potassium pump [22], which maintains Na+ and K+ levels across the plasma membrane against a concentration gradient. During hyperthermia, membrane permeability towards several compounds is altered, including polyamines, glucose, and anticancer drugs [23-25].
Despite the large number of documented cellular changes, the nature of the critical lesions that lead to cell death following heat treatment remains unknown. Proteins appear to be the first target of hyperthermia in the clinically-relevant temperature range of 39 to 45°C (Figure 2). The alteration of cellular homeostasis after exposure to hyperthermia entails a certain number of post-translational modifications such as glycosylation, acylation, phosphorylation, farnelysation and ubiquitination [18,26]. Several studies reported that hyperthermia can cause DNA fragmentation and the formation of double strand breaks (DBSs) [27,28], which could arise from the inhibition of DNA repair mechanisms [21]. However, it appears that nuclear protein damage may be the key factor rather than direct DNA damage itself. Nuclear proteins, in particular, appear to be very sensitive to hyperthermia and undergo aggregation [21]. Nuclear protein aggregation has been linked to the inhibition of transcription and DNA replication.
Figure 2.
Hyperthermia-induced cellular changes that could lead to tumour cell death.
Elevated temperatures can increase the rates of biochemical reactions and this would increase cell metabolism, which should cause increased oxidative stress (Figure 2). Levels of reactive oxygen species (ROS) were shown to increase after exposure to both lethal (≥42°C) [29-31] and non-lethal (40°C) temperatures [32,33]. This would arise principally from the increased generation of ROS such as superoxide and hydrogen peroxide (H2O2), likely as a result of dysfunction of the mitochondrial respiratory chain. Other potential sources of increased ROS generation would be increased activity of superoxide-producing enzymes such as NADPH oxidase and xanthine oxidase at elevated temperatures. Hyperthermia could also increase the reactivity of these ROS; indeed, the cytotoxicity of hydrogen peroxide was increased at elevated temperatures (41 to 43°C) compared to the physiological temperature (37°C) [34]. Hyperthermia also inactivated cellular antioxidant defenses against H2O2 such as the pentose phosphate pathway [35], which maintains the intracellular antioxidant glutathione in its reduced form, GSH [36]. An increase in the generation of ROS can cause oxidative damage to proteins, lipids and nucleic acids. A hyperthermia-induced decrease in tumor growth was accompanied by an increase in lipid peroxidation in rabbits [37]. Another consequence of increased ROS generation by hyperthermia is that molecules such as H2O2 can perturb mitochondrial membrane potential [38]. A temperature-induced increase in cell metabolism could also cause acidosis of the tumor tissue [39,40].
2.3. Cytotoxicity of hyperthermia
As a consequence of different cellular changes, hyperthermia causes mitotic catastrophe, permanent G1 arrest and a loss of clonogenic or reproductive cell capacity [21] (Figure 2). Cells can die by processes such as apoptosis and/or necrosis, which are dependent on the cell type as well as the temperature and duration of heat exposure [32,41]. Another consequence is that cells can become sensitized to other cytotoxic modalities such as radiation [16]. Hyperthermia was reported to cause centrosomal dysfunction and mitotic catastrophe [42], which have been implicated in thermal radio-sensitization [43]. Hyperthermia (42 to 44°C) has been reported to cause chromatin condensation and apoptotic DNA fragmentation (formation of DNA ladders) leading to apoptosis in many different cell types including HeLa cells [44], T lymphocytes [45,46], HL-60 leukemic cells [47], and mice embryonic fibroblasts [48]. In rats treated with whole body hyperthermia (41.5°C for 2 h), both the extent and kinetics of hyperthermia-induced apoptosis differed between two different tumor types (fibrosarcoma and colon carcinoma) [49]. Additionally, the same study revealed another important advantage; the induction of apoptosis was higher in tumor tissues in comparison to normal tissues. Most of the studies that have investigated the mechanisms of heat shock-induced cytotoxicity concluded that apoptosis is the main form of cell death and proposed the pro-apoptotic effects of hyperthermia as the potential desired outcome of hyperthermia in cancer therapy.
2.4. Hyperthermia and physiological changes
Several physiological factors including oxygenation, pH and blood flow were shown to play a role in the sensitivity of cells/tissues to moderate hyperthermia. The intrinsic sensitivity to heat varies significantly among different cell types. Several studies indicate that cancer cells are more susceptible to heat injury than normal cells [21,50]. This could be caused, at least in part, by the differential expression of heat shock proteins (Hsps) and other proteins involved in the cellular defense system against different stressors, including heat shock. However, there is no consistency in findings about heat sensitivity between tumor and normal cells [21]. The sensitivity of cells to heat also varies with phase of the cell cycle, where cells in S phase and mitosis were reported to be most sensitive [51].
Another reason for the use of hyperthermia in cancer treatment is the fact that tumor tissues are poorly vascularized in comparison to normal tissues. This may lead to a differential heating, with higher temperatures being achieved in tumors compared with normal tissue, where heat may be dissipated by circulating blood. Hyperthermia also appears to be complementary to other forms of treatment by being able to destroy tumor cells that are relatively resistant to radiation therapy or chemotherapy. Tumor cells located in the hypoxic centers of tumors are relatively resistant to chemotherapy due to poor drug delivery. Several chemotherapeutic drugs also require oxygen to generate free radicals in order to cause tumor cytotoxicity. Further, most chemotherapeutic drugs are more effective against proliferating cells. However, hypoxia has been shown to cause decreased proliferation, which may partially explain the reason for resistance of tumor cells to chemotherapy [52-54]. Cells located in hypoxic areas of tumors are also resistant to radiation therapy.
Heating of human tumours is heterogeneous. Some areas of the tumour reach cytotoxic temperatures such as 43 to 45°C, whereas other areas only reach 39 to 42°C. It is more difficult to heat larger or deep-seated tumours to cytotoxic temperatures that are adequate to cause cell death or vascular damage.
Tumors are unable to adapt their blood circulation to the effects of high temperatures (≥42°C), which enables hyperthermia to cut off the supply of nutrients and oxygen, leading to lower interstitial pH and a collapse in tumor vasculature [55]. These conditions render cells more susceptible to heat treatment. Indeed, cells at lower (acidic) pH and decreased oxygen tension, as in the center of tumors, are more sensitive to heat treatment [56,57]. Cells in a nutrient-deprived environment are also more sensitive to elevated temperatures. This effect appears to correlate with changes in cellular ATP levels [58]. Cells that were deprived of glucose exhibited increased sensitivity to the cytotoxicity of hyperthermia [35]. This effect could be linked to a decrease in antioxidant defenses involving the glutathione redox cycle, since glucose metabolism, through the pentose phosphate pathway, is required for maintaining intracellular levels of GSH. On the other hand, heating at milder temperatures (e.g. 39° to 42°C) can increase tumor blood flow, which leads to improved tumor oxygenation [59,60]. This could render tumors more sensitive to radiation and certain anticancer drugs.
Hyperthermia (≥42°C) has been shown to cause vascular damage in rodent tumours, which leads to decreased oxygenation and necrosis [61]. Although, the vasculature of human tumours appears to be more resistant to hyperthermia than that of rodent tissues, hyperthermia has been shown to cause disturbances in the microcirculation of cancer tissue in human osteosarcoma [62].
Milder temperatures in the range of 40 to 41°C appear to be able to stimulate various elements of the immune system, thus increasing immune surveillance and protecting against tumor growth (see reviews, [63-65]). The exposure of immune effector cells (e.g. macrophages, T cells, and natural killer (NK) cells) to mild temperatures has been shown to: (1) enhance the migration of immune cells to target sites, which could allow better control of infection and tumor burden; (2) increase the expression of cell surface molecules (e.g. involved in antigen presentation); (3) increase the release of soluble factors involved in immune effector cell activity (e.g. pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-10, and IL-12; (4) regulate immune cell proliferation; and (5) increase the cytotoxicity of immune cells against target (tumor) cells.
2.5. Thermotolerance: The other side of hyperthermia
The exposure of cells to lethal temperatures such as 43 to 45°C during short periods of time, ranging from 10 to 30 minutes, allows the development of tolerance towards subsequent exposure to multiple stresses; this phenomenon is termed “thermotolerance” [66,67]. Thermotolerance is an adaptive survival response induced by heat preconditioning whereby cells become resistant to a subsequent lethal insult such as that triggered by heat shock, reactive oxygen species (ROS), and environmental stressors including heavy metals [68,69]. If the level of stress is very low, cells attempt to survive by activating stress responses that protect essential biochemical processes such as DNA repair, protein folding, and the elimination of damaged proteins [70]. Once the stress stimulus is removed, cells can recover their normal cellular function. If the stress continues or is too severe, then the cell will likely die by apoptosis or necrosis.
The acquisition of thermotolerance is characterized by numerous biochemical and molecular changes. Thermotolerance is generally associated with the accumulation of Hsps [19,63,68,71-73]. Hsp expression is regulated by a stress-responsive transcription factor known as heat shock factor 1 (HSF-1), through its interaction with the heat shock element (HSE) [74]. In addition, changes in the expression of about 50 to 200 other genes, not traditionally considered Hsps, have been found during or after heat stress (see review, [20]). These include genes for transcription factors, protein degradation, DNA repair enzymes, metabolic enzymes, cell cycle arrest, transport and detoxification, and signal transduction. The reason for the induction of these other cell-protective pathways by heat shock is probably to protect nascent chain synthesis and folding, prevent protein misfolding and aggregation, and to promote recovery from stress-induced damage [75]. Proteomic analyses showed a change in the phosphorylation of 93 proteins between control RIF-1 and their thermotolerant derivatives, TR-RIF-1 cells [76]. These phosphorylated proteins are responsible for a range of cellular functions, which include chaperones, ion channels, signal transduction, transcription and translation, biosynthesis of amino acids, oxidoreduction, energy metabolism, and cell motility or structure.
The heat shock response is highly conserved in all organisms from yeast to humans, which suggests that it is important for survival in a stressful environment [74]. In addition to heat, the heat shock response can be induced by other insults such as oxidative stress, heavy metals, ethanol, toxins and bacterial infections.
The major classes of Hsps induced by the heat shock response are Hsp90, Hsp70, Hsp60, and Hsp27. Hsps appear to play an important role in thermotolerance. Many studies suggest a correlation between the accumulation of Hsp70 and the acquisition of a thermotolerant state in mammals, amphibians, insects [77-79] and fish [80]. Under conditions of stress, Hsp70s can prevent the formation of protein aggregates and assist the refolding of aggregated proteins into their native structures [19]. Other studies have shown that the state of thermotolerance correlated with an increase in the expression of Hsp110 [81]. Hsp110 is as effective as Hsp70 in preventing protein aggregation, and contributes, along with Hsp70 and Hsp40, to the refolding of denatured proteins. In addition to their protective role against a subsequent lethal heat shock, Hsps are known to protect cells against other forms of stress, such as oxidative stress and radiation [82].
Hsps play an important and yet complex role in the regulation of apoptosis. The specific roles of different Hsps such as Hsp27, Hsp60, Hsp70 and Hsp90 in the regulation of the mitochondrial and death receptor pathways of apoptosis have been reviewed [82-85]. The induction of apoptosis through the Fas death receptor can be regulated by Hsp70 and Hsp27 [86,87]. Hsp27 and Hsp70 can regulate the death receptor pathway of apoptosis by preventing t-Bid translocation to mitochondria, which in turn inhibits cytochrome c release [88, 89]. Hsp90 was shown to be a negative regulator of caspase-2 activation [90]. Hsp27, Hsp70, and Hsp90 can attenuate apoptosis upstream of mitochondria [91], as well as interfering with apoptosome formation, post-mitochondrial events, and caspase activation [92]. Furthermore, Hsp70 and phosphorylated Hsp27 can protect cells against oxidative stress, a potent activator of apoptosis [93,94].
The development of thermotolerance by lethal hyperthermia has been the subject of intensive studies during the past three decades, whereas thermotolerance induced at mild, fever-range temperatures has received relatively little attention. Thermotolerance can be developed following exposure for shorter times (e.g. 30 min) to lethal temperatures (42 to 45°C) [68,71], or during continuous heating (e.g. 3 to 24 h) at non-lethal temperatures (39 to 41.5°C) [95,96]. The development of thermotolerance by exposure of cells to mild hyperthermia (40°C) for 3 to 24 h led to the accumulation of Hsps 27, 32, 60, 70, 90 and 110 [32,95]. This phenomenon is of notable importance for fundamental research given that it is a physiological fever-range temperature and suggests that thermotolerance could protect healthy tissue against stressors during clinical therapies. The treatment of BALB/c mice in vivo with fever-range whole body hyperthermia (39.5 to 40°C) for 6h led to increased expression of Hsp70 and Hsp110 in several mouse tissues [97].
Mild thermotolerance developed at 40°C created an apoptosis-resistant phenotype. The activation of the mitochondrial pathway of apoptosis by moderate hyperthermia (42 to 43°C) was attenuated in these thermotolerant cells [44]. Similarly, activation of the death receptor signaling pathway through the Fas receptor by lethal heat shock (42 to 43°C) was inhibited in thermotolerant cells [32]. Furthermore, thermotolerance developed at 40°C protected cells against the induction of apoptosis by oxidative stress (H2O2), mediated through the mitochondrial and death receptor pathways [33,38]. This apoptosis-resistant phenotype could be conferred by increased levels of both Hsps (Hsps 27, 32, 60, 70, 90, and 110 kDa) and antioxidants (catalase, manganese superoxide dismutase, glutathione) [32,33]. Mild thermotolerance also inhibited hyperthermia-induced ROS generation [32], and this could be explained by the ROS-inhibitory effect of Hsps such as Hsp27 and Hsp70 [93,94].
Hsps play overlapping roles in tumour development and growth by promoting cell proliferation and by inhibiting cell death pathways [98]. Hsp70 is a survival protein that is overexpressed in various malignant tumors and its expression correlates with increased cell proliferation, poor differentiation and poor therapeutic outcome in human breast cancer [99]. The increased expression of Hsp70 in tumors can prevent the activation of caspases and proteases, and thus abolish apoptotic cell death [98]. Moreover, the increased expression of Hsps appears to be involved in the acquisition of drug-resistant phenotypes. Several studies have reported that Hsp27 may be involved in the development of resistance to chemotherapeutic agents such as doxorubicin and cisplatin [100-104].
2.6. Hyperthermia in cancer therapy
The biological rational for the use of hyperthermia in cancer treatment is very strong. Temperatures of 42.5°C and above are able to kill cancer cells. Findings from in vitro studies generally indicate that there is no intrinsic difference in heat sensitivity between normal and tumour cells [105]. However, a tumour selective effect of hyperthermia could occur at higher temperatures in vivo. In solid tumours, the vascular system is chaotic, which results in regions with hypoxia and low pH levels, compared to normal tissues. These conditions render cells more sensitive to the cytotoxic effects of hyperthermia. Therefore, hyperthermia can be beneficial by causing direct cytotoxicity to tumour cells, in addition to selective destruction of tumour cells in hypoxic and low pH environments within solid tumours. A further benefit is that mild hyperthermia can activate certain responses of the immune system, which could also provide protection against tumour growth [64,106]. In the clinic, hyperthermia has been shown to be most beneficial when used in combination with radiation therapy and/or chemotherapy.
2.6.1. Hyperthermia in combination with radiotherapy
One of the most promising aspects of hyperthermia in cancer treatment is the ability to eliminate radiation-resistant tumour cells [see review, 5]. Indeed, this renders hyperthermia as one of the most effective radiation sensitizers known. The basis for this effect is that hyperthermia has the ability to kill cells that are under conditions of hypoxia, low pH and that are in the S-phase of cell division, which are all conditions that render cells resistant to radiation. The mechanisms responsible for heat-induced radio-sensitization are not entirely understood, particularly for milder temperatures [21]. For temperatures of 43°C and above, nuclear protein damage is considered to be a critical event [107]. It was suggested that hyperthermia interferes with the repair of radiation-induced DNA damage. In support of this idea, hyperthermia increased the amount of radiation-induced chromosomal aberrations [13,108]. It was suggested that heat-induced enhancement of chromosomal aberrations could arise from the inhibition of repair of radiation-induced DNA damage. Hyperthermia could exert its major effect on radio-sensitization by specifically inhibiting base excision repair of DNA damage [109,110].
2.6.2. Hyperthermia in combination with chemotherapy
The combined use of regional hyperthermia with systemic chemotherapy has considerable potential in cancer treatment mainly because localized heat delivery could enhance cytotoxic activity of anticancer drugs within a defined target region. This may lead to an improved therapeutic ratio by allowing targeting of chemotherapy, as can be achieved with radiation therapy. At present, targeted treatment with anticancer drugs can only be accomplished when they are administered either topically or intra-arterially. There is also evidence to suggest that the cytotoxic effects of hyperthermia and anticancer drugs may prove to be complementary. Tumour cells that are located in less well-vascularized regions of a tumour, such as the tumour center, may be relatively resistant to systemic chemotherapy because they are exposed to lower concentrations of drug. The benefit of hyperthermia is that it kills cells most efficiently in the low pH and hypoxic environment of the tumour core. Furthermore, the temperature achieved in poorly vascularized regions of the tumour may be higher because of less efficient cooling by circulating blood. Another potential benefit is that regional hyperthermia at 40–43°C causes an increase in tumour blood supply [111]. Blood flow and vascular permeability, which are increased by hyperthermia, are critical factors for drug uptake [112].
Laboratory and in vivo studies have shown that the combined use of hyperthermia and chemotherapy leads to increased cytotoxic effects of several anticancer drugs such as cisplatin, anthracyclines, cyclophosphamide, ifosfamide, nitrosoureas, bleomycin, mitomycin, and nitrogen mustards such as melphalan [16,25,105,113-118]. Optimal heat enhancement of drug cytotoxicity generally occurs between 40.5°C and 43°C. For drugs such as cisplatin, alkylating agents, and nitrosoureas, interactions between heat and drug are more than additive (or synergistic), whereas in other cases, interactions are simply additive [119]. For bleomycin and Adriamycin, there is a threshold temperature of about 42.5°C to 43°C for enhancement of drug cytotoxicity. The antimetabolites (e.g. 5-fluorodeoxyuridin and methotrexate) and Vinca alkaloids or taxanes have independent interactions with hyperthermia. In general, the most effective heat-drug sequence is drug treatment immediately before heat delivery. The mechanisms of heat-induced enhancement of drug cytotoxicity are not well understood. Possible mechanisms include improved drug delivery to the tumour due to increased blood perfusion, increased intracellular uptake of drugs, and increased rates of reaction of drugs with cellular targets (e.g. increased drug alkylation, increased DNA damage).
2.6.2.1. Resistance to chemotherapeutic agents
One of the major limitations to the successful use of chemotherapy in cancer treatment is the development of resistance to multiple anticancer drugs. Cross-resistance occurs between different anticancer agents that have distinct structures and mechanisms of cytotoxicity. Multidrug resistance (MDR) is characterized by cross-resistance to four classes of commonly used anticancer drugs such as Vinca alkaloids, anthracyclines, taxanes, and epipodophyllotoxins. Classical MDR was discovered about 35 years ago and was initially related to the overexpression of the cellular 170-kDa protein P-glycoprotein (Pgp) [120], a member of the ATP-binding cassette (ABC) transporters. Pgp acts as an ATP-dependent transmembrane pump. Once anticancer drugs enter cells, they are immediately expulsed out of cells by Pgp. This results in decreased levels of drugs inside cells, rendering the drugs less effective against the tumour cells. In addition to Pgp, several other transporter proteins have been implicated in MDR in human cancer: multidrug resistance-associated protein 1 (MRP1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) [121]. MRP1 is a 190-kDa member of the ABC transporter family of proteins [122]. MRP1-mediated transport requires GSH, as well as ATP binding and hydrolysis. The overexpression of the protein MRP1 can cause cellular resistance to several anticancer drugs, including Adriamycin (doxorubicin), epipodophyllotoxins, and Vinca alkaloids such as vincristine, [123]. The substrate spectrum of MRP proteins also comprises amphiphilic anion conjugates of lipophilic compounds with glutathione (GSH), glucuronate, or sulfate [124], as well as cysteinyl leukotriene (LTC4), prostaglandins, and the anticancer drug methotrexate [125].
Eventually, other distinct mechanisms were also implicated in the MDR phenotype [126]. These mechanisms engage other proteins involved in cellular defenses such as glutathione S-transferase (GST), an enzyme involved in the cellular detoxification of xenobiotics, which include certain anticancer drugs, toxins and environmental pollutants that undergo conjugation with the antioxidant GSH [127]. Other cellular defenses utilized by the MDR phenotype include metallothionein, thioredoxin, thymidylate synthase, dihydrofolate reductase, Hsps and topoisomerase II [126].
Clinical drug resistance appears to be a very complex and multifactorial problem [128] with multiple mechanisms involved. There is often overlapping substrate specificity between different drug transporters, and they are commonly co-expressed in many normal tissues and tumours. Overcoming MDR in cancer treatment presents a formidable challenge [129].
To date, three generations of inhibitors have been used to increase the efficacy of chemotherapy by inhibiting transporter-mediated drug efflux. However, the development of clinical inhibitors of ABC transporters as targets for clinical intervention in oncology has been difficult and new approaches are clearly needed. Clinical drug resistance is a major barrier which, if overcome, should lead to a significant improvement in patient survival.
2.6.2.2. Hyperthermia and reversal of resistance to chemotherapeutic agents
A beneficial effect of hyperthermia is its ability to reverse resistance to certain chemotherapeutic drugs [130]. Hyperthermia increased the cytotoxicity of anticancer drugs such as methotrexate [131], cisplatin [132], and mitomycin c [133] in cells exhibiting primary drug resistance. In addition, hyperthermia enhanced the cytotoxicity of melphalan in MDR Chinese hamster ovary CHRC5 cells that overexpress Pgp [117]. CHRC5 cells are resistant to anticancer drugs such as colchicine, Vinca alkaloids, Adriamycin, and melphalan [134].
Among the earlier strategies to overcome MDR, Pgp-modulating agents such as cyclosporin A and verapamil were developed. These chemosensitizers appear to act by decreasing Pgp-mediated efflux of anticancer drugs from cells, which allows increased accumulation of drugs to more cytotoxic levels inside cells. However, clinical studies showed that these chemosensitizers were effective only at toxic doses [128]. Therefore, chemosensitizers with improved MDR-reversing ability and lower toxicity need to be developed, as well as novel approaches. Hyperthermia (42 to 43°C) showed beneficial effects by reversing MDR involving Pgp when melphalan or Adriamycin was combined with Pgp modulators such as cyclosporin A [135,136]) or verapamil [137,138]. When combined with hyperthermia (43°C), the Pgp modulator PSC 833 reduced resistance to vinblastine in MDR K562 leukaemia cells and MESSA leiomyosarcoma cells [139]. Moreover, ultrasound-induced hyperthermia (USHT) increased Adriamycin cytotoxicity in the MDR human lung adenocarcinoma cell line MV522 [140]. The alkylating agent melphalan is mainly detoxified through conjugation with GSH, which can be catalyzed by GST [141]. In addition to overexpression of Pgp, CHRC5 cells also overexpress the alpha and pi forms of GST, compared to the drug-sensitive AuxB1 cells [142]. Hyperthermia was beneficial by enhancing melphalan cytotoxicity in MDR cells when GST was inhibited using ethacrynic acid [142].
2.6.2.3. Sensitivity of multidrug resistant cells to hyperthermia
Another important advantage for the clinical use of hyperthermia is that MDR cells overexpressing Pgp or MRP1 do not display cross-resistance to heat [25,143]. Indeed, these MDR cells exhibit equivalent sensitivity to the cytotoxic and apoptosis-inducing effects of hyperthermia (41-45°C) as their drug-sensitive counterparts. Moreover, drug-resistant sub-clones of human T-lineage acute lymphoblastic leukaemia (ALL) and acute myeloblastic leukaemia (AML) cells were as sensitive to hyperthermia as were the drug-sensitive sub-clones [144]. Results from these studies indicate that, in addition to enhancing drug cytotoxicity in resistant cells, hyperthermia alone can successfully eliminate MDR cells. Together, these findings clearly show that hyperthermia could be useful by destroying subpopulations of drug-resistant tumour cells, which have survived chemotherapy treatments, where the overexpression of Pgp and MRP1 is involved.
Apoptosis is considered to be a physiological mechanism for the elimination of damaged and abnormal cells, such as tumour cells. One of the hallmark characteristics of tumour cells is their ability to evade destruction by apoptosis [145]. The up-regulation of different anti-apoptotic proteins, to provide a survival advantage, has been a frequent explanation for the resistance of cancer cells to elimination by apoptosis [146]. The induction of death receptor and mitochondria-mediated signaling pathways of apoptosis by hyperthermia (41 to 43°C) in MDR CHRC5 cells was compared to drug-sensitive CHO cells [147]. Differences were found between MDR and drug-sensitive cells in terms of induction of apoptosis by hyperthermia. For death receptor-mediated apoptosis, MDR cells contained higher levels of the anti-apoptosis protein c-FLIP and they had a lower level of activation of initiator caspase-8 and caspase-10 in response to hyperthermia. In the mitochondria-mediated pathway of heat-induced apoptosis, MDR cells showed higher mitochondrial levels of the pro-apoptosis proteins Bax and tBid, more pronounced mitochondrial membrane depolarization, and increased levels of the apoptosome protein Apaf-1 (apoptosis protease activating factor 1). The MDR cells appeared to show some resistance to death receptor-mediated apoptosis [147], in agreement with other studies in leukaemia cells [148, 149], but this resistance appeared to be compensated for by the pro-apoptosis changes in mitochondrial apoptosis. For the execution stage of apoptosis, the MDR and drug-sensitive cells showed similar levels of hyperthermia-induced caspase-3 activation, as well cleavage of caspase-3 substrates poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated DNase (ICAD) [147]. Similar levels of nuclear chromatin condensation were induced by hyperthermia, showing that overall, MDR cells are not resistant to hyperthermia-induced apoptosis compared to the drug-sensitive cells. In summary, MDR and drug-sensitive cells showed similar responses to heat in terms of clonogenic cell survival and apoptosis, which indicates that hyperthermia could be a promising strategy for eradicating MDR tumour cells in the cancer clinic.
2.7. Hyperthermia in the cancer clinic
2.7.1. Techniques to increase tumour temperatures
In the cancer clinic, hyperthermia is administered by exposing tumour tissues to conductive heat sources, or non-ionizing radiation (e.g. electromagnetic or ultrasonic fields). Hyperthermia can be applied by either invasive or noninvasive techniques, using externally applied power. To increase tumour temperatures, hyperthermia can be applied by several different techniques: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia [150].
2.7.1.1. Local hyperthermia
Local hyperthermia entails elevating the temperature of superficial or deep-seated subcutaneous tumours while sparing the surrounding normal tissue, using external, intraluminal or interstitial heating modalities. The area can be heated externally with high-frequency waves (e.g. electromagnetic or ultrasound energy) aimed at the tumour from a device outside the body. To achieve internal heating, one of several types of sterile probes may be used, including thin heated wires, hollow tubes filled with warm water, implanted microwave antennae, radio-frequency electrodes and ultrasound. Local hyperthermia has allowed the use of hyperthermia in conjunction with other modalities of antineoplastic therapy. Local hyperthermia is more appropriate for the treatment of solid tumours, rather than blood diseases such as leukaemia. Despite advances in the technology of heating, the non-homogeneous character of the treatment region (i.e. tissue characteristics and blood flow) can often affect the uniformity of the heat dispersion in the treated area. This means that it can be difficult to obtain a uniform regional rise in the temperature that is reproducible [151-155]. Deep regional hyperthermia combined with chemotherapy, also known as hyperthermic intraperitoneal chemotherapy, is one of the promising methods for the treatment of prostate carcinoma [156,157] and bladder cancer [158].
2.7.1.2. Perfusion hyperthermia
This technique involves regional heating through the perfusion of a limb, organ (liver, pelvis, stomach), or body cavity using heated fluids [159-161]. In perfusion, the patient\'s blood can be removed, heated, and then pumped into the region that is to be heated internally. Perfusion hyperthermia can be applied with or without a cytotoxic drug. When applied to limbs without a cytotoxic agent, a temperature of about 43°C can be used for about two hours. Lower temperatures are used when perfusion is performed in combination with cytotoxic agents, to avoid drug toxicity.
2.7.1.3. Whole body hyperthermia
Externally-induced whole body hyperthermia can be used to treat metastatic cancers that have spread throughout the body. Whole body hyperthermia can be applied using different methods and involves heating the patient to a maximum temperature of 41.8 to 42°C. A newer approach is to increase the temperature to about 40°C for a longer duration, and use a combination of mild hyperthermia with cytokines and/or cytotoxic drugs [118].
Many studies are focusing on improving the heating techniques. This is one of the main challenges that currently limit the clinical use of hyperthermia. Furthermore, improvements are required to heat effectively the deep-seated tumours that are localized in internal organs. The use of nanoparticles and the induction heating of magnetic materials that are implanted into tumors are among the new approaches that are currently being investigated for the improved application of hyperthermia.
2.7.2. Progress in the cancer clinic
In the cancer clinic, hyperthermia (40 to 44°C) is mainly used as an adjuvant to radiation and chemotherapy [2,5,16,150]. The major limitations of these conventional cancer treatments are lack of specificity and normal tissue toxicity. An important advantage of hyperthermia is that the cytotoxicity of radiotherapy and chemotherapy can be targeted to the tumour volume, thereby decreasing toxic side effects. The effectiveness of hyperthermia depends on the temperature rise and the duration of treatment at the elevated temperature. At least 19 randomized studies using a combination of hyperthermia with radiotherapy, chemotherapy or both, have shown significant improvement in clinical outcome in oncology patients, without a significant increase in side effects [150]. In all of these studies, the differences were very large. The combination of hyperthermia with radiation resulted in higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates in many Phase II clinical trials [162-171]. These studies focused on many types of cancer including tumors of the head and neck, cervix, rectum, breast, brain, bladder, lung, esophagus, liver, appendix, prostate, peritoneal lining (mesothelioma), soft-tissue sarcoma and melanoma [2,3,105]. Based on results from a randomized study [171], radiation combined with hyperthermia was included in the 2007 Breast Cancer Guidelines for recurrent breast cancer and other localized cancer recurrences by the National Comprehensive Cancer Network (NCCN, U.S.A.).
Despite positive phase III trials, the clinical application of hyperthermia remains limited. This could be partly due to inadequate monitoring of tumour temperatures or thermal dose, during heat treatments. The temperature distribution throughout a tumour during clinical treatment is not homogeneous due to variable tissue properties and changes in blood flow [172] To ensure high quality of treatments, precise tumour temperature measurements and rigorous thermal dosimetric data are essential. Most hyperthermia centers obtain a sparse number of temperature measurements within intraluminal or interstitial catheters [173]. Thermal dose parameters are dependent on the number of measurement sites and on characteristics such as blood flow and tumor size [174]. It is eventually hoped that temperature measurements during hyperthermia treatment can be improved by measuring 3D thermal distribution in tumours by magnetic resonance imaging (MRI) techniques.
In general, hyperthermia treatments are well tolerated by patients. Hyperthermia can cause some toxicity, including skin burns, but this is usually of limited clinical relevance [166]. Normal tissue damage and toxicity do not generally occur during 1 hour of treatment with temperatures that are below 44°C [175]. Nervous and gastrointestinal tissues appear to be most sensitive.
3. Conclusion
Throughout the past two decades, hyperthermia has been used as a particularly efficient complement to standard cancer treatments such as radiation therapy and chemotherapy. Furthermore, considerable progress has been made in our understanding of the biology, physics and bioengineering involved in hyperthermia. Significant improvement in clinical outcome has been demonstrated for many different types of tumours, including head and neck, breast, brain, bladder, cervix, rectum, lung, esophagus, liver, prostate, melanoma and sarcoma [150]. In Europe, hyperthermia is a standard for the treatment of cervical cancer and some sarcomas. It is a successful alternative for the treatment of other types of cancer such as brain, bladder, rectal and esophageal cancer. Moreover, transurethral microwave thermotherapy (TUMT) has been found to be safe and effective as an alternative to surgery and drug treatment for chronic urogenital pathologies such as benign prostatic hyperplasia [176]. TUMT is a minimally invasive therapy that aims to maintain a good quality of life.
In spite of good clinical results, hyperthermia has received little attention [150]. Several problems associated with the acceptance of this promising treatment modality concern the limited availability of equipment for heating tumours, the lack of awareness concerning clinical results, and the lack of financial resources. Hyperthermia is currently under study in many clinical trials, particularly in Europe, Japan and the US, to improve and better understand this promising technique. Future areas of challenge and opportunity for hyperthermia include: improved understanding of thermal biology; improved technologies for delivery and monitoring of heat treatments in patients; successful high-quality clinical trials; and combination of hyperthermia with emerging cancer therapies [170].
Acknowledgments
Financial support is gratefully acknowledged from the Natural Sciences and Engineering Research Council of Canada (NSERC) (DAB).
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Averill-Bates",authors:[{id:"61148",title:"Prof.",name:"Diana",middleName:null,surname:"Averill-Bates",fullName:"Diana Averill-Bates",slug:"diana-averill-bates",email:"averill.diana@uqam.ca",position:null,institution:null},{id:"62367",title:"Dr.",name:"Ahmed",middleName:null,surname:"Bettaieb",fullName:"Ahmed Bettaieb",slug:"ahmed-bettaieb",email:"abettaieb@ucdavis.edu",position:null,institution:null},{id:"62368",title:"Dr.",name:"Paulina",middleName:null,surname:"K. Wrzal",fullName:"Paulina K. Wrzal",slug:"paulina-k.-wrzal",email:"paulina.wrzal@mail.mcgill.ca",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Hyperthermia",level:"1"},{id:"sec_2_2",title:"2.1. Scientific history",level:"2"},{id:"sec_3_2",title:"2.2. Cellular changes",level:"2"},{id:"sec_4_2",title:"2.3. Cytotoxicity of hyperthermia",level:"2"},{id:"sec_5_2",title:"2.4. Hyperthermia and physiological changes",level:"2"},{id:"sec_6_2",title:"2.5. Thermotolerance: The other side of hyperthermia",level:"2"},{id:"sec_7_2",title:"2.6. Hyperthermia in cancer therapy",level:"2"},{id:"sec_7_3",title:"2.6.1. Hyperthermia in combination with radiotherapy ",level:"3"},{id:"sec_8_3",title:"2.6.2. Hyperthermia in combination with chemotherapy ",level:"3"},{id:"sec_8_4",title:"2.6.2.1. Resistance to chemotherapeutic agents ",level:"4"},{id:"sec_9_4",title:"2.6.2.2. Hyperthermia and reversal of resistance to chemotherapeutic agents ",level:"4"},{id:"sec_10_4",title:"2.6.2.3. Sensitivity of multidrug resistant cells to hyperthermia",level:"4"},{id:"sec_13_2",title:"2.7. Hyperthermia in the cancer clinic",level:"2"},{id:"sec_13_3",title:"2.7.1. Techniques to increase tumour temperatures",level:"3"},{id:"sec_13_4",title:"2.7.1.1. Local hyperthermia",level:"4"},{id:"sec_14_4",title:"2.7.1.2. Perfusion hyperthermia",level:"4"},{id:"sec_15_4",title:"2.7.1.3. Whole body hyperthermia ",level:"4"},{id:"sec_17_3",title:"2.7.2. Progress in the cancer clinic",level:"3"},{id:"sec_20",title:"3. Conclusion",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"2"}],chapterReferences:[{id:"B1",body:'Eheman C. et al. Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer, 2012. 118(9): 2338-66.'},{id:"B2",body:'van der Zee J. Heating the patient: a promising approach? Ann Oncol, 2002. 13(8): p. 1173-84.'},{id:"B3",body:'Van der Zee J and MC Erasmus. Hyperthermia in addition to radiotherapy. Clin Oncol (R Coll Radiol), 2007. 19(3 Suppl): S18.'},{id:"B4",body:'Ahmed M and SN Goldberg. Basic science research in thermal ablation. Surg Oncol Clin N Am, 2011. 20(2): 237-58.'},{id:"B5",body:'Horsman MR and J Overgaard. Hyperthermia: a potent enhancer of radiotherapy. Clin Oncol (R Coll Radiol), 2007. 19(6): 418-26.'},{id:"B6",body:'Bryan CP. 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Department of Nutrition, University of California, Davis, California, USA
'},{corresp:null,contributorFullName:"Paulina K. Wrzal",address:null,affiliation:'
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
'},{corresp:null,contributorFullName:"Diana A. Averill-Bates",address:null,affiliation:'
Département des sciences biologiques, Université du Québec à Montréal, Succursale Centre-Ville, Montréal, Québec, Canada
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1. Introduction
Parasites since antiquity [1] are a serious threat for millions of humans and animals worldwide which bring about chronic debilitating, periodically disabling disease and are responsible for the overwhelming financial loss [2, 3, 4, 5, 6]. Mosquitoes (Diptera: Culicidae) [7, 8] are among them as they can act as vectors for serious parasites and pathogens, including malaria, filariasis, and important arboviruses, such as dengue, yellow fever, chikungunya, West Nile virus, and Zika viruses [9, 10]. Mosquito control and personal protection from mosquito bites are the most meaningful measures for controlling several life-threatening diseases transmitted exclusively by bites from bloodsucking mosquitoes. Repellents evolved, dates back to antiquity; the Pharaoh Sneferu, reigned from around 2613–2589 BCE and the founder of the fourth dynasty of Egypt, and Cleopatra VII, the last pharaoh of ancient Egypt, used bed nets as protection against mosquitoes; the ancient Egyptians used essential oils (EOs) for repelling insects, medicinal benefits, beauty care, and spiritual enhancement and in literally all aspects of their daily life [1]. Insect-repellent plants have been applied traditionally for thousands of years through different civilizations [11]. Such plants were used in various forms such as hanged bruised plants in houses, crude fumigants where plants were burnt to drive away mosquitoes, and oil formulations applied to the skin or clothes [12]. Smoke is undoubtedly the most extensively exploited means of repelling mosquitoes, typically by burning plants in rural tropics and by utilizing spiral-shaped incenses like Katori Senk—an archetypal icon of the humid Japanese summers [13].
Mosquitoes have been considered as a major obstacle to the tourism industry and socioeconomic development of developing countries particularly in the tropical and endemic regions [14]. Mosquito problems are ancient as old as the pyramids, and the presence of malaria in Egypt from circa 800 BCE onward has been confirmed using DNA-based methods, and antigens produced by Plasmodium falciparum leading to tertian fever in mummies from all periods were detected, and all mummies were suffering from malaria at the time of their death [1]. Herodotus noted down that the builders of the Egyptian pyramids (circa 2700–1700 BCE) were given large amounts of garlic almost certainly to protect them against malaria [1]. Despite recent considerable efforts to control vector-borne diseases, malaria alone produces 250 million cases per year and 800,000 deaths including 85% of children under 5 years [15]. Global warming has moved the mosquitoes on the way to some temperate and higher altitudes, affecting people who are vulnerable to such diseases [16]. Recently, malaria is a great problem in Africa, but it was well controlled in Egypt [1]. Ahead of the development and commercial success of synthetic insecticides in the mid-1930–1950s, botanical insecticides were the leading weapons for insect control. Synthetic insecticides are distinguished by their efficacy, speed of action, ease of use, and low cost. Therefore, they drove many natural control methods as botanicals, predators, and parasitoids to shadows [8, 17, 18]. Insecticidal treatment of house walls, in particular, could provide a very helpful reduction of mosquito incidence, but such measures need financial and organizational demand, but poor rural areas in endemic regions do not have sufficient resources for such costly protective measures. Because of health and environmental concerns [8, 17], there is an urgent need to identify new nonhazardous vector management strategies that replace harmful chemical insecticides and repellents. There are no vaccines or other specific treatments for arboviruses transmitted by mosquitoes; therefore, avoidance of mosquito bites remains the first line of defense [9, 18]. Hence, the use of the mosquito repellents (MRs) on exposed skin area is highly recommended.
Insect repellents usually work by providing a vapor barrier deterring mosquitoes from meeting the skin surface. Insect repellents had been used for thousands of years against biting arthropods. Several species of primates were observed anointing their pelage via rubbing millipedes and plants as Citrus spp., Piper marginatum, and Clematis dioica. Wedge-capped capuchins (Cebus olivaceus) were observed rubbing the millipede Orthoporus dorsovittatus onto their coat during the period of maximum mosquito activity [19]. Such millipede contains benzoquinones and insect-repellent chemicals, and it was hypothesized that the anointing behavior was intended to deter biting insects. Laboratory studies revealed a significant repellent effect of benzoquinones against Aedes (Stegomyia) aegypti (the yellow fever mosquito) and Amblyomma americanum (the lone star tick). Such anointing behavior to deter blood-feeding arthropods is also common among birds, and it could be genetically expressed as an “extended phenotype” as it has an obvious adaptive advantage. Evidence for this lies in the fact that benzoquinones applied to filter paper elicited anointing activity among captive-born capuchins [12]. The World Health Organization (WHO) also recommends repellents for protection against malaria as the resistance of Plasmodium falciparum to anti-malarial drugs such as chloroquine is increased. Most of the commercial MRs are prepared using non-biodegradable, synthetic chemicals like N,N-diethyl-3-methylbenzamide (DEET), dimethylphthalate (DMP), and allethrin which may lead to the environment and, hence, the unacceptable health risks in the case of their higher exposure. With an increasing concern for public safety, a renewed interest in the use of natural products of plant origin is desired because natural products are effective, environmentally friendly, biodegradable, inexpensive, and readily available [7, 8, 13, 17, 20]. Repellent application is a reliable mean of personal protection against annoyance and pathogenic infections not only for local people but also for travelers in disease risk areas, particularly in tropical countries; therefore, this chapter focused on assets and liabilities, safety, and future perspective of synthetic and natural MRs that could potentially prevent mosquito-host interactions, thereby playing an important role in reducing mosquito-borne diseases when used correctly and consistently.
2. Synthetic repellents
The history of synthetic repellents had been reviewed [12]; before World War II, MRs were primarily plant-based with the oil of citronella being the most widely used compound and the standard against which others were evaluated. At that time, the emergence of synthetic chemical repellents starts. There were only three principal repellents: dimethylphthalate discovered in 1929, Indalone® (butyl-3,3-dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylate) patented in 1937, and Rutgers 612 (ethyl hexanediol), which became available in 1939. Later on and for military use, 6-2-2 of M-250 (a mixture of six parts DMP and two parts each Indalone® and Rutgers 612) was used [13]. The event of World War II was the primary switch on in the development of new repellent technologies because the Pacific and North African theaters posed significant disease threats to allied military personnel. Over 6000 chemicals had been tested from 1942 to 1947 in a variety of research institutions led to the identification of multiple successful repellent chemistries. Such great aim established several independent research projects that inevitably identified one of the most effective and widely used insect repellents to date, DEET. From then on, several compounds have been synthesized relying on previous research, which identified amide and imide compounds as highly successful contact repellents. Among these are picaridin, a piperidine carboxylate ester, and IR3535, which are currently considered DEET competitors in some repellency bioassays [21]. The chemical structures of some synthetic repellents are shown in Figure 1.
Figure 1.
Chemical structures of some synthetic repellents.
2.1 DEET
DEET (N,N-diethyl-3-methylbenzamide) is the standard and most effective broad-spectrum insect-repellent component with a long-lasting effect on mosquitoes, ticks, as well as biting flies, chiggers, and fleas. DEET was discovered as a mosquito repellent by the US Department of Agriculture and patented by the US Army in 1946. It was allowed for public use in 1957, and since then it has been a standard repellent for several insects and arthropods [14]. DEET is the most studied insect repellent and mainly used as a positive control to compare the efficacy of many repellent substances. DEET has a dose-dependent response: the higher the concentration, the longer the protection. DEET, 20–25%, is the conventional concentration used in commercial products. The shorter protection time depended on the mixture as well [14]. In fact, DEET plays a limited role on disease control in endemic regions because of its high cost, unpleasant odor, and inconvenience of the continuous application on the exposed skin at high concentrations [22, 23].
2.2 Permethrin
Permethrin is a pyrethroid insecticide derived from the plant Chrysanthemum cinerariifolium. It was registered in the US in 1979 as both repellent and insecticide. Recently, it is the most common insecticide available for use on fabrics such as clothing, bed nets, etc. for its exclusive role as a contact insecticide via neural toxicity and equally as an insect repellent [7, 8, 13, 17]. The protection offered against a broad range of bloodsucking arthropods with negligible safety concerns ranked permethrin-treated clothing an important arthropod protection technique especially when used in combination with other protection strategies as applying topical repellents [13].
2.3 Picaridin
Picaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester) is a colorless, nearly odorless piperidine analog that was developed by Bayer in the 1980s through molecular modeling [12]. It is also known as KBR 3023, icaridin, hydroxyethyl isobutyl piperidine carboxylate, and sec-butyl-2-(2-hydroxyethyl)-piperidine-1-carboxylate. Its trade names include Bayrepel and Saltidin, among others. Picaridin was first marketed in Europe in the 1990s and later in the US in 2005 [24, 25]. The efficacy of picaridin is as good as DEET, and notably, 20% picaridin spray was found to protect against three main mosquito vectors, Aedes, Anopheles, and Culex for about 5 h with better efficacy than that of DEET. Therefore, repeated application is required every after 4–6 h [13]. In Australia, a formulation containing 19.2% picaridin provided similar protection as 20% DEET against Verrallina lineata [26]. The same formulation provided >95% protection against Culex annulirostris for 5 h but only 1-hour protection against Anopheles spp. [26]. Picaridin at concentrations of 2–13% v/v in 90% ethanol showed better protection against anophelines in Africa than comparable formulations containing DEET [27]. Field studies against mosquitoes in two locations in Australia indicated that a 9.3% formulation only provided 2-hour protection against V. lineata [26, 28]. It had been concluded that studies showed little significant difference between DEET and picaridin when applied at the same dosage, with a superior persistence for picaridin [29]. To maintain effectiveness than with the higher concentrations (>20%) of picaridin used in the field.
2.4 DEPA
N,N-diethyl-2-phenyl-acetamide (DEPA) is a repellent developed around the same time as DEET and repels a wide range of insects, but DEPA did not get its reputation. The repellency of DEPA has demonstrated almost similar to DEET against mosquito vectors as Ae. aegypti, Ae. albopictus, An. stephensi, and C. quinquefasciatus [13]. It has regained interest recently and could prove to be an important competitor to DEET especially in developing countries due to its low cost, $25.40 per kg compared to $48.40 per kg for DEET [30].
2.5 Insect repellent 3535
Learning from nature offered a molecule with an impressive performance in comparison to a natural and pure synthetic repellent solution called insect repellent 3535 (IR3535). Scientists got inspirations from nature for the development of the topical IR 3535 with the intention to create a molecule with optimized protection times and low toxicity. The naturally occurring amino acid β-alanine was used as a basic module, and the selected end groups were chosen to avoid toxicity and increase efficacy. IR 3535 was developed by Merck in 1970 and thus named as Merck IR3535; it has been available in Europe, but it was not available in the USA until 1999 [12]. IR3535 is used for humans and animals, as it is effective against mosquitoes, ticks, flies, fleas, and lice. Its chemical formula is C11H21NO3, and its other names are ethyl-N-acetyl-N-butyl-β-alaninate, ethyl butylacetylaminopropionate (EBAAP), β-alanine, and N-acetyl-N-butyl-ethyl ester. The protection of IR 3535 may be comparable to DEET, but it requires frequent reapplication in every 6–8 h. IR3535 is found in products including Skin So Soft Bug Guard Plus Expedition (Avon, New York, NY) [31]. Although 20% IR 3535 provides complete protection against Aedes and Culex mosquitoes (up to 7–10 h), it offers lesser protection against Anopheles (about 3.8 h), which affects its application in malaria-endemic areas [13].Several field studies were identified and indicated that IR 3535 is as effective as similarly, DEET in repelling mosquitoes of the Aedes and Culex genera but may be less effective than DEET in repelling anopheline mosquitoes; an uncontrolled field study of a controlled release formulation of IR 3535 reported that these formulations may provide complete protection against mosquito biting for 7.1–10.3 h [32].
2.6 Ethyl anthranilate
Ethyl anthranilate (EA) is a new member in the scope of entomology which drew a significant attention in repellent research in the recent years and is being considered as an improved alternative to DEET [13, 33]. It is a nontoxic, the US FDA approved volatile food additive. EA is novel and repellent against Ae. aegypti, An. stephensi, and Cx. quinquefasciatus as its ED50 values of EA were 0.96, 5.4, and 3.6% w/v, respectively, and CPTs of EA, 10% w/v, throughout the arm-in-cage method were 60, 60, and 30 min, respectively. Moreover, its spatial repellency was found to be extremely effective in repelling all the three tested species of mosquitoes. EA provided comparable results to standard repellent DEPA. As a result, the repellent activity of EA is promising for developing effective, safe, and eco-friendly alternative to the existing harmful repellents for personal protection against different mosquito species [34].
2.7 Comparative efficacy of synthetic repellents
The comparative efficacy of synthetic repellents had been summarized [14] as follows: Aedes species demonstrated an aggressive biting behavior and Ae. Aegypti, above all, proved to be tolerant to many repellent products. Ae. albopictus was easier to be repelled than Ae. aegypti. DEET is the most studied insect repellent; at higher concentrations, it presented superior efficacy against Aedes species, providing up to 10 h of protection. Although IR3535 and picaridin showed good repellency against this mosquito genus, their efficacy was on average inferior to that provided by DEET. Fewer studies have been conducted on the mosquito species Anopheles and Culex. The repellency profile against Anopheles species was similar for the four principal repellents of interest: DEET provided on average 5–11 h, IR 3535 4–10 h, picaridin 6–8 h, and Citriodora 1–12 h of protection, depending on study conditions and repellent concentration. Culex mosquitoes are easier to repel, and each repellent provided good protection against this species. DEET showed 5–14 h of protection and IR 3535 2–15 h, depending on product concentration, while the test proving the efficacy of picaridin and commercial products containing PMD was discontinued after 8 h of protection. To go over the main points, DEET remains probably the most efficient insect repellent against mosquitoes, effective against sensitive species as Culex as well as more repellent-tolerant species such as Aedes and Anopheles. Even though fewer studies have been conducted on these non-DEET compounds, picaridin and to some extent IR 3535 represent valid alternatives. Consequently, the choice of repellents could be adjusted somehow according to the profile of biting vectors at the travelers’ destination.
3. Botanicals
Nature is an old unlimited source of inspiration for people [1, 11, 18, 35] as well as for scientific and technological innovations. Recently, global attention has been paid toward exploring the medicinal benefits of plant extracts [4, 11, 36, 37]. Repellents of natural origin are derived from members of the families as Asteraceae, Cupressaceae, Labiatae, Lamiaceae, Lauraceae, Meliaceae, Myrtaceae, Piperaceae, Poaceae, Rutaceae, Umbelliferae, and Zingiberaceae. They have been evaluated for repellency against various mosquito vectors, but few compounds have been found commercially. Increased curiosity in plant-based arthropod repellents was generated after the United States Environmental Protection Agency (US EPA) added a rule to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) in 1986 exempting compounds considered to be minimum hazardous pesticides [30]. Increased interest has also been driven by the rapid registration process of plant-based repellents by US EPA, which are often registered in less than a year, while the conventional pesticides are registered in an average of 3 years [30]. The public considers botanicals as safer and suitable alternative repellents; most of them are produced and distributed locally and appear on the market for only a short time. Even though many studies have shown that almost all registered commercial products based on botanical active ingredients offer limited protection and require frequent reapplication than even a low concentration of DEET-based repellents, the growing demand for natural alternative repellents in the community illustrates further need to evaluate new botanical repellents critically for personal protection against mosquitoes and mosquito-borne illnesses [7, 8, 13, 17]. The repellent activity of EOs includes some metabolites, such as the monoterpenes α-pinene, cineole, eugenol, limonene, terpinolene, citronellol, citronellal, camphor, and thymol that are repellents against mosquitoes; the sesquiterpene, β-caryophyllene, is repellent against A. aegypti, and phytol, a linear diterpene alcohol, is repellent against Anopheles gambia. Most of the arthropod-repellent compounds are oxygenated, having the hydroxyl group linked to a primary, secondary, or aromatic carbon. In some metabolites having a hydroxyl group linked to a tertiary carbon, as linalool, α-terpineol, and limonene, the repellent activity is suppressed against A. gambiae, suggesting the likelihood that the type of carbon where the hydroxyl substitution is there modulates repellency. Most insect repellents are volatile terpenoids such as terpinen-4-ol. Other terpenoids can act as attractants. More information is widely discussed [7, 38], and chemical structures of some natural repellent compounds are shown in Figure 2.
Figure 2.
Chemical structures of some natural repellent compounds found in botanical species.
3.1 PMD and lemon-scented eucalyptus
Compound p-menthane-3,8-diol (PMD is derived from lemon-scented eucalyptus (Eucalyptus citriodora, Myrtaceae) leaves, and its importance as a repelling agent is increasing due to its good efficacy profile as well as its natural basis. PMD is a potent and commercially available repellent discovered in the 1960s via mass screening of plants for repellent activity, for instance, lemon eucalyptus and Corymbia citriodora (Myrtaceae) formerly known as Eucalyptus maculata citriodora. Lemon eucalyptus EO contains 85% citronellal and is already used in cosmetic industries due to its fresh smell. It was discovered when the waste distillate remaining after hydro-distillation of the EO was far more effective at repelling mosquitoes than the EO itself, and it provides very high protection from a broad range of insect vectors for several hours as well [7, 39]. The EO from C. citriodora also contains active constituents like citronella, citronellol, geraniol, isopulegol, and δ-pinene which play important roles in repelling both mosquitoes and ticks. Such compounds provide short-term repellency against mosquitoes, but PMD has a longer protection time than other plant-derived compounds because it is a monoterpene with low volatility than volatile monoterpenes found in most EOs and does not tend to evaporate rapidly after skin application [7, 8, 14].
There have been attempts to commercialize and market the insecticides/repellent products containing eucalyptus oil as such or based upon them. Crude eucalyptus oil was primarily registered as an insecticide and miticide in the USA in 1948, and 29 of such compounds have been registered in the USA until the year 2007 for use as natural insecticide/insect repellent/germicide. Only four products of them have been active, whereas 25 have been canceled. These include Citriodiol, Repel essential insect repellent lotion (two variants), Repel essential insect repellent pump spray, and Repel insect repellent 30 by the United Industrial Corp., USA. Some eucalyptus-based products include the following: Quwenling is successfully marketed as an insect repellent in China and provides protection against anopheles mosquitoes parallel to DEET and has exchanged the widely used synthetic repellent dimethylphthalate; Quwenling contains a mixture of PMD, citronellol, and isopulegone. Mosiguard Natural contains 50% eucalyptus oil, Buzz Away is a commercially available product in China based on citronellal, and MyggA1 Natural is based on PMD from lemon eucalyptus and is shown to repel ticks. More details are widely discussed [40].
3.2 Citronella
The name “Citronella” is derived from the French word “citronelle” around 1858. It was extracted to be used in perfumery and used by the Indian Army to repel mosquitoes at the beginning of the twentieth century and was then registered for commercial use in the USA in 1948. Today, citronella (5–10%) is one of the most widely used natural repellents on the market; such concentrations are lower than most other commercial repellents, whereas higher concentrations can cause skin sensitivity. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. EOs and extracts belonging to plants in the Citronella genus (Poaceae) are commonly used as ingredients of plant-based mosquito repellents, mostly Cymbopogon nardus that is sold in Europe and North America in commercial preparations [39]. Citronella contains citronellal, citronellol, geraniol, citral, α-pinene, and limonene giving an effect similar to that of DEET, but the oils rapidly evaporate causing loss of efficacy and leaving the user unprotected. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. For travelers heading to disease-endemic areas, citronella-based repellents should not be recommended, but if efficacious alternatives are prohibitively expensive or not available, the use of citronella to prevent mosquito bites may provide important protection from disease vectors. Even though citronella-based repellents only give protection from host-seeking mosquitoes for a short time (2 h), formulations could prolong such time (please see the formulation section).
3.3 Neem and methyl jasmonate
The aromatic plants of the Meliaceae family which include neem, Azadirachta indica, Carapa procera, Melia azedarach, Khaya senegalensis, and Trichilia emetica contain substances of the limonoid group and insecticidal and repellent effects on insects [18]. Neem provided a protection of 98.2% for 8 h against An. darlingi. Regardless of being not approved by US EPA for use as a topical insect repellent, neem is widely advertised as a natural alternative to DEET, and it has been tested for repellency against a wide range of arthropods of medical and veterinary importance. MiteStop®, based on a neem seed extract, had a considerable repellent effect on bloodsucking mosquitoes, tabanids, ceratopogonids, simuliids, as well as licking flies [41]. Several field studies from India have shown the very high efficacy of neem-based preparations, contrasting with findings of intermediate repellency by other researchers. However, these contrasting results may be due to differing methodologies and the solvents used to carry the repellents.
Methyl jasmonate (MJ) is derived from the nonvolatile jasmonic acid and has the ultimate vapor pressure for a repellent (0.001 mmHg at 25°C) which is quite higher than DEET. It repels only Cx. quinquefasciatus but does not repel Ae. aegypti, An. gambiae, Phlebotomus flies, and Glossina morsitans, which restricts the application of MJ to C. quinquefasciatus mosquitoes only. On the other hand, MJ has been found to cause aversion in a number of ticks such as nymphal I. ricinis and Hyalomma marginatum rufipes Koch, etc. [30].
3.4 Essential oils
EOs are used against insects [20, 42, 43, 44, 45, 46, 47, 48, 49, 50] throughout the globe. EOs are distilled from members of the Lamiaceae (mint family), Poaceae (aromatic grasses), and Pinaceae (pine and cedar family). EOs could be used for farm animal protection against nuisance flies and lice [47]. Almost all of the botanical repellents are also used for food flavoring or in the perfume industry, indicating that they are safer than DEET. The most effective oils include thyme, geraniol, peppermint, cedar, patchouli, and clove that have been found to repel malaria, filarial, and yellow fever vectors for a period of 60–180 mins. Most of these EOs are highly volatile, and this contributes to their poor longevity as mosquito repellents. As a result, repellents containing only EOs in the absence of an active ingredient such as DEET should not be recommended as repellents for use in disease-endemic areas, whereas those containing high levels of EOs could cause skin irritation, especially in the presence of sunlight [39]. Although EOs effectively repel mosquitoes as irritants, repellents, antifeedants, or maskants, unfortunately, relatively few have been commercialized, despite being widely used in candles and as topical insect repellents. Botanical, herbal, or natural-based repellents include one or several plant EOs. These oils are considered safe by the EPA at low concentrations but provide a limited duration of protection against mosquitoes (<3 h). Citronella (discussed previously) is the principal and sometimes only active ingredient in many plant-based insect repellents [7]. Eucalyptus oil is used as an antifeedant mainly against biting insects as eucalyptus-based products used on humans as insect repellent can give protection from biting insects up to 8 h depending upon the concentration of the essential oil. Such repellent activity could be extended up to 8 days when eucalyptus EOs are applied on the clothes. Eucalyptus oil (30%) can prevent mosquito bite for 2 h; however, the oil must have at least 70% cineole content [40]. On the other hand, E. citriodora EO alone showed an insufficient protection against the three main mosquito species [14].
4. Safety of repellents
4.1 Safety of synthetic repellents
Insect repellents containing DEET are broadly used among populations. DEET should be used with caution as it may damage spandex, rayon, acetate, and pigmented leather and it could dissolve plastic and vinyl (e.g., eyeglass frames). Moreover, DEET damages synthetic fabrics and painted and varnished surfaces, precluding its use in bed nets and in many urban settings [51]. Being the gold standard of repellents, the safety profile of DEET is largely studied. There is an estimated 15 million people in the UK, 78 million people in the USA, and 200 million people globally that use DEET each year safely when it is applied to the skin at the correct dose indicated at the commercial preparation (in the case of it not being swallowed or rubbed into the mucous membranes). DEET has been used since 1946 with a tiny number of reported adverse effects, many of which had a history of excessive or inappropriate use of repellent. Its toxicology has been more closely scrutinized than any other repellent, and it has been deemed safe for human use, including its use on children, pregnant women, and lactating women [39]. Even though insect repellents containing DEET are safe, some side effects have been described, mainly after inappropriate use such as dermatitis, allergic reactions, neurologic and cardiovascular side effects, as well as encephalopathy in children. In addition, there are a small number of reports of systemic toxicity in adults following dermal application. The safety profile in the second and third trimester of pregnancy has been well known through inspection of very low placental cord concentrations after maternal application of DEET, but animal models do not indicate any teratogenic effects. DEET also blocks mammalian sodium and potassium ion channels contributing to the numbness of lip following the application of DEET [13]. Approval for use in young children is a controversial issue between countries, with some recommending lower concentrations, whereas others suggesting that higher strengths can be used. However, the causation between the few reported cases of encephalopathy in children and the topical use of DEET cannot be supported by a good evidence base [14, 39].
When permethrin is impregnated appropriately in cloths and nets, toxicity fearfulness is minimal [52]. Although synthetic pyrethroids are utilized worldwide as active ingredients in MRs [15] due to their relatively low toxicity to mammals [53], inappropriate application at high doses initiates neurotoxic effects such as tremors, loss of coordination, hyperactivity, paralysis, and an increase in body temperature. Other side effects include skin and eye irritation, reproductive effects, mutagenicity, alterations in the immune system, etc. [13]. Recent studies also showed that some pyrethroids are listed as endocrine disruptors and possible carcinogens [53] and pyrethroids might cause behavioral and developmental neurotoxicity, with special concern revolving around infants and children, due to their potential exposure during a sensitive neurodevelopmental stage [54]. More evidence in the recent years indicates that pyrethroid insecticides can reduce sperm count and motility, cause deformity of the sperm head, increase the count of abnormal sperm, damage sperm DNA, induce its aneuploidy rate, affect sex hormone levels, and produce reproductive toxicity [55]. Moreover, an elevated concentration of transfluthrin in the gaseous phase during the indoor application of an electric vaporizer was detected, but they found inhalation risk of airborne transfluthrin was low. The exposure levels and potential risk of pyrethroids during the applications of other types of commonly used MRs remain unknown [53]. On the other hand, long-term exposure to pyrethroid-based MRs in indoor environments causes chronic neurotoxicity, for example, dysfunction of blood-brain barrier permeability, oxidative damage to the brain, [56] and cholinergic dysfunction which cause learning and memory deficiencies [57]. Even though ventilation through natural air exchange and conditioner dissipate of airborne pollutants, residues persisting in the air and/or on indoor surfaces could potentially cause continuous exposure to the residents.
US EPA-OPP’s Biochemical Classification Committee classified IR 3535 as a biochemical in 1997, because it is functionally identical to naturally occurring beta-alanine in that both repel insects, the basic molecular structure is identical, the end groups are not likely to contribute to toxicity, and it acts to control the target pest via a nontoxic mode of action [58]. No reported toxicity has been made so far against IR 3535, and it induces less irritation to mucous membranes and exhibits safer oral and dermal toxicity than DEET which makes it an attractive alternative to DEET in disease-inflicted endemic regions [13]. The ester structure of the propionate grants essential advantages because of a short metabolic degradation and quick excretion as a simple water-soluble acid [58]. Picaridin has the advantage of being odorless and non-sticky or greasy. Moreover, unlike DEET, picaridin does not damage plastics and synthetics. In some studies, picaridin induces no adverse toxic reactions in animal studies but exhibits low toxicity and less dermatologic and olfactory irritant in other studies. Consequently, picaridin’s comparable efficacy to DEET and its suitability of application and favorable toxicity profile ranked it as an attractive option and unquestionably an acceptable alternative for protection against mosquitoes and other hematophagous arthropods to control the menace of vector-borne diseases in endemic areas [13]. DEPA does not show cytotoxicity or mutagenicity [59], thereby increasing its suitability in direct skin application. It also exhibits moderate oral toxicity (mouse oral LD50 900 mg/kg) and low to moderate dermal toxicity (rabbit and female mouse LD50 of 3500 and 2200 mg/kg, respectively) [60]. Acute and subacute inhalation toxicity studies of DEPA have also been reported [61] which indicate its applicability as aerosol formulations. Indalone was an early synthetic repellent effective against both mosquitoes and ticks. It was even more effective than DEET; however, its chronic exposure induced kidney and liver damage in rodents which restricted its application [13]. EA is approved by the US FDA, WHO and European Food Safety Authority (EFSA) [62, 63]. Furthermore, EA has been listed in the “generally recognized as safe” [64] list by the Flavour and Extract Manufacturers Association (FEMA) [65]. EA does not damage synthetic fabrics, plastics, and painted and varnished surfaces which further widen the utility of EA in bed nets, cloths, and different surfaces in the endemic settings [14, 66].
4.2 Safety of plant-based repellents
Because many conventional pesticide products fall into disfavor with the public, botanical-based pesticides should become an increasingly popular choice as repellents. There is a perception that natural products are safer for skin application and for the environment, just because they are natural and used for a long time compared to synthetic non-biodegradable products [14]. In contrast to DEET, some natural repellents are safer than others, and plant-based repellents do not have this strictly tested safety evidence, and many botanical repellents have compounds that need to be used with caution [39]. PMD has no or very little toxicity to the environment and poses no risks to humans and animals. PMD has been developed and registered for use against public health pests and is available as a spray and lotion. Not much is known about the toxicity of eucalyptus oils; however, they have been categorized as GRAS by the US EPA. Further, the oral and acute LD50 of eucalyptus oil and cineole to rat is 4440 mg/kg body weight (BW) and 2480 mg/kg BW, respectively, making it much less toxic than pyrethrins (LD50 values 350–500 mg/kg BW; US EPA, 1993) and even technical grade pyrethrum (LD50 value 1500 mg/kg BW) [40]. PMD is an important component of commercial repellents in the US and registered by US EPA and Canadian Pest Management Regulatory Agency in 2000 and 2002, respectively [13]. In contrary, lemon eucalyptus EO does not have US EPA registration for use as an insect repellent. PMD is the only plant-based repellent that has been advocated for use in disease-endemic areas by the Centers for Disease Control (CDC), due to its proven clinical efficacy to prevent malaria, and is considered to pose no risk to human health [39]. In 2005, the US Centers for Disease Control and Prevention made use of its influence by endorsing products containing “oil of lemon eucalyptus” (PMD), along with picaridin and DEET as the most effective repellents of mosquito vectors carrying the West Nile virus [67]. PMD provides excellent safety profile with minimal toxicity. In studies using laboratory animals, PMD demonstrated no adverse effects apart from eye irritation. It is safe for both children and adults as the toxicity of PMD is very low. However, the label indicates it should not be used on children under the age of 3 [7].
The safety of neem is extensively reviewed; azadirachtin is nontoxic to mammals and did not show chronic toxicity. Even at high concentrations, neem products were neither mutagenic nor carcinogenic, and they did not produce any skin irritations or organic alterations in mice and rats. On the other hand, reversible reproduction disturbances could occur due to the daily feeding of aqueous leaf extract for 6 and 9 weeks led to infertility of rats at 66.7 and 100%, respectively. Using unprocessed and aqueous neem-based products should be encouraged if applied with care. The pure compound azadirachtin, the unprocessed materials, the aqueous extracts, and the seed oil are safe to use even as insecticides to protect stored food for human consumption, whereas nonaqueous extracts turn out to be relatively toxic [8]. From the ecological and environmental standpoint, azadirachtin is safe and nontoxic to fish, natural enemies, pollinators, birds, and other wildlife. Azadirachtin is classified by the US EPA as class IV (practically nontoxic) [7, 8, 17] as azadirachtin breaks down within 50–100 h in water and is degraded by sunlight as the half-life of azadirachtin is only 1 day, leaving no residues. Safety and advantages of EOs are widely discussed [7, 8, 17, 39]. There is a popular belief that EOs are benign and harmless to the user. Honestly, increasing the concentration of plant EOs as repellents could increase efficacy, but high concentrations may also cause contact dermatitis. Some of the purified terpenoid ingredients of EOs are moderately toxic to mammals. Because of their volatility, EOs have limited persistence under field conditions. With few exceptions, the oils themselves or products based on them are mostly nontoxic to mammals, birds, and fish. Many of the commercial products that include EOs (EOs) are on the “generally recognized as safe” [64] list fully approved by the US FDA and EPA for food and beverage consumption. Moreover, EOs are usually devoid of long-term genotoxic risks, and some of them show a very clear antimutagenic capacity which could be linked to an anticarcinogenic activity. The prooxidant activity of EOs or some of their constituents, like that of some polyphenols, is capable of reducing local tumor volume or tumor cell proliferation by apoptotic and/or necrotic effects. Due to the capacity of EOs to interfere with mitochondrial functions, they may add prooxidant effects and thus become genuine antitumor agents. The cytotoxic capacity of the essential oils, based on a prooxidant activity, can make them outstanding antiseptic and antimicrobial agents for personal uses, that is, for purifying air, personal hygiene, or even internal use via oral consumption and for insecticidal use for the preservation of crops or food stocks. Some EOs acquired through diet are actually beneficial to human health [68, 69]. Eugenol is an eye and skin irritant and has been shown to be mutagenic and tumorigenic. Citronellol and 2-phenylethanol are skin irritants, and 2-phenylethanol is an eye irritant, mutagen, and tumorigenic; they also affect the reproductive and central nervous systems [30]. Hence, it is advised that EOs with toxic profile should be used for treating clothing rather than direct application to individual’s skin [13]. Although EOs are exempt from registration through the US EPA, they can be irritating to the skin, and their repellent effect is variable, dependent on formulation and concentration. The previously mentioned safety and advantages designate that EOs could find their way from the traditional into the modern medical, insecticidal, and repellent domain.
5. Conclusions and challenges for future research
Several diseases transmitted by mosquitoes cause high losses of human and animal lives every year. DEET is considered as a “gold standard” to which other candidate repellents are compared; therefore, DEET is the most ever-present active ingredient used in commercially available repellents, with noteworthy protection against mosquitoes and other biting insects. Unfortunately, the widespread use and effectiveness of commercial formulations containing DEET and other synthetic substances could lead to resistance [70, 71]. Some health and environmental concerns lead to the search for natural alternative repellents. The use of repellent plants has been used since antiquity [1], and it is the only effective protection available for the poor people against vectors and their associated diseases [71]. Ethnobotanical experience is passed on orally from one generation to another, but it needs to be preserved in a written form and utilized as a rich source of botanicals in repellent bioassays. Then again, the growing demand for natural repellents points up the further necessity to evaluate new plant-based products critically for personal protection against mosquitoes and mosquito-borne diseases [7, 8, 17, 18]. Regarding environmental and health concerns, plant-based repellents are better than synthetic molecules. Even though many promising plant repellents are available, their use is still limited; therefore, advance understanding of the chemical ecology of pests and the mode of repellency would be helpful for identifying competitor semiochemicals that could be incorporated into attractant or repellent formulations. There are numerous commercially available formulations enhancing the longevity of repellent, by controlling the rate of delivery and the rate of evaporation. Such formulations are very useful to people living in the endemic areas in the form of sprays, creams, lotions, aerosols, oils, evaporators, patch, canister, protective clothing, insecticide-treated clothing, and insecticide-treated bed nets [7, 8, 17]. The potential uses and benefits of microencapsulation and nanotechnology are enormous including enhancement involving nanocapsules for pest management and nanosensors for pest detection [7, 8]. Nanoparticles are effectively used to control larvae [72, 73, 74, 75, 76] and to repel adults of mosquitoes [77, 78].
Polymer-based formulations allow entrapping active ingredients and provide release control. Encapsulation into polymeric micro/nanocapsules, cyclodextrins, polymeric micelles, or hydrogels constitutes an approach to modify physicochemical properties of encapsulated molecules. Such techniques, applied in topical formulations, fabric modification for personal protection, or food packaging, have been proven to be more effective in increasing repellency time and also in reducing drug dermal absorption, improving safety profiles of these products. In this work, the main synthetic and natural insect repellents are described as well as their polymeric carrier systems and their potential applications [79]. Encapsulated EO nanoemulsion is prepared to create stable droplets to increase the retention of the oil and slow down release. The release rate correlates well to the protection time so that a decrease in release rate can prolong mosquito protection time. Microencapsulation is another way to slowly release the active ingredients of repellents. In laboratory conditions, the microencapsulated formulations of the EOs showed no significant difference with regard to the duration of repellent effect compared to the microencapsulated DEET used at the highest concentration (20%). It exhibited >98% repellent effect for the duration of 4 h, whereas, in the field conditions, these formulations demonstrated the comparable repellent effect (100% for a duration of 3 h) to Citriodiol®-based repellent (Mosiguard®). In both test conditions, the microencapsulated formulations of the EOs presented longer duration of 100% repellent effect (between 1 and 2 h) than non-encapsulated formulations [80]. Microencapsulation reduces membrane permeation of CO while maintaining a constant supply of the citronella oil [81]. Moreover, using gelatin Arabic gum microcapsules also prolonged the effect of natural repellents. In addition, the functionalization of titanium dioxide nanoparticles on the surface of polymeric microcapsules was investigated as a mean to control the release of encapsulated citronella through solar radiation. The results showed that functionalizing the microcapsules with nanoparticles on their surface and then exposing them to ultraviolet radiation effectively increased the output of citronella into the air for repelling the mosquitoes without human intervention, as the sunlight works as a release activator [82].
It is recommended to use US EPA-registered insect repellents including one of the active ingredients: DEET, Picaridin, IR3535, Oil of lemon eucalyptus (OLE), Para-menthane-diol (PMD), and 2-undecanone. Synthetic MRs are applied for years but induced some safety and environmental concerns; as a result, the advancement in the development of repellents from the botanical origin is encouraged. But some obstacles are hindering botanical repellents which as the source availability, standardization, commercialization, and analyses in order to certify the efficacy and safety [7]. Commercially available repellents are provided in Table 1. For saving time and efforts, a high-throughput chemical informatics screen via a structure-activity approach, molecular-based chemical prospecting [83], as well as computer-aided molecular modeling [84] would accelerate the exploration of new environmentally safe and cost-effective novel repellents which activated the same chemosensory pathways as DEET at a fairly shorter time and lower costs [13]. The selection of various repellents could be tailored along with the profile of safety concerns and biting vectors at the travelers’ and military destinations by reducing annoyance and the incidence of illness. The use of these technologies to enhance the performance of natural repellents may revolutionize the repellent market and make EOs a more viable option for use in long-lasting repellents. Green technologies and cash cropping of repellent plants afford a vital source of income for small-scale farmers and producers in developing countries and raise the national economy. Moreover, in some developing countries where tourism is a chief source of national income, the use of repellents would increase the pleasure and comfort of tourists. Finally, much faster work needs to be done to discover new and safe repellents for personal protection from mosquitoes.
Repellent composition
Dose
Study variety
Mosquito spp.
Mean CPT
Protection
Reference
%
Time interval
Bio Skincare®
Natural oil of jojoba, rapeseed, coconut, and vit. E
\n',keywords:"repellent plants, synthetic repellents, treated clothes, nanoparticles, microencapsulation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68538.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68538.xml",downloadPdfUrl:"/chapter/pdf-download/68538",previewPdfUrl:"/chapter/pdf-preview/68538",totalDownloads:911,totalViews:0,totalCrossrefCites:1,dateSubmitted:"October 13th 2017",dateReviewed:"June 5th 2019",datePrePublished:"August 8th 2019",datePublished:"December 11th 2019",dateFinished:null,readingETA:"0",abstract:"Mosquitoes are serious vectors of diseases threading millions of humans and animals worldwide, as malaria, filariasis, and important arboviruses like dengue, yellow fever, chikungunya, West Nile virus, and Zika viruses. The swift spread of arboviruses, parasites, and bacteria in conjunction with the development of resistance in the pathogens, parasites, and vectors represents a great challenge in modern parasitology and tropical medicine. Unfortunately, synthetic insecticides had led to some serious health and risk concerns. There are no vaccines or other specific treatments for arboviruses transmitted by mosquitoes. Accordingly, avoidance of mosquito bites remains the first line of defense. Insect repellents usually work by providing a vapor barrier deterring mosquitoes from coming into contact with the skin surface, and this chapter focused on assets and liabilities, mechanism of action, improving efficacy, safety, and future perspective of synthetic and natural repellents that could potentially prevent mosquito-host interactions, thereby playing an important role in reducing mosquito-borne diseases when used correctly and consistently.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68538",risUrl:"/chapter/ris/68538",signatures:"Hanem Fathy Khater, Abdelfattah M. Selim, Galal A. Abouelella, Nour A. Abouelella, Kadarkarai Murugan, Nelissa P. Vaz and Marimuthu Govindarajan",book:{id:"7839",title:"Malaria",subtitle:null,fullTitle:"Malaria",slug:"malaria",publishedDate:"December 11th 2019",bookSignature:"Fyson H. Kasenga",coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",fullName:"Hanem Fathy Khater",slug:"hanem-fathy-khater",email:"hanemkhater@gmail.com",position:null,institution:{name:"Banha University",institutionURL:null,country:{name:"Egypt"}}},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",fullName:"Marimuthu Govindarajan",slug:"marimuthu-govindarajan",email:"drgovind1979@gmail.com",position:null,institution:null},{id:"192870",title:"Dr.",name:"Nelissa",middleName:null,surname:"P. Vaz",fullName:"Nelissa P. Vaz",slug:"nelissa-p.-vaz",email:"nelissavaz@gmail.com",position:null,institution:{name:"Federal University of Paraná",institutionURL:null,country:{name:"Brazil"}}},{id:"229581",title:"Prof.",name:"Kadarkarai",middleName:null,surname:"Murugan",fullName:"Kadarkarai Murugan",slug:"kadarkarai-murugan",email:"kmvvkg@gmail.com",position:null,institution:null},{id:"310230",title:"Dr.",name:"Abdelfattah M.",middleName:null,surname:"Selim",fullName:"Abdelfattah M. Selim",slug:"abdelfattah-m.-selim",email:"abdelfattah.selim@fvtm.bu.edu.eg",position:null,institution:null},{id:"310231",title:"Dr.",name:"Galal A.",middleName:null,surname:"Abouelella",fullName:"Galal A. Abouelella",slug:"galal-a.-abouelella",email:"galal_ahmed_bue@yahoo.com",position:null,institution:null},{id:"310232",title:"Dr.",name:"Nour A.",middleName:null,surname:"Abouelella",fullName:"Nour A. Abouelella",slug:"nour-a.-abouelella",email:"nour131733@bue.edu.eg",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Synthetic repellents",level:"1"},{id:"sec_2_2",title:"2.1 DEET",level:"2"},{id:"sec_3_2",title:"2.2 Permethrin",level:"2"},{id:"sec_4_2",title:"2.3 Picaridin",level:"2"},{id:"sec_5_2",title:"2.4 DEPA",level:"2"},{id:"sec_6_2",title:"2.5 Insect repellent 3535",level:"2"},{id:"sec_7_2",title:"2.6 Ethyl anthranilate",level:"2"},{id:"sec_8_2",title:"2.7 Comparative efficacy of synthetic repellents",level:"2"},{id:"sec_10",title:"3. Botanicals",level:"1"},{id:"sec_10_2",title:"3.1 PMD and lemon-scented eucalyptus",level:"2"},{id:"sec_11_2",title:"3.2 Citronella",level:"2"},{id:"sec_12_2",title:"3.3 Neem and methyl jasmonate",level:"2"},{id:"sec_13_2",title:"3.4 Essential oils",level:"2"},{id:"sec_15",title:"4. Safety of repellents",level:"1"},{id:"sec_15_2",title:"4.1 Safety of synthetic repellents",level:"2"},{id:"sec_16_2",title:"4.2 Safety of plant-based repellents",level:"2"},{id:"sec_18",title:"5. 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Cell. 2013;155(6):1365-1379'},{id:"B85",body:'Govere J et al. Efficacy of three insect repellents against the malaria vector Anopheles arabiensis. Medical and Veterinary Entomology. 2000;14(4):441-444'},{id:"B86",body:'Witting-Bissinger B et al. Novel arthropod repellent, BioUD, is an efficacious alternative to deet. Journal of Medical Entomology. 2008;45(5):891-898'},{id:"B87",body:'Barnard DR, Xue R-D. Laboratory evaluation of mosquito repellents against Aedes albopictus, Culex nigripalpus, and Ochlerotatus triseriatus (Diptera: Culicidae). Journal of Medical Entomology. 2004;41(4):726-730'},{id:"B88",body:'Webb CE, Russell RC. Is the extract from the plant catmint (Nepeta cataria) repellent to mosquitoes in Australia? Journal of the American Mosquito Control Association. 2007;23(3):351-354'},{id:"B89",body:'Lindsay LR et al. Evaluation of the efficacy of 3Vo citronella candles and 5Vo citronella incense for protection against field populations of Aedes mosquitoes. 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Repellency of aerosol and cream products containing fennel oil to mosquitoes under laboratory and field conditions. Pest Management Science. 2004;60(11):1125-1130'},{id:"B95",body:'Trongtokit Y, Curtis CF, Rongsriyam Y. Efficacy of repellent products against caged and free flying Anopheles stephensi mosquitoes. Southeast Asian Journal of Tropical Medicine and Public Health. 2005;36(6):1423'},{id:"B96",body:'Mittal P et al. Efficacy of advanced odomos repellent cream (N,N-diethyl-benzamide) against mosquito vectors. The Indian Journal of Medical Research. 2011;133(4):426'},{id:"B97",body:'McPhatter LP, Mischler PD, Webb MZ, Chauhan K, Lindroth EJ, Richardson AG, et al. Laboratory and semi-field evaluations of two (Transfluthrin) spatial repellent devices against Aedes aeģypti (L.)(Diptera: Culicidae). US Army Medical Department Journal. January-June 2017, pp.13-22. Available from: https://www.researchgate.net/profile/Lee_Mcphatter/publication/323016579_Laboratory_and_semi-field_evaluations_of_two_transfluthrin_spatial_repellent_devices_against_Aedes_aegypti_L_Diptera_Culicidae/links/5b7ef0f74585151fd12e6481/Laboratory-and-semi-field-evaluations-of-two-transfluthrin-spatial-repellent-devices-against-Aedes-aegypti-L-Diptera-Culicidae.pdf#page=15'},{id:"B98",body:'Lucas J et al. US Laboratory and field trials of metofluthrin (SumiOne®) emanators for reducing mosquito biting outdoors. Journal of the American Mosquito Control Association. 2007;23(1):47-54'},{id:"B99",body:'Xue R-D et al. Field evaluation of the off! Clip-on mosquito repellent (metofluthrin) against Aedes albopictus and Aedes taeniorhynchus (Diptera: Culicidae) in northeastern Florida. Journal of Medical Entomology. 2012;49(3):652-655'},{id:"B100",body:'Dame DA et al. Field evaluation of four spatial repellent devices against Arkansas rice-land mosquitoes. Journal of the American Mosquito Control Association. 2014;30(1):31-36'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hanem Fathy Khater",address:"hanemkhater@gmail.com;, hanem.salem@fvtm.bu.edu.eg",affiliation:'
Department of Parasitology, Faculty of Veterinary Medicine, Benha University, Egypt
'},{corresp:null,contributorFullName:"Abdelfattah M. Selim",address:null,affiliation:'
Department of Infectious Disease, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
'},{corresp:null,contributorFullName:"Galal A. Abouelella",address:null,affiliation:'
Faculty of Pharmacy, British University of Egypt, Egypt
'},{corresp:null,contributorFullName:"Nour A. Abouelella",address:null,affiliation:'
Faculty of Pharmacy, British University of Egypt, Egypt
Unit of Vector Control, Phytochemistry and Nanotechnology, Department of Zoology, Annamalai University, India
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A commonly accepted hypothesis in microbial growth is the speed of cellular reproduction, which is proportional to the concentration of cells at that instant. The constant of proportionality between the speed of growth and cell concentration is called cell growth rate, μ. In many occasions, the cell growth rate is considered constant. This leads to conclude that the concentration of cells versus time presents an exponential function. The consideration of this equation provides a good adjustment in the beginning of central phase of the anaerobic fermentation process. However, it moves away from the measurements when there is a limited reproduction due to lack of nutrients and competition between the cells in the environment. This produces a sigmoidal variation in concentration. To find a suitable fit function for all phases of the process, Gompertz proposes a model that considers the cell growth rate as variable. In this chapter, the Gompertz model, kinetic models, transference, and cone models are evaluated. Different adaptations to fit the variables to the obtained values in the experiments have been reviewed.",signatures:"Borja Velázquez-Martí, Orlando W. Meneses-Quelal, Juan Gaibor-Chavez and Zulay Niño-Ruiz",authors:[{id:"25356",title:"Dr.",name:"Borja",surname:"Velazquez-Marti",fullName:"Borja Velazquez-Marti",slug:"borja-velazquez-marti",email:"borvemar@dmta.upv.es"},{id:"268541",title:"Mr.",name:"Orlando",surname:"Meneses-Quelal",fullName:"Orlando Meneses-Quelal",slug:"orlando-meneses-quelal",email:"wasmeque@cam.upv.es"},{id:"268542",title:"Dr.",name:"Juan",surname:"Gaibor-Chávez",fullName:"Juan Gaibor-Chávez",slug:"juan-gaibor-chavez",email:"juanelogaibor@yahoo.com"},{id:"268543",title:"Dr.",name:"Zulay",surname:"Niño-Ruiz",fullName:"Zulay Niño-Ruiz",slug:"zulay-nino-ruiz",email:"znino09@gmail.com"}],book:{title:"Anaerobic Digestion",slug:"anaerobic-digestion",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"25356",title:"Dr.",name:"Borja",surname:"Velazquez-Marti",slug:"borja-velazquez-marti",fullName:"Borja Velazquez-Marti",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitat Politècnica de València",institutionURL:null,country:{name:"Spain"}}},{id:"146985",title:"Dr.",name:"Anna",surname:"Sikora",slug:"anna-sikora",fullName:"Anna Sikora",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/146985/images/system/146985.jpg",biography:"A professor at the Institute of Biochemistry and Biophysics PAS, Warsaw, Poland. PhD in Biochemistry at the IBB PAS. Master of biology specialized in microbiology at the Faculty of Biology University of Warsaw, Poland. \nScientific interests and experience in:\n(i) Anaerobic digestion, fermentation processes, biogases (biohydrogen and biomethane) production;\n(ii) Microbial communities, nutritional interactions between microorganisms;\n(iii) Microbial iron reduction;\n(iv) Mutagenesis and DNA repair in bacteria\nPrincipal investigator of the grant projects funded by the Polish institutions: The National Center for Research and Development, The National Science Centre, and Ministry of Science and High Education. Cooperates with the industry and foreign and domestic research centers. Supervisor of MSc and PhD theses. 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In September 2010, he\nwas joined the Department of Electrical Engineering, Debre Markos University\nas an Assistant Lecturer. Since September 2014, he is a Lecturer in the\nDepartment of Electrical Engineering, Debre Markos University. His research\ninterests include renewable energy, distributed generation, smart grid and\ndistribution system automation, flexible AC transmission systems, high-voltage\nDC, and power quality. Currently, he is a member of the Ethiopia Teacher\nAssociation (ETA), Ethiopia Space Science Society (ESSS) and Society of\nEthiopia Electrical Engineers (SEEE).",institutionString:null,institution:null},{id:"268541",title:"Mr.",name:"Orlando",surname:"Meneses-Quelal",slug:"orlando-meneses-quelal",fullName:"Orlando Meneses-Quelal",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"268543",title:"Dr.",name:"Zulay",surname:"Niño-Ruiz",slug:"zulay-nino-ruiz",fullName:"Zulay Niño-Ruiz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"269433",title:"MSc.",name:"Anna",surname:"Detman",slug:"anna-detman",fullName:"Anna Detman",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"269435",title:"Dr.",name:"Damian",surname:"Mielecki",slug:"damian-mielecki",fullName:"Damian Mielecki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"269436",title:"Dr.",name:"Aleksandra",surname:"Chojnacka",slug:"aleksandra-chojnacka",fullName:"Aleksandra Chojnacka",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"partnerships",title:"Partnerships",intro:"
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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The International Association of Scientific, Technical and Medical Publishers (STM) is the leading global trade association for academic and professional publishers. As a member, IntechOpen has not only made a commitment to STM's Ethical Principles.
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COPE
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The Committee on Publication Ethics (COPE) provides advice to editors and publishers on all aspects of publication ethics and, in particular, how to handle cases of misconduct in research and publication. IntechOpen has been a member of COPE since 2013 and adheres to the COPE Code of Conduct and Best Practice Guidelines, ensuring that we maintain the highest ethical standards.
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Crossref is the official Digital Object Identifier (DOI) Registration Agency for scholarly and professional publications with a goal of making scholarly communications more effective. IntechOpen deposits metadata and registers DOIs for all content using the Crossref System. IntechOpen also deposits its references and uses the Crossref Cited-by service that enables researchers to track citation statistics.
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Altmetric and Dimensions from Digital Science
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Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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CLOCKSS
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CLOCKSS preserves scholarly publications in original formats, ensuring that they always remain available and openly accessible to everyone.
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Counter
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COUNTER provides the Code of Practice that enables publishers and vendors to report usage of their electronic resources in a consistent way. This enables libraries to compare data received from different publishers and vendors.
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DORA
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DORA is a worldwide initiative covering all scholarly disciplines which recognizes the need to improve the ways in which the outputs of scholarly research are evaluated and seeks to develop and promote best practice. To date it has been signed by over 1500 organizations and around 14,700 individuals.
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iThenticate
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iThenticate is the leading provider of professional plagiarism detection and prevention technology and is used worldwide by scholarly publishers and research institutions to ensure the originality of written work before publication. IntechOpen uses the iThenticate plagiarism software to ensure content originality and the research integrity of our published work.
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Enago
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IntechOpen collaborates with Enago, through its sister brand, Ulatus, one of the world’s leading providers of book translation services. Their services are designed to convey the essence of your work to readers from across the globe in the language they understand.
\n\t
IntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit https://www.enago.com/intech
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SPi Global
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SPi Global is the market leader in technology-driven solutions for the extraction, enrichment and transformation of content assets. IntechOpen publishing services are designed to meet the unique needs of Authors. As part of our commitment to that objective, we have an ongoing partnership agreement for production solutions.
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Amazon
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Amazon is the world’s largest online retailer and cloud services provider. IntechOpen books have been available on Amazon since 2017, guaranteeing more visibility for our Authors and Academic Editors.
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
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