Neurotoxic Mode Of Action Research Articles

Neurotoxic pesticides change respiratory parameters in early gill-breathing, but not in skin-breathing life-stages of zebrafish (Danio rerio)

Neurotoxic compounds can interfere with active gill ventilation in fish, which might lead to premature death in adult fish, but not in skin-breathing embryos of zebrafish, since these exclusively rely on passive diffusion across the skin. Regarding lethality, this respiratory failure syndrome (RFS) has been discussed as one of the main reasons for the higher sensitivity of adult fish in the acute fish toxicity test (AFT), if compared to embryos in the fish embryo toxicity test (FET). To further elucidate the relationship between the onset of gill respiration and death by a neurotoxic mode of action, a comparative study into oxygen consumption (MO2), breathing frequency (fv) and amplitude (fampl) was performed with 4 d old skin-breathing and 12 d old early gill-breathing zebrafish. Neurotoxic model substances with an LC50 FET/AFT ratio of > 10 were used: chlorpyrifos, permethrin, aldicarb, ziram, and fluoxetine. Exposure to hypoxia served as a positive control, whereas aniline was tested as an example of a narcotic substance interfering non-specifically with gill membranes. In 12 d old larvae, all substances caused an increase in MO2, fv and partly fampl, whereas effects were minor in 4 d old embryos. An increase of fv in 4 d old embryos following exposure to chlorpyrifos, aldicarb and hypoxia could not be correlated with an increased MO2 and might be attributed either to (1) to the successfully postponed decrease of arterial partial pressure of oxygen (PO2) through support of skin respiration by increased fv, (2) to an unspecific stimulation of the sphincter muscles at the base of the gill filaments, or (3) to the establishment of oxygen sensing for later stages. In gill-breathing 12 d old zebrafish, a concentration-dependent increase of fv was detected for aniline and chlorpyrifos, whereas for aldicarb, fluoxetine and permethrin, a decline of fv at higher substance concentrations was measured, most likely due to the onset of paralysis and/or fatigue of the gill filament sphincter muscles. Since alterations of fv serve to postpone the decrease in arterial PO2 and MO2 increased with decreasing fv, the respiratory failure syndrome could clearly be demonstrated in 12 d old zebrafish larvae. Passive respiration across the skin in zebrafish embryos could thus be confirmed as a probable reason for the lower sensitivity of early life-stages to neurotoxicants. Integration of respiratory markers into existing testing protocols with non-protected developmental stages such as embryos might help to not underestimate the toxicity of early life-stages of fish.

Paediatrics: how to manage pediculosis capitis.

BackgroundPediculosis capitis is a common human parasitic infestation in childhood. This article aims to provide a narrative updated review on the management of pediculosis capitis.MethodsA PubMed search was performed with Clinical Queries using the key terms “pediculosis capitis” OR “head lice” OR “head louse”. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews published within the past 10 years. The search was restricted to articles published in English literature. The information retrieved from the search was used in the compilation of the present article.ResultsTopical permethrin and pyrethrin formulated with piperonyl butoxide are the pediculicides of choice in areas where resistance to these products is low. When resistance to these products is suspected based on local levels of resistance or when treatment with these products fails despite their correct use, and reinfestation does not seem to be responsible, other topical treatment options include malathion, benzyl alcohol, dimethicone, spinosad and ivermectin. Wet combing should be considered for children younger than 2 years. Oral ivermectin and trimethoprim/sulfamethoxazole should be reserved for patients who do not respond to appropriate topical pediculicides.ConclusionMany topical pediculicides are effective for the treatment of pediculosis capitis. The use of some of these pediculicides is limited for safety reasons, especially in children younger than 2 years. Resistance to pediculicides, especially those with a neurotoxic mode of action, is another concern which may limit the use of some of these pediculicides. New products should be evaluated for effectiveness and safety. Wet combing is time-consuming and should not be used as the sole intervention in the general population.

Applicability of the fish embryo acute toxicity (FET) test (OECD 236) in the regulatory context of Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH).

In 2013 the Organisation for Economic Co-operation and Development (OECD) test guideline (236) for fish embryo acute toxicity (FET) was adopted. It determines the acute toxicity of chemicals to embryonic fish. Previous studies show a good correlation of FET with the standard acute fish toxicity (AFT) test; however, the potential of the FET test to predict AFT, which is required by the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) regulation (EC 1907/2006) and the Classification, Labelling and Packaging (CLP) Regulation (EC 1272/2008), has not yet been fully clarified. In 2015 the European Chemicals Agency (ECHA) requested that a consultant perform a scientific analysis of the applicability of FET to predict AFT. The purpose was to compare the toxicity of substances to fish embryos and to adult fish, and to investigate whether certain factors (e.g., physicochemical properties, modes of action, or chemical structures) could be used to define the applicability boundaries of the FET test. Given the limited data availability, the analysis focused on organic substances. The present critical review summarizes the main findings and discusses regulatory application of the FET test under REACH. Given some limitations (e.g., neurotoxic mode of action) and/or remaining uncertainties (e.g., deviation of some narcotic substances), it has been found that the FET test alone is currently not sufficient to meet the essential information on AFT as required by the REACH regulation. However, the test may be used within weight-of-evidence approaches together with other independent, relevant, and reliable sources of information. The present review also discusses further research needs that may overcome the remaining uncertainties and help to increase acceptance of FET as a replacement for AFT in the future. For example, an increase in the availability of data generated according to OECD test guideline 236 may provide evidence of a higher predictive power of the test. Environ Toxicol Chem 2018;37:657-670. © 2017 SETAC.

The fish embryo test (FET): origin, applications, and future.

Originally designed as an alternative for the acute fish toxicity test according to, e.g., OECD TG 203, the fish embryo test (FET) with the zebrafish (Danio rerio) has been optimized, standardized, and validated during an OECD validation study and adopted as OECD TG 236 as a test to assess toxicity of embryonic forms of fish. Given its excellent correlation with the acute fish toxicity test and the fact that non-feeding developmental stages of fish are not categorized as protected stages according to the new European Directive 2010/63/EU on the protection of animals used for scientific purposes, the FET is ready for use not only for range-finding but also as a true alternative for the acute fish toxicity test, as required for a multitude of national and international regulations. If-for ethical reasons-not accepted as a full alternative, the FET represents at least a refinement in the sense of the 3Rs principle. Objections to the use of the FET have mainly been based on the putative lack of biotransformation capacity and the assumption that highly lipophilic and/or high molecular weight substances might not have access to the embryo due to the protective role of the chorion. With respect to bioactivation, the only substance identified so far as not being activated in the zebrafish embryo is allyl alcohol; all other biotransformation processes that have been studied in more detail so far were found to be present, albeit, in some cases, at lower levels than in adult fish. With respect to larger molecules, the extension of the test duration to 96h (i.e., beyond hatch) has-at least for the substances tested so far-compensated for the reduced access to the embryo; however, more research is necessary to fully explore the applicability of the FET to substances with a molecular weight >3kDa as well as substances with a neurotoxic mode of action. An extension of the endpoints to also cover sublethal endpoints makes the FET a powerful tool for the detection of teratogenicity, dioxin-like activity, genotoxicity and mutagenicity, neurotoxicity, as well as various forms of endocrine disruption.

Treatment of pediculosis capitis: a critical appraisal of the current literature.

Pediculosis capitis is the most common ectoparasitic disease in children in industrialized countries and extremely common in resource-poor communities of the developing world. The extensive use of pediculicides with a neurotoxic mode of action has led to the development and spread of resistant head lice populations all over the world. This triggered the development of compounds with other modes of action. The current literature on treatment approaches of head lice infestation was searched, and published randomized controlled trials were critically analyzed. The following compounds/family of compounds were identified: spinosad, a novel compound with a new neurotoxic mode of action, isopropyl myristate, 1,2-octanediol, ivermectin, plant-based products, and dimeticones. The efficacy and safety of these compounds are reviewed and recommendations for the treatment of pediculosis capitis in individuals as well as the interruption of ongoing epidemics are provided.

Treatment of parasitic skin diseases with dimeticones a new family of compounds with a purely physical mode of action.

Epidermal parasitic skin diseases (EPSD) are common in the tropics and sub-tropics. They are caused by mites, lice and other blood-sucking insects. In resource-poor countries they are associated with considerable morbidity. Hitherto, EPSD are treated with insecticides with a neurotoxic mode of action. The efficacy of this treatment is variable, and the development and spread of resistant mites and lice is alarming.A new concept for treating EPSD is presented which is based on the topical application of dimeticones, silicone oils of low viscosity which rapidly kill insects and mites by a physical mode of action. They creep into the respiratory system and block oxygen supply. The physical mode of action makes the development of resistant parasite strains very unlikely. Due to their safety and efficacy, dimeticones are promising candidates for population-based intervention programmes targeted against EPSD in resource-poor settings.

Pediculosis capitis: new insights into epidemiology, diagnosis and treatment

Pediculosis capitis is a ubiquitous parasitic skin disease caused by Pediculus humanus capitis. Head lice are highly specialised parasites which can propagate only on human scalp and hair. Transmission occurs by direct head-to-head contact. Head lice are vectors of important bacterial pathogens. Pediculosis capitis usually occurs in small epidemics in play groups, kindergartens and schools. Population-based studies in European countries show highly diverging prevalences, ranging from 1% to 20%. The diagnosis of head lice infestation is made through the visual inspection of hair and scalp or dry/wet combing. The optimal method for the diagnosis of active head lice infestation is dry/wet combing. Topical application of a pediculicide is the most common treatment. Compounds with a neurotoxic mode of action are widely used but are becoming less effective due to resistant parasite populations. Besides, their use is restricted by safety concerns. Dimeticones, silicone oils with a low surface tension and the propensity to perfectly coat surfaces, have a purely physical mode of action. This group of compounds is highly effective and safe, and there is no risk that head lice become resistant. The control of epidemics requires active contact tracing and synchronised treatment with an effective and safe pediculicide.

1-D and 2-D NMR metabolomics of earthworm responses to sub-lethal trifluralin and endosulfan exposure

Environmental contextEnvironmental metabolomics is an emerging field that examines the metabolic changes in organisms in response to potential environmental stressors. In this study, nuclear magnetic resonance spectroscopy is used to investigate earthworm metabolic responses to sub-lethal exposure of environmentally persistent pesticides. The study identifies two toxic modes of action elicited by the pesticides, and highlights the potential of metabolomics for the chemical assessment of persistent environmental contaminants. Abstract1-D and 2-D nuclear magnetic resonance (NMR) spectroscopy is used to examine the metabolic response of the earthworm (Eisenia fetida) after contact test exposure to an organofluorine pesticide, trifluralin, and an organochlorine pesticide, endosulfan. Three sub-lethal concentrations were used for each pesticide (0.1, 0.5 and 1.0 mg cm–2 for trifluralin and 0.5, 1.0 and 2.0 μg cm–2 for endosulfan). Principal component analysis of the trifluralin and endosulfan NMR datasets showed separation between the unexposed and the exposed earthworm groups. Alanine, glycine, maltose and ATP were significant in the highest concentration (1.0 mg cm–2) for trifluralin-exposed earthworms and may result from a non-polar narcosis toxic mode of action (MOA). Leucine, phenylalanine, tryptophan, lysine, glutamate, valine, glycine, isoleucine, methionine, glutamine, alanine, maltose, glucose, meibiose, malate, fumarate and ATP were detected as significant for the two highest concentrations (1.0 and 2.0 μg cm–2) for endosulfan-exposed earthworms and a neurotoxic MOA is postulated. This study highlights the use of 1-D and 2-D metabolomics for understanding the biochemical response of environmental contaminants to model organisms such as earthworms.

Effects of Diazepam on Gene Expression and Link to Physiological Effects in Different Life Stages in Zebrafish Danio rerio

We applied zebrafish whole genome microarrays to identify molecular effects of diazepam, a neuropharmaceutical encountered in wastewater-contaminated environments, and to elucidate its neurotoxic mode of action. Behavioral studies were performed to analyze for correlations between altered gene expression with effects on the organism level. Male zebrafish and zebrafish eleuthero-embryos were exposed for 14 d or up to 3 d after hatching, respectively, to nominal levels of 273 ng/L and 273 μg/L (determined water concentrations in the adult experiment 235 ng/L and 291 μg/L). Among the 51 and 103 altered transcripts at both concentrations, respectively, the expression of genes involved in the circadian rhythm in adult zebrafish and eleuthero-embryos were of particular significance, as revealed both by microarrays and quantitative PCR. The swimming behavior of eleuthero-embryos was significantly altered at 273 μg/L. The study leads to the conclusion that diazepam-induced alterations of genes involved in circadian rhythm are paralleled by effects in neurobehavior at high, but not at low diazepam concentrations that may occur in polluted environments.

Editorial: [New Advances in Head Lice

In the past years, head lice infestations have increased in many countries all over the world, with important consequences for the health sector. However, little attention is given in the scientific literature on this topic. Thus, the present special issue is aimed to highlight new developments in the field of head lice. A focus is given on resistance studies to commonly used pediculicides with a neurotoxic mode of action, new treatment options, diagnosis and transmission. John Clark's up-to-date review on laboratory methods used for monitoring permethrin resistance also presents data on resistance, detected in 10 out of 14 examined countries throughout the globe. The head lice were characterized by determining prevalence, allele frequency and allele zygosity of three gene mutations of the voltage-sensitive sodium channel, known to reduce the sensitivity of head lice to permethrin. Interestingly, in about 3/4 of all head lice populations, he detected the presence of knockdown resistance alleles. Due to this increasing resistance, treatment options are limited. As a consequence, head lice therapy is at the edge of a paradigm shift, from the common use of pediculicides with a neurotoxic mode of action mainly to those acting by physical means. Recently, several studies have been performed to assess the efficacy of new compounds containing dimeticone, spinosad, ivermectin or benzyl alcohol. We present exemplarily dimeticones and their use in head lice therapy. These silicone oils have a proven physical mode of action and are the compounds with most evidences available (ex vivo and clinical studies). High concentration two-phase dimeticone has been shown to reveal excellent clinical, pediculicidal and ovicidal efficacy, and the development of future resistance is virtually inconceivable. Hermann Feldmeier's up-to-date review presents most current data on diagnosis of pediculosis. Diagnosis of head lice infestation is a crucial aspect for treatment and control. He describes, based on evidence, that wet combing has a sensitivity of more than 90% for diagnosis of active infestation and that in resource-pour settings self-diagnosis is a feasible approach. Deon Canyon and Rick Speare from the James Cook University in Australia discuss another controversial issue, the indirect transmission of head lice via inanimate objects. Their review focuses on current evidence available from experimental and field studies regarding fomite transmission. They conclude that data on this topic are still scanty and that additional studies are needed to define whether head lice on inanimate objects constitute an important transmission route. Finally, Susanne Sonnberg et al. present their studies on development of head lice eggs, by adapting a historical method for rearing eggs, published decades ago. They describe systematically the development of eggs under standardized conditions and show that continuous feeding of adult head lice on a human host is a feasible approach to obtain eggs of known age and with a high hatch rate. As the field of pediculosis is growing permanently, this special issue cannot be a comprehensive review on all new topics. However, we believe that the up-to-date selection is of great interest for readers and that it provides important information for head lice management and control.

Dimeticone-Based Pediculicides: A Physical Approach to Eradicate Head Lice

Resistance of head lice to insecticides with a neurotoxic mode of action, such as permethrin and malathion, is increasing in incidence and geographic extent. As a consequence, physically acting pediculicidal products have emerged. Dimeticones are synthetic silicone oils of low surface tension and can therefore coat most surfaces, thus also killing head lice (Pediculus humanus capitis) by physical means. Considering this mode of action, the development of head lice resistance in the future is very unlikely. In this review, ex vivo and clinical evidence on the efficacy of dimeticones against head lice is presented. Besides the high adulticidal and excellent ovicidal ex vivo efficacy, clinical efficacy of high concentrated dimeticone has been shown. We conclude that dimeticone-based products are a safe and effective option for those patients who prefer not to use pediculicides with a neurotoxic mode of action, especially in areas where resistances of head lice against permethrin and malathion-based products have been reported, or are suspected.