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Systemic insecticides are applied to plants using a wide variety of methods, ranging from foliar sprays to seed treatments and soil drenches. Neonicotinoids and fipronil are among the most widely used pesticides in the world. Their popularity is largely due to their high toxicity to invertebrates, the ease and flexibility with which they can be applied, their long persistence, and their systemic nature, which ensures that they spread to all parts of the target crop. However, these properties also increase the probability of environmental contamination and exposure of nontarget organisms. Environmental contamination occurs via a number of routes including dust generated during drilling of dressed seeds, contamination and accumulation in arable soils and soil water, runoff into waterways, and uptake of pesticides by nontarget plants via their roots or dust deposition on leaves. Persistence in soils, waterways, and nontarget plants is variable but can be prolonged; for example, the half-lives of neonicotinoids in soils can exceed 1,000 days, so they can accumulate when used repeatedly. Similarly, they can persist in woody plants for periods exceeding 1 year. Breakdown results in toxic metabolites, though concentrations of these in the environment are rarely measured. Overall, there is strong evidence that soils, waterways, and plants in agricultural environments and neighboring areas are contaminated with variable levels of neonicotinoids or fipronil mixtures and their metabolites (soil, parts per billion (ppb)-parts per million (ppm) range; water, parts per trillion (ppt)-ppb range; and plants, ppb-ppm range). This provides multiple routes for chronic (and acute in some cases) exposure of nontarget animals. For example, pollinators are exposed through direct contact with dust during drilling; consumption of pollen, nectar, or guttation drops from seed-treated crops, water, and consumption of contaminated pollen and nectar from wild flowers and trees growing near-treated crops. Studies of food stores in honeybee colonies from across the globe demonstrate that colonies are routinely and chronically exposed to neonicotinoids, fipronil, and their metabolites (generally in the 1–100 ppb range), mixed with other pesticides some of which are known to act synergistically with neonicotinoids. Other nontarget organisms, particularly those inhabiting soils, aquatic habitats, or herbivorous insects feeding on noncrop plants in farmland, will also inevitably receive exposure, although data are generally lacking for these groups. We summarize the current state of knowledge regarding the environmental fate of these compounds by outlining what is known about the chemical properties of these compounds, and placing these properties in the context of modern agricultural practices.

Concerns over the role of pesticides affecting vertebrate wildlife populations have recently focussed on systemic products which exert broad-spectrum toxicity. Given that the neonicotinoids have become the fastest-growing class of insecticides globally, we review here 150 studies of their direct (toxic) and indirect (e.g. food chain) effects on vertebrate wildlife—mammals, birds, fish, amphibians and reptiles. We focus on two neonicotinoids, imidacloprid and clothianidin, and a third insecticide, fipronil, which also acts in the same systemic manner. Imidacloprid and fipronil were found to be toxic to many birds and most fish, respectively. All three insecticides exert sub-lethal effects, ranging from genotoxic and cytotoxic effects, and impaired immune function, to reduced growth and reproductive success, often at concentrations well below those associated with mortality. Use of imidacloprid and clothianidin as seed treatments on some crops poses risks to small birds, and ingestion of even a few treated seeds could cause mortality or reproductive impairment to sensitive bird species. In contrast, environmental concentrations of imidacloprid and clothianidin appear to be at levels below those which will cause mortality to freshwater vertebrates, although sub-lethal effects may occur. Some recorded environmental concentrations of fipronil, however, may be sufficiently high to harm fish. Indirect effects are rarely considered in risk assessment processes and there is a paucity of data, despite the potential to exert population-level effects. Our research revealed two field case studies of indirect effects. In one, reductions in invertebrate prey from both imidacloprid and fipronil uses led to impaired growth in a fish species, and in another, reductions in populations in two lizard species were linked to effects of fipronil on termite prey. Evidence presented here suggests that the systemic insecticides, neonicotinoids and fipronil, are capable of exerting direct and indirect effects on terrestrial and aquatic vertebrate wildlife, thus warranting further review of their environmental safety.

We assessed the state of knowledge regarding the effects of large-scale pollution with neonicotinoid insecticides and fipronil on non-target invertebrate species of terrestrial, freshwater and marine environments. A large section of the assessment is dedicated to the state of knowledge on sublethal effects on honeybees (Apis mellifera) because this important pollinator is the most studied non-target invertebrate species. Lepidoptera (butterflies and moths), Lumbricidae (earthworms), Apoidae sensu lato (bumblebees, solitary bees) and the section “other invertebrates” review available studies on the other terrestrial species. The sections on freshwater and marine species are rather short as little is known so far about the impact of neonicotinoid insecticides and fipronil on the diverse invertebrate fauna of these widely exposed habitats. For terrestrial and aquatic invertebrate species, the known effects of neonicotinoid pesticides and fipronil are described ranging from organismal toxicology and behavioural effects to population-level effects. For earthworms, freshwater and marine species, the relation of findings to regulatory risk assessment is described. Neonicotinoid insecticides exhibit very high toxicity to a wide range of invertebrates, particularly insects, and field-realistic exposure is likely to result in both lethal and a broad range of important sublethal impacts. There is a major knowledge gap regarding impacts on the grand majority of invertebrates, many of which perform essential roles enabling healthy ecosystem functioning. The data on the few non-target species on which field tests have been performed are limited by major flaws in the outdated test protocols. Despite large knowledge gaps and uncertainties, enough knowledge exists to conclude that existing levels of pollution with neonicotinoids and fipronil resulting from presently authorized uses frequently exceed the lowest observed adverse effect concentrations and are thus likely to have large-scale and wide ranging negative biological and ecological impacts on a wide range of non-target invertebrates in terrestrial, aquatic, marine and benthic habitats.

The side effects of the current global use of pesticides on wildlife, particularly at higher levels of biological organization : populations, communities and ecosystems, are poorly understood (Köhler and Triebskorn 2013). Here, we focus on one of the problematic groups of agrochemicals, the systemic insecticides fipronil and those of the neonicotinoid family. The increasing global reliance on the partly prophylactic use of these persistent and potent neurotoxic systemic insecticides has raised concerns about their impacts on biodiversity, ecosystem functioning and ecosystem services provided by a wide range of affected species and environments. The present scale of use, combined with the properties of these compounds, has resulted in widespread contamination of agricultural soils, freshwater resources, wetlands, non-target vegetation and estuarine and coastal marine systems, which means that many organisms inhabiting these habitats are being repeatedly and chronically expose.

The majority of lifetime smokers begin using nicotine during adolescence, a critical period of brain development wherein neural circuits critical for mood, affect and cognition are vulnerable to drug-related insults. Specifically, brain regions such as the medial prefrontal cortex (mPFC), the ventral tegmental area (VTA), nucleus accumbens (NAc) and hippocampus, are implicated in both nicotine dependence and pathological phenotypes linked to mood and anxiety disorders. Clinical studies report that females experience higher rates of mood/anxiety disorders and are more resistant to smoking cessation therapies, suggesting potential sex-specific responses to nicotine exposure and later-life neuropsychiatric risk. However, the potential neural and molecular mechanisms underlying such sex differences are not clear. In the present study, we compared the impacts of adolescent nicotine exposure in male vs. female rat cohorts. We performed a combination of behavioral, electrophysiological and targeted protein expression analyses along with matrix assisted laser deionization imaging (MALDI) immediately post-adolescent exposure and later in early adulthood. We report that adolescent nicotine exposure induced long-lasting anxiety/depressive-like behaviors, disrupted neuronal activity patterns in the mPFC-VTA network and molecular alterations in various neural regions linked to affect, anxiety and cognition. Remarkably, these phenotypes were only observed in males and/or were expressed in the opposite direction in females. These findings identify a series of novel, sex-selective biomarkers for adolescent nicotine-induced neuropsychiatric risk, persisting into adulthood.

Electronic cigarettes (e-cigarettes, ECIGs) were introduced into the market a decade ago as an alternative to tobacco smoking. Whether ECIGs are safe and whether they qualify as smoking cessation tool is currently unknown. Their use has markedly expanded in that period, despite the fact that potential toxic effects of the vapour created by the e-cigarette and the nicotine-containing cartridge fluid have been incompletely studied. Marketing targets diverse groups including older smokers but also young people. Whereas the adverse health effects of nicotine inhaled by users of ECIGs has been well documented, less is known about the other components. An increasing number of in vitro and in vivo studies demonstrate a range of adverse effects of both the vapour created by ECIGs as well as the nicotine-containing fluid. Importantly, these studies demonstrate that toxicity from ECIGs, although this may be less than that caused by tobacco products, not only arises from its nicotine content. Furthermore, there are no data on the long-term consequences of ECIG use. The wide range of ECIG products available to consumers and the lack of standardisation of toxicological approaches towards ECIG evaluation complicates the assessment of adverse health effects of their use. Here we review the current data on preclinical studies on ECIGs describing their effects in cell culture and animal models.

Background The use of electronic cigarettes (e-cigs) is increasing and there is widespread perception that e-cigs are safe. E-cigs contain harmful chemicals; more research is needed to evaluate the safety of e-cig use. Our aim was to investigate the effects of e-cigs on the inflammatory response of human neutrophils. Methods Neutrophils were exposed to e-cig vapour extract (ECVE) and the expression of CD11b and CD66b was measured by flow cytometry and MMP-9 and CXCL8 by ELISA. We also measured the activity of neutrophil elastase (NE) and MMP-9, along with the activation of inflammatory signalling pathways. Finally we analysed the biochemical composition of ECVE by ultra-high performance liquid chromatography mass spectrometry. Results ECVE caused an increase in the expression of CD11b and CD66b, and increased the release of MMP-9 and CXCL8. Furthermore, there was an increase in NE and MMP-9 activity and an increase in p38 MAPK activation. We also identified several harmful chemicals in ECVE, including known carcinogens. Conclusions ECVE causes a pro-inflammatory response from human neutrophils. This raises concerns over the safety of e-cig use.

Cigarette smoking by pregnant women is associated with a significant increase in the risk for cognitive disorders in their children. Preclinical models confirm this risk by showing that exposure of the developing brain to nicotine produces adverse behavioral outcomes. Here we describe behavioral phenotypes resulting from perinatal nicotine exposure in a mouse model, and discuss our findings in the context of findings from previously published studies using preclinical models of developmental nicotine exposure. Female C57Bl/6 mice received drinking water containing nicotine (100μg/ml) + saccharin (2%) starting 3 weeks prior to breeding and continuing throughout pregnancy, and until 3 weeks postpartum. Over the same period, female mice in two control groups received drinking water containing saccharin (2%) or plain drinking water. Offspring from each group were weaned at 3-weeks of age and subjected to behavioral analyses at 3 months of age. We examined spontaneous locomotor activity, anxiety-like behavior, spatial working memory, object based attention, recognition memory and impulsive-like behavior. We found significant deficits in attention and working memory only in male mice, and no significant changes in the other behavioral phenotypes in male or female mice. Exposure to saccharin alone did not produce significant changes in either sex. The perinatal nicotine exposure produced significant deficits in attention and working memory in a sex-dependent manner in that the male but not female offspring displayed these behaviors. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and have been reported in other studies that used pre- or perinatal nicotine exposure. Therefore, we suggest that preclinical models of developmental nicotine exposure could be useful tools for modeling ADHD and related disorders.

BackgroundNicotine is a major oral irritant in smokeless tobacco products and has an aversive taste. Mentholated smokeless tobacco products are highly popular, suggesting that menthol increases their palatability and may facilitate initiation of product use. While menthol is known to reduce respiratory irritation by tobacco smoke irritants, it is not known whether this activity extends to oral nicotine and its aversive effects.Study designThe two-bottle choice drinking assay was used to characterise aversion and preference in C57BL/6 mice to a range of menthol concentrations (10–200 µg/mL). Then, effects of menthol on oral nicotine aversion were determined. Responses were compared with those in mice deficient in the cold/menthol receptor, TRPM8, expressed in trigeminal sensory neurons innervating the oral cavity.ResultsMice showed aversion to menthol concentrations of 100 µg/mL and above. When presented with a highly aversive concentration of nicotine (200 µg/mL), mice preferred solutions with 50 or 100 µg/mL menthol added over nicotine alone. In contrast to wild-type mice, Trpm8−/− showed a strong aversion to mentholated (100 µg/mL) nicotine (200 µg/mL) and preferred nicotine alone. Trpm8−/− mice show aversion to lower concentrations of menthol than wild-type mice.ConclusionsOral menthol can reduce the aversive effects of oral nicotine and, at higher concentrations, acts as an irritant by itself. Menthol's effects in relation to nicotine require TRPM8, the cool temperature sensing ion channel that activates analgesic and counterirritant mechanisms. These mechanisms may underlie preference for menthol-containing smokeless tobacco products and may facilitate initiation of product use.

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system—a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide.Models for Cardiovascular Toxicity Testing E-cigarettes and nicotine delivery systems can be examined using multiple model systems. In silico models might predict adverse cardiovascular effects that can be screened for using 2-D and 3-D models using induced pluripotent stem cell (iPSC) derived cardiac tissue and “omics” profiling such as single-cell RNA sequencing (scRNA-seq) or high-throughput functional analysis with a multiple electrode array (MEA). Biologic plausibility of detected effects can be corroborated using ex vivo or in vivo models, which may also lead to the discovery of new biomarkers or treatments for CVD.