Pesticide action is predominantly measured as a toxicological outcome, with pharmacological impact of sublethal doses on bystander species left largely undocumented. Likewise, chronic exposure, which often results in responses different from acute administration, has also been understudied. In this article, we propose the application of standard pharmacological principles, already used to establish safe clinical dosing regimens in humans, to the \'dosing of the environment\'. These principles include relating the steady state dose of an agent to its beneficial effects (e.g. pest control), while minimising harmful impacts (e.g. off-target bioactivity in beneficial insects). We propose the term \'environmental therapeutic window\', analogous to that used in mammalian pharmacology, to guide risk assessment. To make pharmacological terms practically useful to environmental protection, quantitative data on pesticide action need to be made available in a freely accessible database, which should include toxicological and pharmacological impacts on both target and off-target species.

In this paper, we review the effects of large-scale neonicotinoid contaminations in the aquatic environment on non-target aquatic invertebrate and vertebrate species. These aquatic species are the fauna widely exposed to environmental changes and chemical accumulation in bodies of water. Neonicotinoids are insecticides that target the nicotinic type acetylcholine receptors (nAChRs) in the central nervous systems (CNS) and are considered selective neurotoxins for insects. However, studies on their physiologic impacts and interactions with non-target species are limited. In researches dedicated to exploring physiologic and toxic outcomes of neonicotinoids, studies relating to the effects on vertebrate species represent a minority case compared to invertebrate species. For aquatic species, the known effects of neonicotinoids are described in the level of organismal, behavioral, genetic and physiologic toxicities. Toxicological studies were reported based on the environment of bodies of water, temperature, salinity and several other factors. There exists a knowledge gap on the relationship between toxicity outcomes to regulatory risk valuation. It has been a general observation among studies that neonicotinoid insecticides demonstrate significant toxicity to an extensive variety of invertebrates. Comprehensive analysis of data points to a generalization that field-realistic and laboratory exposures could result in different or non-comparable results in some cases. Aquatic invertebrates perform important roles in balancing a healthy ecosystem, thus rapid screening strategies are necessary to verify physiologic and toxicological impacts. So far, much of the studies describing field tests on non-target species are inadequate and in many cases, obsolete. Considering the current literature, this review addresses important information gaps relating to the impacts of neonicotinoids on the environment and spring forward policies, avoiding adverse biological and ecological effects on a range of non-target aquatic species which might further impair the whole of the aquatic ecological web.

This review specifically examines the development of sample preparation methods for residue analyses of neonicotinoid insecticides in agricultural and environmental matrices. Pesticide residue analysis is fundamentally important to ensure the safety of foods and processed foods of plant and animal origin, and to preserve the environment, particularly soil and water. For the development of pesticide residue analysis, the sample preparation process is an important key to maximizing the analytical performance of highly sensitive and accurate chromatographic instruments and to acquiring reliable analytical results. This review outlines sample preparation methods that have been proposed to date for extraction of neonicotinoids that might remain in a complicated sample matrix in quantitatively trace amounts, and for cleaning up, to the greatest extent possible, the interfering components that coexist in the sample extract.

The EFSA was asked by the European Commission to perform an updated risk assessment of neonicotinoids, including thiamethoxam, as regards the risk to bees, as a follow-up of previous mandates received from the European Commission on neonicotinoids. The context of the evaluation was that required by the European Commission in accordance with Article 21 of Regulation (EC) No 1107/2009 to review the approval of active substances in light of new scientific and technical knowledge and monitoring data. In this context and in accordance with Article 31 of Regulation (EC) No 178/2002, EFSA has been previously asked by European Commission to organise an open call for data in order to collect new scientific information as regards the risk to bees from the neonicotinoid pesticide active substances clothianidin, thiamethoxam and imidacloprid applied as seed treatments and granules in the EU. The conclusions were reached on the basis of the evaluation of the supported uses as an insecticide of thiamethoxam applied as seed treatments and granules, on the new relevant data collected in the framework of the open call organised by EFSA and on the updated literature search performed by EFSA. The reliable endpoints, appropriate for use in regulatory risk assessment derived from the submitted studies and literature data as well as any other relevant data available at national level and made available to EFSA, are presented. Concerns are identified.

The EFSA was asked by the European Commission to perform an updated risk assessment of neonicotinoids, including imidacloprid, as regards the risk to bees, as a follow-up of previous mandates received from the European Commission on neonicotinoids. The context of the evaluation was that required by the European Commission in accordance with Article 21 of Regulation (EC) No 1107/2009 to review the approval of active substances in light of new scientific and technical knowledge and monitoring data. In this context and in accordance with Article 31 of Regulation (EC) No 178/2002, EFSA has been previously asked by the European Commission to organise an open call for data in order to collect new scientific information as regards the risk to bees from the neonicotinoid pesticide active substances clothianidin, thiamethoxam and imidacloprid applied as seed treatments and granules in the EU. The conclusions were reached on the basis of the evaluation of the supported uses as an insecticide of imidacloprid applied as seed treatments and granules, on the new relevant data collected in the framework of the open call organised by EFSA and on the updated literature search performed by EFSA. The reliable endpoints, appropriate for use in regulatory risk assessment derived from the submitted studies and literature data as well as any other relevant data available at national level and made available to EFSA, are presented. Concerns are identified.

EFSA was asked by the European Commission to perform an updated risk assessment of neonicotinoids, including clothianidin, as regards the risk to bees, as a follow up of previous mandates received from the European Commission on neonicotinoids. The context of the evaluation was that required by the European Commission in accordance with Article 21 of Regulation (EC) No 1107/2009 to review the approval of active substances in light of new scientific and technical knowledge and monitoring data. In this context and in accordance with Article 31 of Regulation (EC) No 178/2002, EFSA has been previously asked by European Commission to organise an open call for data in order to collect new scientific information as regards the risk to bees from the neonicotinoid pesticide active substances clothianidin, thiamethoxam and imidacloprid applied as seed treatments and granules in the EU. The conclusions were reached on the basis of the evaluation of the supported uses as an insecticide of clothianidin applied as seed treatments and granules, on the new relevant data collected in the framework of the open call organised by EFSA and on the updated literature search performed by EFSA. The reliable endpoints, appropriate for use in regulatory risk assessment derived from the submitted studies and literature data as well as any other relevant data available at national level and made available to EFSA, are presented. Concerns are identified.

Neonicotinoids are the most widely used insecticide class worldwide, and unfortunately, the widely used neonicotinoid imidacloprid is problematic for pollinators and other nontarget organisms. These nontarget impacts and the development of resistance prompt the ongoing development and testing of new neonicotinoids. The novel neonicotinoid cycloxaprid was described in 2011 and registered in China in 2015. Studies investigating its use and effect on target and nontarget species are recent and ongoing, and empirical evidence has not yet been collectively considered. Therefore, a systematic review was performed to identify and summarize data associated with target and nontarget, lethal and sublethal impacts of cycloxaprid for its use as a new insecticide. We performed keyword literature searches in Web of Science, PubMed, Academic Search Complete, and Google Scholar and explored citations used in identified articles. The search strategy yielded 66 citations; 25 citations fulfilled eligibility criteria and were included in the review. Under experimental conditions, cycloxaprid reduced populations of plant-feeding insect pests, suppressed populations of sucking and biting insect pests, and affected reproduction, development time, longevity, growth, gene regulation and expression, and phloem-feeding behavior of various life stages of certain insects. Studies focus on pest control efficacy and comparison with imidacloprid. Five nontarget organisms have been evaluated: Apis mellifera, Chrysoperla sinica, Harmonia axyridis, Daphnia magna, and Eisenia fetida. Variation in study design, to date, precludes a metaanalysis. However, these results provide valuable insight into possible effects to target and nontarget arthropods. Because cycloxaprid is a new insecticide, additional research is needed to clarify the mechanism of action of cycloxaprid and its metabolites, and to determine if it harms natural enemies or other nontarget organisms, if resistance develops, and if it exhibits cross-resistance with other insecticides. Although research on target arthropods will inform some effects on nontarget organisms, studies focusing explicitly on impacts to nontarget organisms are needed. Integr Environ Assess Manag 2020;16:831-840. © 2020 SETAC.

Due to their systemic character and high efficacy to insect controls, neonicotinoid insecticides (neonics) have been widely used in global agriculture since its introduction in early 1990. Recent studies have indicated that neonics may be ubiquitous, have longer biological half-lives in the environment once applied, and therefore implicitly suggested the increasing probability for human exposure to neonics. Despite of neonics\' persistent characters and widespread uses, scientific literature in regard of pathways in which human exposure could occur is relatively meager. In this review, we summarized results from peer-reviewed articles published prior to 2017 that address potential human exposures through ingestion and inhalation, as well as results from human biomonitoring studies. In addition, we proposed the use of relative potency factor approach in order to facilitate the assessment of concurrent exposure to a mixture of neonics with similar chemical structures and toxicological endpoints. We believe that the scientific information that we presented in this review will aid to future assessment of total neonic exposure and subsequently human health risk characterization.

A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.