Neonicotinoids: insecticides or a threat to public health?

Neonicotinoid insecticides, developed in the 1990s, are widely used in agriculture due to their effectiveness against insect pests (Zhao et al., 2020). Their mechanism disrupts the insect nervous system by mimicking nicotine (Buszewski et al., 2019). When first introduced to the market, they were promoted as safe to handle and for consumers; therefore, they were widely accepted and soon became the best-selling insecticides internationally, displacing older-generation insecticides such as organophosphates, methylcarbamates, and pyrethroids (Tomizawa and Casida, 2005). Neonicotinoids, along with fipronil (another systemic insecticide), constitute one-third of the global insecticide market. These insecticides are systemic, allowing distribution throughout the plant (Simon-Delso et al., 2015), enabling effective pest management strategies (Jeschke and Nauen, 2008). Additionally, they have high mobility in soil, promoting contamination of groundwater and surface water through runoff (Sánchez Bayo and Tennekes, 2020). Importantly, concentrations detected in aquatic and terrestrial environments have been reported within ranges associated with sublethal and lethal effects in sensitive non-target organisms, indicating that their environmental presence is not merely incidental but toxicologically relevant (Pisa et al., 2021;Wood and Goulson, 2017). Along with their systemic properties, neonicotinoids are relatively persistent, offering potential for long-term phytosanitary activity. The half-lives of these compounds under aerobic soil conditions can vary widely. For clothianidin, laboratory-derived estimates range from 148 to 6,931 days, with the upper extreme reflecting controlled conditions of optimal temperature and moisture designed for regulatory This opinion piece is motivated by three concurrent developments that require critical synthesis: the rapid accumulation of epidemiological and mechanistic evidence on human health risks published since 2022 (Zhang and Lu, 2022;Song et al., 2025); the growing regulatory asymmetry between jurisdictions that have restricted key neonicotinoids and those that continue to expand their use (Orikpete et al., 2025;Phan et al., 2023); and the absence of an integrative framework that addresses human toxicity, ecological disruption, and agricultural transition within a One Health perspective. Together, these gaps justify a timely and critical reappraisal of neonicotinoids' role in contemporary agriculture and public health policy. This article critically examines the available evidence on neonicotinoid risks to human health and ecosystems, identifies the limitations of current regulatory frameworks, and discusses pathways toward safer agricultural alternatives, with the aim of informing ongoing scientific and policy debates.Widespread environmental presence means human exposure occurs through ingestion, inhalation, and dermal absorption (Smagghe et al., 2023;Song et al., 2025). Despite initial beliefs of low mammalian toxicity, emerging evidence suggests neurological and metabolic health risks (Shareefdeen and Elkamel, 2024). Neurological effects are particularly concerning. Acute poisonings cause nicotiniclike symptoms, with Japanese studies linking exposure to finger tremors, impaired memory, and headaches (Smagghe et al., 2023). Imidacloprid binds to mammalian nicotinic acetylcholine receptors, causing harmful neuronal responses (Passoni et al., 2021). Of particular mechanistic significance is its main mammalian metabolite, desnitro-imidacloprid, which forms through hepatic nitro-group reduction after oral exposure (Passoni et al., 2021). Unlike the parent compound, whose selectivity for insect-type nAChRs is determined by the electronegativity of its nitroguanidine pharmacophore, desnitro-imidacloprid lacks this structural constraint and binds with much greater potency to mammalian nAChR subtypes, including the α4β2 and α7 receptors that are central to cognitive function, attention, and memory consolidation in the human brain (Loser et al., 2021a;Loser et al., 2021b). This metabolic activation represents a qualitative shift in toxicological profile: the compound to which mammalian tissues are effectively exposed is pharmacologically distinct from, and more dangerous to humans than, the compound subject to regulatory evaluation. This distinction has critical implications for pre-market risk assessment, which currently evaluates parent compounds in isolation and does not require systematic toxicological characterization of major human metabolites. As a result, regulatory acceptable daily intakes and safety thresholds established for imidacloprid may significantly underestimate the actual neurotoxic risk associated with dietary and environmental exposure in humans (Loser et al., 2021a;Smagghe et al., 2023).Metabolic concerns also exist. Cross-sectional studies have reported associations between neonicotinoid exposure and increased fasting glucose and obesity, particularly in females, although the observational design of these studies precludes causal inference (Zhang et al., 2024). Vulnerable populations face greater risks. Epidemiological studies have reported associations between maternal neonicotinoid exposure and adverse birth outcomes, including elevated congenital heart disease incidence, though causal relationships remain to be established through prospective designs (Song et al., 2025) and potential neurodevelopmental disruption in children (Song et al., 2025). In rodent gavage models, behavioral changes in offspring exposed to imidacloprid during fetal and early postnatal periods are similar to those observed after nicotine exposure, suggesting shared developmental neurotoxicity mechanisms through nAChR pathways (Burke et al., 2018). However, these findings should be interpreted with caution in the human context, as gavage administration differs from dietary exposure routes, rodent cytochrome P450 metabolism of imidacloprid occurs at rates not directly comparable to humans, and neurodevelopmental timelines between species are not equivalent. Direct human epidemiological evidence for these specific neurodevelopmental endpoints remains limited. These findings demand continued research, particularly longitudinal epidemiological studies on vulnerable populations, enhanced toxicological surveillance, and human biomonitoring to assess health outcomes and inform evidence-based policies (Song et al., 2025).Neonicotinoids, including imidacloprid, are increasingly recognized for neurotoxic effects extending beyond insects to mammals, with concerns focusing on neurodevelopmental disorders, learning, and memory impairments (Han et al., 2018;Costas-Ferreira and Faro, 2021).Rodent studies demonstrate that low-dose chronic imidacloprid exposure causes significant neurological impairments, including memory deficits and altered immune responses (Hernandez et al., 2018). Mammalian susceptibility following early developmental exposure leads to altered behavioral and biochemical profiles in adulthood (Burke et al., 2018). Maternal imidacloprid exposure produces behavioral alterations resembling nicotine exposure effects, indicating common developmental neurotoxicity mechanisms (Burke et al., 2018). Epidemiological research has reported associations between neonicotinoid exposure and cognitive decline in adults, findings that require confirmation through longitudinal study designs before causal conclusions can be drawn (Sass and Raichel, 2024).Children are considered particularly vulnerable populations, with some studies detecting neonicotinoid metabolites in the urine of most children (Song et al., 2025). At the neurological level, experimental evidence indicates that imidacloprid can dysregulate neurogenesis and impair cognitive function in animal models, and has been associated with molecular alterations that overlap with pathological features observed in Alzheimer's disease, including disrupted cholinergic signaling and impaired synaptic plasticity (Rossetti et al., 2020). However, it must be emphasized that these findings come from experimental models using defined doses and exposure durations that may not reflect human environmental exposure, and that Alzheimer's disease is a complex, multifactorial condition involving genetic, vascular, metabolic, and environmental determinants. The available evidence does not establish neonicotinoid exposure as a causative or sufficient factor in its development. These observations are best interpreted as preliminary mechanistic evidence warranting further investigation, not as a demonstrated link between neonicotinoid exposure and clinical Alzheimer's disease. Its presence has been detected in cerebrospinal fluid (Laubscher et al., 2022), along with a decrease in brain antioxidant enzymes (Terayama et al., 2016), alteration of cell signaling, impairment of sensorimotor performance, and disruption of brain development in early stages (Kimura-Kuroda et al., 2012).Neurotoxic effects are attributed to several interconnected mechanisms. Neonicotinoids act as agonists at nicotinic acetylcholine receptors (nAChRs), disrupting normal cholinergic signaling pathways vital for cognitive functions (Costas-Ferreira and Faro, 2021). Chronic exposure induces oxidative damage, leading to cellular damage and neuronal death (Costas-Ferreira and Faro, 2021;Chung et al., 2023). Additionally, imidacloprid induces neuroinflammation involving glial cell activation, compromising the blood-brain barrier and contributing to neurological dysfunction (Chung et al., 2023;Imam et al., 2025). These mechanisms often act in concert, with nAChR activation leading to oxidative stress and neuroinflammation, ultimately resulting in neuronal apoptosis and impaired plasticity (Costas-Ferreira and Faro, 2021;Narasimhamurthy et al., 2024).Beyond their recognized neurotoxic effects, neonicotinoid insecticides are increasingly implicated in metabolic and endocrine disruptions, raising significant public health concerns. Research suggests a potential link between exposure to these ubiquitous pesticides and conditions such as obesity, insulin resistance, and thyroid dysfunction, pointing to their role as endocrine-disrupting chemicals (EDC). A growing body of evidence connects neonicotinoid exposure to metabolic disturbances. Experimental studies have shown that neonicotinoids, including imidacloprid, can promote lipid accumulation and contribute to weight gain in animal and in vitro models, though extrapolating these findings to human metabolic outcomes requires caution (Mesnage et al., 2018;Mikolić and Karačonji, 2018). In crosssectional human studies conducted in South China, neonicotinoids and their metabolites were frequently detected in blood samples, with positive associations observed between these chemicals and high fasting blood glucose and obesity in both normal-weight and obese populations (Zhang et al., 2024). As these are cross-sectional data, they indicate a statistical association but cannot establish temporality or rule out residual confounding; longitudinal studies are needed to assess the direction and independence of this relationship. Experimental models further support these findings, demonstrating that imidacloprid can potentiate high-fat diet-induced adiposity and insulin resistance in male mice, affecting genes regulating lipid and glucose metabolism (Sun et al., 2016).Neonicotinoids also appear to interfere with thyroid hormone regulation. In vitro evidence indicates that certain neonicotinoids interact with thyroid hormone receptors (Leemans et al., 2019). Animal studies have provided in vivo support; for example, thiamethoxam exposure has been shown to increase T3 and T4 levels in lizards, while a mixture of thiacloprid and deltamethrin increased T3 and T4 levels in rats' serum. In addition, animals exposed to imidacloprid reported decreased plasma levels of thyroid hormones (T4 and TSH) (Diba-Lahmidi et al., 2024). The observed metabolic and thyroid-related disturbances align with the classification of neonicotinoids as potential endocrinedisrupting chemicals. Several neonicotinoids, including imidacloprid, clothianidin, and thiamethoxam, have exhibited EDC-like behavior in various studies (Baines et al., 2017). Laboratory investigations have specifically revealed that imidacloprid can act as an endocrine disruptor by interfering with metabolic homeostasis and steroidogenesis (Mikolić and Karačonji, 2018). The widespread use and environmental persistence of neonicotinoids underscores their potential threat to public health through metabolic and endocrine disruption. Endocrinologically, thyroid lesions with alterations in luteinizing hormone, follicle-stimulating hormone, and progesterone (Xu et al., 2021) have been documented in association with exposure to imidacloprid.Research primarily in animal models indicates that neonicotinoids, including imidacloprid, thiacloprid, and acetamiprid, can adversely affect the reproductive system. These effects manifest as impaired testicular development, damage to spermatogenesis, reduced sperm quality, and altered ovarian morphology (Gu et al., 2013). For instance, exposure to thiacloprid during gestation has been linked to significant spermatogenic defects in offspring, including increased testis-to-body weight ratios and meiotic errors (Dali et al., 2024). More broadly, these insecticides often act as endocrine disruptors, interfering with the crucial synthesis, secretion, transport, and action of hormones essential for reproduction and development (El-Din et al., 2023). Neonicotinoids have been shown to increase aromatase expression, an enzyme implicated in breast cancer and developmental processes (Nicolopoulou-Stamati et al., 2016).Immunological systems are also vulnerable. Studies in mammals demonstrate that imidacloprid can induce immunotoxic effects, altering immune cell populations and function. In male albino rats, oral administration of imidacloprid led to an increase in total leukocyte counts and immunoglobulins but simultaneously decreased phagocytic activity and cellular movement. Histological examinations revealed lymphocytic depletion in the spleen and thymus (Mohany, 2011). Similarly, in female BALB/c mice, imidacloprid exposure caused immunotoxic effects over a 28-day period (Badgujar et al., 2013). The underlying mechanism involves the interaction of neonicotinoids with nAChRs present on immune cells, which play a role in regulating T cell and responses and 2024). cellular effects, thiacloprid has been shown to impair antioxidant and increase of oxidative stress in immune of et al., 2024). The immune system is also with significant in observed et al., of reproductive and come from animal studies models such as rats, mice, and However, human remain (Zhang et al., 2024). Despite human exposure is of the three and neonicotinoid levels (Dali et al., 2024). Neonicotinoids and their metabolites have been frequently detected in human blood samples, with concentrations observed in (Zhang et al., particularly is the potential for effects, health to exposure through evidence from a animal study suggests that thiacloprid may induce effects through exposure, specifically alterations in sperm in (Dali et al., 2024). These findings should be interpreted with as they are on a rodent and the of in mammals remains can the major during and early the to which such effects are and the to which rodent mechanisms are to human and mechanistic are before these observations can be considered evidence of a in and exposure to in the immune system and of both exposed and their offspring et al., 2023). pesticides have demonstrated effects in directly exposed and but significant adverse outcomes in and affecting conditions such as disease, obesity, and disease et al., widespread use of neonicotinoid insecticides has significant concerns within the framework due to their and effects on non-target organisms, and human These systemic pesticides beyond their leading to environmental contamination with implications for and the health of a threat to global particularly terrestrial and aquatic as as et al., 2025). such as and are the most with studies neonicotinoid use with their et al., 2021). These insecticides and affecting a of species et al., 2025). significant effects from neonicotinoid primarily through the reduction of their insect et al., has demonstrated that in are linked to neonicotinoid et al., 2025). neonicotinoids also affect and of pest et al., the the study of neonicotinoids and their on aquatic is an emerging the presence of these insecticides in of water such as and This is due to the use of neonicotinoids in which are to water by For example, an decrease in reported in causing the to from to in et al., systemic of neonicotinoids their throughout ecosystems, through their within et al., 2025). in aquatic may be neonicotinoids can in the tissues of various and be through terrestrial levels and et al., ecological caused by neonicotinoids have and critical implications for and on insect and the widespread use of these insecticides directly these vital and agriculture development et al., 2024). The and chronic on global are major effects on crucial such as which are to and development et al., the by neonicotinoids an such as the et al., 2023). This the of and environmental Neonicotinoids demonstrate their effects and populations, agricultural through reduced and soil and to widespread contamination of et al., and of neonicotinoid insecticides present a by the limitations of toxicological the of chronic and low-dose effects, the of and exposure, and significant in regulatory global These the for a more and framework to public and environmental such as imidacloprid, clothianidin, thiamethoxam, acetamiprid, and insect nicotinic receptors, leading to neuronal activation, and death et al., 2024). regulatory to neonicotinoids significantly from to and frameworks, reflecting of the available evidence on their risks et al., 2025). In remains with continued widespread use et al., et al., toxicological often designed toxicity, have for the long-term of These on lethal doses or observed concentrations over exposure such as or et al., et al., 2021). This the actual risks by neonicotinoids, which can and effects at low doses and over durations (Pisa et al., chemicals are in to for the effects of a common in environmental exposure (Smagghe et al., 2023). early chronic studies often used doses or species that were not of the of sensitive or leading to an of risk (Baines et al., 2017). The the of systemic have in conclusions their ecological safety et al., significant of risk is the systematic of chronic effects and the potency of low-dose neonicotinoid Research that neonicotinoids can have and effects, that levels of can to significant exposure is et al., 2023). For example, studies in sensitive species have that the lethal of imidacloprid under chronic exposure can be to greater under exposure reflecting its of action at nicotinic acetylcholine receptors (Pisa et al., and Tennekes, 2020). not to human risk assessment, this is toxicologically significant considered human biomonitoring Imidacloprid and its metabolites have been detected in the urine of at concentrations from to with levels reported in agricultural and children (Zhang and Lu, 2022;Song et al., current regulatory acceptable daily intakes for imidacloprid are at body in major the suggests that safety thresholds from studies may not against the neurological and metabolic effects associated with chronic low-dose exposure at concentrations detected in human is often as exposed may not but or after of exposure (Pisa et al., 2021). The relationships and effects of neonicotinoids further risk assessment, as they can significant at concentrations considered safe (Pisa et al., non-target species face a in isolation but of neonicotinoids and along with various environmental and Goulson, 2017). neonicotinoids to the a risk are conducted for et al., This can in or the of pesticides or the of their Studies have documented in some effects in neonicotinoids at relevant although the distinction between and on the specific and and requires further characterization a range of et al., et al., vary significantly the The has a more leading to more including on the use of several key neonicotinoids imidacloprid, clothianidin, and thiamethoxam et al., et al., 2025). In such as of demonstrate significant regulatory gaps and more In changes have the of pesticides that are restricted in and these changes have been associated with of increased et al., 2021). evidence for a causal link between the changes and increased human or ecological exposure outcomes remains this regulatory the of global in the absence of et al., et al., 2025). regulatory are toward greater the is of several neonicotinoids, including imidacloprid, clothianidin, thiamethoxam, and acetamiprid, under its ongoing which of and human health risk The outcomes of these to in risk and potential use a significant development in the regulatory that affect of the agricultural evidence in this article an to on neonicotinoid insecticides and the transition to pest management that are harmful to human health and Several are including such as and and from and disruption and pest management that use as a et al., et al., and 2024). However, the shift to these including a absence of the of system to and in regulatory and to the by of systemic insecticide use and et al., et al., 2024). this transition require action regulatory frameworks, agricultural research support and with to and in and pest management article out to the of neonicotinoids their continued widespread use in of the evidence on their risks to human health and on the evidence critically in the the is that it does This does not that to humans is beyond but that the current evidence as a is sufficient to justify a regulatory that has not been in most in this article identifies specific findings that support this and beyond the established in the the mammalian of imidacloprid, desnitro-imidacloprid, greater potency at mammalian nicotinic acetylcholine receptors the parent compound, regulatory safety thresholds are for the parent This of risk represents a structural in current pre-market cross-sectional and experimental evidence neonicotinoid exposure to metabolic, and effects though the these Neurological associations in humans are the most by both mechanistic and epidemiological though these are In human epidemiological evidence for and effects remains with most findings from animal models whose to humans is by and in this The policy in this article should be as reflecting a are most in the neurological and metabolic mechanistic and epidemiological the though for regulatory are reproductive and effects, animal evidence is but human are are most effects, which currently on a rodent study in a as in of this in the regulatory the potential and of the current of the and is on and mechanistic in toxicological underestimate risk by chronic compounds and developmental The that chronic in sensitive can by of at concentrations detected in environmental the regulatory between jurisdictions that have restricted key neonicotinoids and those that have the absence of safety characterization of mixture effects, and the of major regulatory such as the the absence of an evidence-based the ecological documented in this including aquatic and are not merely concerns but of human and health that are by risk on human exposure findings indicate that the in this cannot be by the available evidence the are sufficient to justify but to establish most This is a regulatory In the absence of longitudinal epidemiological risk mixture data, and human biomonitoring to current the the The that regulatory pre-market to major human mixture effects, and chronic low-dose that biomonitoring be established to neonicotinoid and concentrations in vulnerable and that regulatory be to the continued use of compounds in jurisdictions with those that have restricted on that support not for this its the for the support through the of in that not used in the of this in this article are those of the and not those of their or those of the the and the that may be in this or that may be by its is not or by the