Toxicokinetics of temephos after oral administration to adult male rats.

Temephos (Tem) is the larvicide of choice to control mosquito transmission of dengue, Zika, and chikungunya. The toxicokinetic and toxicological information of temephos is very limited. The aim of this work was to determine the toxicokinetics and dosimetry of temephos and its metabolites. Male Wistar rats were orally administered temephos (300 mg/kg) emulsified with saline solution and sacrificed over time after dosing. Temephos and its metabolites were analyzed in blood and tissues by high performance liquid chromatography-diode array detector. At least eleven metabolites were detected, including temephos-sulfoxide (Tem-SO), temephos-oxon (Tem-oxon), temephos-oxon-sulfoxide (Tem-oxon-SO), temephos-oxon-SO-monohydrolyzed (Tem-oxon-SO-OH), 4,4´-thiodiphenol, 4,4´-sulfinyldiphenol, and 4,4´-sulfonyldiphenol or bisphenol S (BPS). The mean blood concentrations of temephos were fitted to a one-compartment model for kinetic analysis. At 2 h, the peak was reached (t1/2 abs = 0.38 h), and only trace levels were detected at 36 h (t1/2 elim = 8.6 h). Temephos was detected in all tissues and preferentially accumulated in fat. Temephos-sulfone-monohydrolyzed (Tem-SO2-OH) blood levels remained constant until 36 h and gradually accumulated in the kidney. Tem-oxon was detected in the brain, liver, kidney, and fat. Clearance from the liver and kidney were 7.59 and 5.52 ml/min, respectively. These results indicate that temephos is well absorbed, extensively metabolized, widely distributed and preferentially stored in adipose tissue. It is biotransformed into reactive metabolites such as Tem-oxons, Tem-dioxons, and BPS. Tem-SO2-OH, the most abundant metabolite of temephos, could be used as an exposure biomarker for toxicokinetic modeling. These results could provide critical insight into the dosimetry and toxicity of temephos and its metabolites.

Resistance to temephos and deltamethrin in Aedes aegypti from Brazil between 1985 and 2017.

BACKGROUND: Aedes aegypti populations in Brazil have been subjected to insecticide selection pressures with variable levels and sources since 1967. Therefore, the Brazilian Ministry of Health (MoH) coordinated the activities of an Ae. aegypti insecticide resistance monitoring network (MoReNAa) from 1999 to 2012. OBJECTIVES: The objective of this study was to consolidate all information available from between 1985 and 2017 regarding the resistance status and mechanisms of Brazilian Ae. aegypti populations against the main insecticide compounds used at the national level, including the larvicide temephos (an organophosphate) and the adulticide deltamethrin (a pyrethroid). METHODS: Data were gathered from two sources: a bibliographic review of studies published from 1985 to 2017, and unpublished data produced by our team within the MoReNAa between 1998 and 2012. A total of 146 municipalities were included, many of which were evaluated several times, totalling 457 evaluations for temephos and 274 for deltamethrin. Insecticide resistance data from the five Brazilian regions were examined separately using annual records of both the MoH supply of insecticides to each state and the dengue incidence in each evaluated municipality. FINDINGS: Ae. aegypti resistance to temephos and deltamethrin, the main larvicide and adulticide, respectively, employed against mosquitoes in Brazil for a long time, was found to be widespread in the country, although with some regional variations. Comparisons between metabolic and target-site resistance mechanisms showed that one or another of these was the main component of pesticide resistance in each studied population. MAIN CONCLUSIONS: (i) A robust dataset on the assessments of the insecticide resistance of Brazilian Ae. aegypti populations performed since 1985 was made available through our study. (ii) Our findings call into question the efficacy of chemical control as the sole methodology of vector control. (iii) It is necessary to ensure that sustainable insecticide resistance monitoring is maintained as a key component of integrated vector management. (iv) Consideration of additional parameters, beyond the supply of insecticides distributed by the MoH or the diverse local dynamics of dengue incidence, is necessary to find consistent correlations with heterogeneous vector resistance profiles.

Community-Effectiveness of Temephos for Dengue Vector Control: A Systematic Literature Review.

The application of the organophosphate larvicide temephos to water storage containers is one of the most commonly employed dengue vector control methods. This systematic literature review is to the knowledge of the authors the first that aims to assess the community-effectiveness of temephos in controlling both vectors and dengue transmission when delivered either as a single intervention or in combination with other interventions. A comprehensive literature search of 6 databases was performed (PubMed, WHOLIS, GIFT, CDSR, EMBASE, Wiley), grey literature and cross references were also screened for relevant studies. Data were extracted and methodological quality of the studies was assessed independently by two reviewers. 27 studies were included in this systematic review (11 single intervention studies and 16 combined intervention studies). All 11 single intervention studies showed consistently that using temephos led to a reduction in entomological indices. Although 11 of the 16 combined intervention studies showed that temephos application together with other chemical vector control methods also reduced entomological indices, this was either not sustained over time or-as in the five remaining studies--failed to reduce the immature stages. The community-effectiveness of temephos was found to be dependent on factors such as quality of delivery, water turnover rate, type of water, and environmental factors such as organic debris, temperature and exposure to sunlight. Timing of temephos deployment and its need for reapplication, along with behavioural factors such as the reluctance of its application to drinking water, and operational aspects such as cost, supplies, time and labour were further limitations identified in this review. In conclusion, when applied as a single intervention, temephos was found to be effective at suppressing entomological indices, however, the same effect has not been observed when temephos was applied in combination with other interventions. There is no evidence to suggest that temephos use is associated with reductions in dengue transmission.

Susceptibility status of Aedes aegypti (L.) (Diptera: Culicidae) to temephos from three districts of Tamil Nadu, India.

BACKGROUND & OBJECTIVES: Dengue is the most rapidly expanding arboviral disease in India. Aedes aegypti is the primary vector of dengue fever. Chemical insecticides have long been used in the vector control programmes along with other control measures. However, continuous use of insecticides targeting Ae. aegypti may lead to development of insecticide resistance. Though resistance in Ae. aegypti has been reported, the mutation in ace-1 gene associated with temephos resistance is not reported in natural populations. The present study aims to evaluate the susceptibility/resistance status of Ae. aegypti to temephos from three districts of Tamil Nadu. METHODS: Ae. aegypti larvae were sampled from different locations in three districts, viz., Dharmapuri, Salem and Namakkal. The standard WHO larval bioassay, biochemical assays and spotting of specific mutation (G119S) in the acetylcholinesterase gene, which is associated with organophosphate resistance, were carried out by PCR and sequencing. RESULTS: The results showed that larvae from Namakkal (NKL) population had an alteration in their susceptibility status (RR = 6.9 fold), while the other populations were moderately susceptible to insecticides. Biochemical assay showed increased activity for α- and ß-esterase in NKL, as well as evidence of acetylcholinesterase insensitivity. G119S mutation was detected in this population with high frequency of 0.24. INTERPRETATION & CONCLUSION: The high activity of esterase, mixed-function oxidase (MFO) and ace-1 mutation frequency were closely associated with temephos resistance. Early detection of resistance alleles in natural vector population could be useful for the successful implementation of insecticide resistance management strategies. The results of this study provide baseline data on temephos resistance in Ae. aegypti populations.

The disappearance of onchocerciasis from the Itwara focus, western Uganda after elimination of the vector Simulium neavei and 19 years of annual ivermectin treatments.

The Itwara onchocerciasis focus is located around the Itwara forest reserve in western Uganda. In 1991, annual treatments with ivermectin started in the focus. They were supplemented in 1995 by the control of the vector Simulium neavei, which was subsequently eliminated from the focus. The impact of the two interventions on the disease was assessed in 2010 by nodule palpations, examinations of skin snips by microscopy and PCR, and Ov16 recombinant ELISA. There was no evidence of any microfilaria in 688 skin snips and only 2 (0.06%) of 3316 children examined for IgG4 were slightly above the arbitrary cut off of 40. A follow up of the same children 21 months later in 2012 confirmed that both were negative for diagnostic antigen Ov-16, skin snip microscopy and PCR. Based on the World Health Organization (WHO) elimination criteria of 2001 and the Uganda onchocerciasis certification guidelines, it was concluded that the disease has disappeared from the Itwara focus after 19 years of ivermectin treatments and the elimination of the vector around 2001. Ivermectin treatments were recommended to be halted.

Effect of temephos on cholinesterase activity in the earthworm Eisenia fetida (Oligochaeta, Lumbricidae).

In this study, adult Eisenia fetida earthworms were exposed to the sub-lethal concentrations of temephos using the contact filter paper test procedure. Since temephos is an organophosphate pesticide, its effects on earthworms were determined by measuring ChE inhibition--a known biomarker of exposure. The ChE activity was measured after a short time of exposure--1 and 2 h. As expected, the lowest ChE activity (72.70% and 38.03% inhibition) was measured at the highest concentration of temephos (120 ng cm(-2)) applied. More interestingly, at the 0.12 ng cm(-2) concentration the ChE activity increased up to 36.28% of activity in the control in all three conducted experiments. Dose-response curves showed an inverted U-shape characteristic for hormesis. This hormetic-like effect could be important for health status of an earthworm.

Trend of temephos resistance in Aedes (Stegomyia) mosquitoes in Thailand during 2003-2005.

The diagnostic dose for temephos susceptibility test was established based on Aedes aegypti, the susceptible Bora (French Polynesia) strain, for practical and routine use. The diagnostic dose was subsequently used to evaluate the susceptibility/resistance status in F1 progenies of field-collected samples from Bangkok and various parts of Thailand. It appeared that Ae. aegypti mosquitoes of one collection site each in Bangkok, Nakhon Sawan (northcentral), and Nakhon Ratchasrima (northeast) were resistant to temephos, with mortality ranging from 50.5 to 71.4%. Moreover, there was a trend of resistance to temephos among Ae. aegypti populations of all studied districts of Nakorn Ratchasima and most areas of Nakhon Sawan, of which those in one area were susceptible. However, various levels of temephos susceptibility were found in Bangkok populations, including resistance and incipient resistance. In Chonburi Province (eastern), all mosquitoes were susceptible to temephos with an indication of tolerance in one sample. Additionally, mosquitoes from Songkhla (south), Chiang Rai (north), Kanchanaburi (west), and Chanthaburi (east) remained susceptible to temephos during the sample collecting period. Bioassay tests on Aedes albopictus populations collected in this study from Nakhon Sawan, Nakorn Ratchasima, Songkhla, and Kanchanaburi revealed high susceptibility to temephos. Although the use of temephos seems to be potentially effective in many areas of the country, a noticeable trend of resistance indicated that alternative vector control methods should be periodically applied.

Efficacy and longevity of a new formulation of temephos larvicide tested in village-scale trials against larval Aedes aegypti in water-storage containers.

Field trials on the initial and long-term efficacy of a new formulation of temephos granules (1% on zeolite) applied at 1 ppm active ingredient (AI) were conducted in water-storage containers against Aedes aegypti in 3 villages in the Kanchanaburi Province in Thailand. A total of 316 water-storage containers of various types and sizes were included in the study. In the initial survey, we found that some containers were positive for larval Ae. aegypti, whereas others were devoid of larvae before the initiation of treatments. The containers all were numbered with paint and divided into 4 groups: with larvae and treated, without larvae and treated, with larvae untreated, and without larvae and untreated. Assessment of larval abundance was made 48 h after treatment and monthly thereafter for 5 months. Containers with larvae and that were treated exhibited almost complete absence of larval Ae. aegypti for 2 months, but a small proportion became positive after 3 months. Most of these positive containers were devoid of zeolite granules, which are visible in the containers. The number of positive containers increased in months 4 and 5, despite the fact that residues of temephos granules were present in some of the larvae-positive containers. The containers initially without larvae and treated with temephos essentially were devoid of larvae for 2 months. After 3, 4, and 5 months, about 6-23% of the containers became positive despite the fact that some had visible amounts of temephos granules. In the 2 control groups initially with and without larvae, sustained and consistent production of larvae occurred. Even in the group initially without a larval population, the containers became positive for larvae 1 month after the start of the experiment and the positivity rate increased as the trial progressed. From these studies, the conclusion can be made that a single application of temephos zeolite granules at 1 ppm AI can provide highly satisfactory control of larval Ae. aegypti in water-storage containers for at least 3 months in the field under normal water-use practices.

Factors influencing the toxicity of xenobiotics against larval mosquitoes.

In order to examine the factors influencing xenobiotic toxicity against larval mosquitoes, the larvicidal performances of two conventional insecticides (temephos and Bacillus thuringiensis var. israelensis: Bti) and a new potential phyto-insecticide (decomposed leaf litter) were compared under different conditions against three detritivorous larval mosquito types. Bioassays performed under standard conditions indicated differential tolerance levels according to the xenobiotic and the larval type. Bioassays performed under different conditions of xenobiotic dose and geometry of the water column indicated differential effects of those parameters on mortality rates. This allowed us to distinguish the performances of temephos versus those of Bti and leaf litter. These toxicological performances were examined as indicators for analysis of xenobiotic bioavailability for mosquito larvae in environmental water, and also for their comparative interest in field mosquito control.

Insecticide susceptibility status of Culex tritaeniorhynchus giles, vector of Japanese encephalitis in Delhi.

Laboratory studies were carried out to ascertain the current susceptibility status of adult and larval stages of the Culex tritaeniorhynchus mosquito, vector of Japanese encephalitis, to various insecticides used under public health programs in India. The present study revealed that exposure of adult mosquitoes to diagnostic concentrations of DDT - 4.0%, malathion - 5.0%, fenitrothion - 1.0%, and propoxur - 0.1% could induce only 50.0, 10. 0, 15.0, and 5.0% mortality, respectively, indicating that the species was resistant to all of these insecticides. The LT50 and LT95 values calculated using diagnostic concentrations of DDT, malathion, fenitrothion, and propoxur were found to be 56.4 and 136, 138 and 272, 185 and 258, and 187 and 249 min, respectively. However, when adult mosquitoes were exposed to the diagnostic concentration of synthetic pyrethroids, viz., deltamethrin - 0.025%, permethrin - 0.25%, and lambdacyhalothrin - 0.1%, 100.0% mortality was observed, indicating that the species was highly susceptible to these adulticides. Larval susceptibility tests carried out using diagnostic dosages of DDT- 0.008, temephos- 0.02, fenthion- 0.008, fenitrothion- 0.125, and malathion- 0.005 mg/l failed to induce any mortality, indicating that larvae were resistant to these larvicides. The LC50 and LC90 values calculated for commonly used larvicides, viz., temephos and fenthion, were 0.1511 and 1.9098, and 0.6151 and 2.395 mg/l, respectively. Increase in tolerance level were estimated at 95.5- and 299.4-fold when these LC90 values were compared with diagnostic dosages of temephos and fenthion, respectively.

Avaliaçäo da açäo residual do larvicida temephós sobre o Aedes aegypti(Diptera, Culicidae)em diferentes tipos de recipientes / Evaluation of the residual action of the larvicide temephos over Aedes aegypti(Diptera-Culicidae)in different types of containers

A açäo residual do larvicida Temephós aegypti foi avaliada através do teste de duas concentraçöes do produto - 1 ppm(400mg/l) e (2 ppm(800mg/l) - distribuidas, respectivamente, em 06 diferentes recipientes - pneu, vaso de barro, bacia de alumínio, aquário de vidro, bacia de plástico e caixa de amianto -, todas com volume constante de 04 litros. Em cada recipiente, foram colocadas 20 larvas de 3§ estádio de Aedes aegypti, avaliadas após 24 horas de exposiçäo ao produto e em seguida retiradas da soluçäo. Essa mesma soluçäo foi mantida por 14 semanas e os testes repetidos a cada 07 dias. A mortalidade das larvas foi o critério utilizado para avaliar a açäo residual do larvicida. A eficácia foi de 100 por cento para os recipientes vaso de barro, bacia de alumínio, aquário de vidro, bacia de plástico e caixa de amianto, durante todo o período do teste, nas duas concentraçöes; no pneu, houve queda de 45 por cento na concentraçäo de 800mg/l a partir da 7ª semana, decrescendo a partir daí, até näo ocorrer mortalidade no último teste

[Evaluation of the efficacy of temephos in the campaign against dracunculosis]. / Evaluation de l'efficacité du téméphos dans la lutte contre la dracunculose.

Efficacy of water source treatment with temephos 200 EC had been tested with three methods after treatment of a natural reservoir in a temporary river bed. 1. Residual pesticide in water treatment was measured with a biological test based on the pesticide toxicity on mosquito larvae from a laboratory stock for which the standard LD50 for the considered pesticide is stable and accurately known. After pesticide treatment, samples of the treated source water were taken. 30 larvae were placed in 200 ml of the treated water either pure or diluted in untreated water (ten dilutions tested). The mortality rate of larvae after 24 hours was observed and marked on a probit scale. The LD50 was read directly from the curve. The corresponding dilution of the water sample that contained one standard LD50 was expressed in mg.l-1, using the value of the standard LD50. This method was found reproducible and sensitive (up to 0.001 p.p.m.), depending on the value of the standard LD50. 2. Lethality of cyclopides was measured by numeration of survivals in 10 liters samples and compared to the natural population of a close untreated water reservoir in the higher part of the same river. Results showed that half-life of temephos was shorter than 3 days and the concentration corresponding to the LD50 for cyclopides was reached a week after treatment. Two or three weeks after treatment the cyclopide population was significant and further pesticide application was needed. 3. Decrease of incidence of dracunculiasis was compiled by weekly examination of the population during the season of transmission. Authors observed an incidence of 37% during the 86/87 season.(ABSTRACT TRUNCATED AT 250 WORDS)

[Campaign against the vectors of onchocerciasis in the surroundings of a refugee camp located in a savanna zone of Cameroon]. / Lutte contre les vecteurs de l'onchocercose aux alentours d'un camp de réfugiés situé en zone de savane du Cameroun.

In view of the risks of onchocerciasis facing Chadian refugees who have settled in a camp in a savanna hyperendemic area of northern Cameroon, the authors concluded that a vector control directed against the black fly larvae located on small seasonal tributaries of the main water course of this area should be carried out during the four to five months of the rainy season, i.e., during the whole period of transmission of this disease. The operations were undertaken during two consecutive rainy seasons. The first year consisted in developing ground-based control techniques and evaluating the larvicidal efficacy at the larval level. The second year was, particularly, devoted to the study of the impact of the vector control on the biting rate and on the transmission of onchocerciasis. Every week, three of the tributaries close to the camp were treated with an Emulsifiable Concentrate of temephos. Throughout the rainy season, the larvicide eliminated almost all the pre-adult black fly stages on these water courses. At the point in a high onchocercal endemicity area, it also reduced the biting rate by 60% and the Annual Transmission Potential by 72%, i.e., to values corresponding to the lower meso-endemicity threshold. Since these results were obtained at a very unfavourable point from the standpoint of black fly density and onchocerciasis transmission, the authors consider that vector control carried out under these conditions protects the local populations and the Chadian refugees effectively from black fly bites and a risk of severe onchocerciasis.