Bee Toxicity Research Articles

Leveraging In Silico Structure-Activity Models to Predict Acute Honey Bee (Apis mellifera) Toxicity for Agrochemicals.

In the realm of crop protection products, ensuring the safety of pollinators stands as a pivotal aspect of advancing sustainable solutions. Extensive research has been dedicated to this crucial topic as well as new approach methodologies in toxicity testing. Hence, within the agricultural and chemical industries, prioritizing pollinator safety remains a constant objective during the development of predictive tools. One of these tools includes computational models like quantitative structure-activity relationships (QSARs) that are valuable in predicting the toxicity of chemicals. This research uses bee toxicity data to develop artificial neural network classification models for predicting honey bee acute toxicity. Bee toxicity data from 1542 compounds were used to develop models; the sensitivity and specificity of the best model were 0.90 and 0.91, respectively. These in silico models can aid in the discovery of next-generation crop protection products. These tools can guide the screening and selection of next-generation crop protection molecules with high margins of safety to pollinators, and candidates with favorable sustainability profiles can be identified at the early discovery stage as precursors to in vivo data generation.

Effects of the insecticide acetamiprid and the fungicide azoxystrobin on locomotion activity and mushroom bodies of solitary bee Centris analis

Pesticide use is a major factor contributing to the global decline in bee populations. Sublethal effects, such as behavior alterations, are neglected in pesticide regulation for pollinators. However, these effects can bring important information to understanding the impacts of pesticides on bees' daily activities. In this study, we aimed to investigate the effects of the insecticide acetamiprid (7 ng/μL) and the fungicide azoxystrobin (10 ng/μL) on the behavior of the Neotropical solitary bee Centris analis. Female and male bees were exposed to these chemicals continuously for 48 h, followed by an additional 48 h without contaminated food, totaling 96 h of observation. We used five experimental groups: control, solvent control, insecticide, fungicide, and pesticide mixture (insecticide + fungicide). Behavioral alterations based on locomotion and light response were assessed by video tracking at 48 (end of pesticide exposure) and 96 h (end of bioassay). In addition, after recording bees at 96 h, the individuals were anesthetized for brain collection and histological evaluation of mushroom bodies to evaluate if pesticides can damage their neurons and impair the cognitive processes and responses of bees to sensory stimuli. Bees exposed to acetamiprid and pesticide mixture showed lethargic movements and impaired locomotion at 48 h. Notably, these behavioral effects were no longer evident after the bees consumed uncontaminated food for an additional 48 h, totaling 96 h from the start of pesticide exposure. Only fungicide exposure did not result in any behavioral or brain histological changes. Therefore, our study showed that acetamiprid at an estimated residual concentration, despite being classified as having low toxicity for bees, can cause significant initial locomotion disruption in solitary bees. These findings highlight the importance of considering sublethal effects in environmental risk assessment.

Design, synthesis, and evaluation of novel isoxazoline derivatives containing 2-phenyloxazoline moieties as potential insecticides

Isoxazoline insecticides have shown broad-spectrum insecticidal activity against a variety of insect pests. However, the high toxicity of isoxazoline compounds towards honeybees restricts their application in crop protection. To mitigate this issue, a series of isoxazoline derivatives containing 2-phenyloxazoline were designed and synthesized. Bioassays revealed that several compounds exhibited promising insecticidal activities against Plutella xylostella, with G28 showing particularly excellent insecticidal activity, reflected by an LC50 value of 0.675 mg/L, which is comparable to that of fluxametamide (LC50 = 0.593 mg/L). Furthermore, G28 also exhibited effective insecticidal activity against Solenopsis invicta. Importantly, bee toxicity experiments indicated that G28 had significantly lower acute oral toxicity (LD50 = 2.866 μg/adult) compared to fluxametamide (LD50 = 1.083 μg/adult) and fluralaner (LD50 = 0.022 μg/adult), positioning it as a promising candidate with reduced toxicity to bees. Theoretical simulation further elucidated the reasons for the selective differences in the ability of isoxazoline to achieve higher insecticidal activity while maintaining lower bee toxicity. This research suggests that isoxazoline compounds containing 2-phenyloxazoline group hold potential as new insecticide candidates and offers insights into the development of novel isoxazoline insecticides with both high efficacy and environmental safety.

Advancing ecotoxicity assessment: Leveraging pre-trained model for bee toxicity and compound degradability prediction

The prediction of ecological toxicity plays an increasingly important role in modern society. However, the existing models often suffer from poor performance and limited predictive capabilities. In this study, we propose a novel approach for ecological toxicity assessment based on pre-trained models. By leveraging pre-training techniques and graph neural network models, we establish a highperformance predictive model. Furthermore, we incorporate a variational autoencoder to optimize the model, enabling simultaneous discrimination of toxicity to bees and molecular degradability. Additionally, despite the low similarity between the endogenous hormones in bees and the compounds in our dataset, our model confidently predicts that these hormones are non-toxic to bees, which further strengthens the credibility and accuracy of our model. We also discovered the negative correlation between the degradation and bee toxicity of compounds. In summary, this study presents an ecological toxicity assessment model with outstanding performance. The proposed model accurately predicts the toxicity of chemicals to bees and their degradability capabilities, offering valuable technical support to relevant fields.

Rational Design of Triazinone Derivatives with Low Bee Toxicity Based on the Binding Mechanism of Neonicotinoids to Apis mellifera.

Bees, one of the most vital pollinators in the ecosystem and agriculture, are currently threatened by neonicotinoids. To explore the molecular mechanisms of neonicotinoid toxicity to bees, the different binding modes of imidacloprid, thiacloprid, and flupyradifurone with nicotinic acetylcholine receptor (nAChR) α1β1 and cytochrome P450 9Q3 (CYP9Q3) were studied using homology modeling and molecular dynamics simulations. These mechanisms provided a basis for the design of compounds with a potential low bee toxicity. Consequently, we designed and synthesized a series of triazinone derivatives and assessed their bioassays. Among them, compound 5a not only displayed substantially insecticidal activities against Aphis glycines (LC50 = 4.40 mg/L) and Myzus persicae (LC50 = 6.44 mg/L) but also had low toxicity to Apis mellifera. Two-electrode voltage clamp recordings further confirmed that compound 5a interacted with the M. persicae nAChR α1 subunit but not with the A. mellifera nAChR α1 subunit. This work provides a paradigm for applying molecular toxic mechanisms to the design of compounds with low bee toxicity, thereby aiding the future rational design of eco-friendly nicotinic insecticides.

Computational Modeling Oriented Substructure Splicing Application in the Identification of Thiazolidine Derivatives as Potential Low Honeybee Toxic Neonicotinoids.

With the aim of identifying novel neonicotinoid insecticides with low bee toxicity, a series of compounds bearing thiazolidine moiety, which has been shown to be low bee toxic, were rationally designed through substructure splicing strategy and evaluated insecticidal activities. The optimal compounds A24 and A29 exhibited LC50 values of 30.01 and 17.08 mg/L against Aphis craccivora, respectively. Electrophysiological studies performed on Xenopus oocytes indicated that compound A29 acted on insect nAChR, with EC50 value of 50.11 μM. Docking binding mode analysis demonstrated that A29 bound to Lymnaea stagnalis acetylcholine binding protein through H-bonds with the residues of D_Arg55, D_Leu102, and D_Val114. Quantum mechanics calculation showed that A29 had a higher highest occupied molecular orbit (HOMO) energy and lower vertical ionization potential (IP) value compared to the high bee toxic imidacloprid, showing potentially low bee toxicity. Bee toxicity predictive model also indicated that A29 was nontoxic to honeybees. Our present work identified an innovative insecticidal scaffold and might facilitate the further exploration of low bee toxic neonicotinoid insecticides.

Discovery of piperonyl-tethered sulfoximines as novel low bee-toxicity aphicides targeting Amelα1/ratβ2 complex

Nicotinic acetylcholine receptor (nAChR) is recognized as a significant insecticide target for neonicotinoids and some agonists. In this study, the nAChR α1 subunit from Apis mellifera was first found to be narrowly tuned to different bee toxicity insecticides, namely, sulfoxaflor (SFX) and flupyradifurone (FPF). Hence, novel sulfoximine derivatives 7a-h were rationally designed and synthesized by introducing a benzo[d][1,3]dioxole moiety into a unique sulfoximine skeleton based on the binding cavity characteristics of Amelα1/ratβ2. The two electrode voltage clamp responses of 7a-h were obviously lower than that of SFX, indicating their potentially low bee toxicity. Besides, representative compounds 7b and 7g exhibited low bee toxicity (LD50 > 11.0 μg/bee at 48 h) revealed by acute contact toxicity bioassays. Molecular modelling results indicated that Ile152, Ala151, and Val160 from honeybee subunit Amelα1 and Lys144 and Trp80 from aphid subunit Mpα1 may be crucial for bee toxicity and aphicidal activity, respectively. These results clarify the toxic mechanism of agonist insecticides on nontargeted pollinators and reveal novel scaffold sulfoximine aphicidal candidates with low bee toxicity. These results will provide a new perspective on the rational design and highly effective development of novel eco-friendly insecticides based on the structure of the nAChR subunit.

Stress Response in the Honeybee (Apis mellifera L.) Gut Induced by Chlorinated Paraffins at Residue Levels Found in Bee Products.

Chlorinated paraffins (CPs) have become global pollutants and are of considerable concern as a result of their persistence and long-distance transmission in the environment and toxicity to mammals. However, their risks to pollinating insects are unknown. Honeybees are classical pollinators and sensitive indicators of environmental pollution. Herein, the effects of CPs on the gut microenvironment and underlying mechanisms were evaluated and explored using Apis mellifera L. Both short- and medium-chain CPs had significant sublethal effects on honeybees at a residue dose of 10 mg/L detected in bee products but did not significantly alter the composition or diversity of the gut microbiota. However, this concentration did induce significant immune, detoxification, and antioxidation responses and metabolic imbalances in the midgut. The mechanisms of CP toxicity in bees are complicated by the complex composition of these chemicals, but this study indicated that CPs could substantially affect intestinal physiology and metabolic homeostasis. Therefore, CPs in the environment could have long-lasting impacts on bee health. Future studies are encouraged to identify novel bioindicators of CP exposure to detect early contamination and uncover the detailed mechanisms underlying the adverse effects of CPs on living organisms, especially pollinating insects.

Effect of entomopathogenic fungus-formulated bioinsecticides on stingless bees (Hymenoptera: Apidae: Meliponini) in the laboratory

Stingless bees are of environmental and economic importance because they pollinate plants of agricultural and native interest. During foraging, bees can come into contact with synthetic insecticides, resulting in lethal and sublethal effects. Biological control using entomopathogenic fungi (EF) is an alternative to the use of synthetic insecticides. However, despite promising results in pest control, gaps in the activity of EF on nontarget organisms, such as stingless bees, have not been completely recognized. Thus, this work aimed to evaluate the effects of three bioinsecticides formulated from Beauveria bassiana (Boveril®WP), Metarhizium anisopliae (Metarril®WP), and Cordyceps fumosorosea (Octane®SC) on Melipona quadrifasciata, Plebeia droryana, and Scaptotrigona bipunctata (Hymenoptera: Apidae). Direct contact with the concentration of 107 conidia.mL−1 indicated a differentiated tolerance between bee species, as well as significant differences in mortality caused by these bioinsecticides. Melipona quadrifasciata showed the lowest tolerance to bioinsecticides, while S. bipunctata had the lowest mortality. According to the classification proposed by the International Organization for Biological Control, the Boveril®WP and Metarril®WP bioinsecticides were characterized as harmless to moderately harmful. Octane®SC caused mortality between 74.7 and 95% and was thus characterized as harmful to all three studied species. Although these bioinsecticides are selective for nontarget organisms, it is evident that the toxicity for stingless bees is dependent on the EF species used. Thus, its use must be carried out according to criteria that minimize damage to bees, effectively resulting in the development of sustainable agriculture.

Genetically engineered varieties and applied pesticide toxicity in U.S. maize and soybeans: Heterogeneous and evolving impacts

The extensive adoption of genetically engineered (GE) varieties in U.S. agriculture has dramatically changed the patterns of pesticide use. How this process ultimately affects environmental risk remains an open question. Previous studies have typically relied on aggregate trends to infer the impact of GE crop adoption on pesticide use, which fails to address selection bias and unobserved heterogeneity. We overcome this limitation by analyzing applied pesticide toxicity using farm-level fixed effects models, estimated with rich plot-level data on >200,000 seed and pesticide choices by U.S. maize and soybean farmers during the 1998–2016 period. We find that applied toxicity was, on average, lowered by the adoption of GE varieties across four target organism groups: mammals, birds, fish, and honey bees. However, most of the toxicity benefits conferred by GE adoption dissipated over time. For herbicide tolerant varieties, this was due to the increased use of old-line herbicides by GE adopters, a likely consequence of the growing problem of glyphosate weed resistance. Applied honey bee toxicity saw the sharpest increase during the GE era, but most of this increase was driven by the adoption of neonicotinoid seed treatments, rather than GE insect resistant traits.

Liquid-assisted mechanochemical synthesis, crystallographic, theoretical and molecular docking study on HIV instasome of novel copper complexes: (µ-acetato)-bis(2,2'-bipyridine)-copper and bromidotetrakis(2-methyl-1H-imidazole)-copper bromide.

In the present work the two new Cu(II) complexes, (µ-acetato)-bis(2,2'-bipyridine)-copper [Cu(bpy)2(CH3CO2)] and bromidotetrakis(2-methyl-1H-imidazole)-copper bromide [Cu(2-methylimid)4Br]Br have been synthesized by liquid assisted mechanochemical method. The [Cu(bpy)2(CH3CO2)] complex (1) and [Cu(2-methylimid)4Br]Br complex (2) characterised by IR and UV-visible spectroscopy and the structure are confirmed by XRD diffraction studies. Complex (1) crystallized in the Monoclinic with the space group of C2/c where a = 24.312(5)Å, b = 8.5892(18)Å, c = 14.559(3)Å, α = 90°, β = 106.177(7)° and γ = 90° and Complex (2) crystallized in the Tetragonal with the space group of P4nc, a = 9.9259(2)Å, b = 9.9259(2)Å, c = 10.9357(2)Å, α = 90°, β = 90° and γ = 90°. The complex (1) has distorted octahedral geometry where the acetate ligand showed bidentate bridging with the central metal ion and complex (2) has slightly deformed square pyramidal geometry. The HOMO-LUMO energy gap value and the low chemical potential showed that the complex (2) is stable and difficult to polarize compare to complex (1). The molecular docking study of complexes with the HIV instasome nucleoprotein showed the binding energy values -7.1 and -5.3kcal/mol for complex (1) and complex (2) respectively. The negative binding energy values showed the complexes have affinity to bind with HIV instasome nucleoproteins. The in-silico pharmacokinetic study of the complex (1) and complex (2) showed non AMES toxicity, non-carcinogens and low honey Bee toxicity but weakly inhibit Human Ether-a-go-go-related gene.

Design and structure optimization of novel butenolide derivatives as low bee-toxicity candidates

The discovery of new neonicotinoid alternatives with high efficiency against pests and eco-safety toward bees has become an increasingly urgent need in recent years. The relationship between the oil-water partition coefficient (logP) and the bee-toxicity of commercial nicotinic acetylcholine receptor (nAChR) competitive modulators was explored in this work. Compared compounds with a high bee-toxicity, compounds with low bee-toxicity were found to have higher logP values. Therefore, two series of novel butenolide derivatives with different hydrophobic groups were designed and synthesized by including different hydrophobic groups. The insecticidal activity study showed that compounds I-01 (LC50=112.96 μg/mL), II-05 (LC50=124.68 μg/mL), and II-11 (LC50=87.89 μg/mL) were with higher insecticidal activity against Aphis glycines and lower calculated logP values among all synthesized compounds. Molecular dynamics simulations indicated that three butenolide compounds formed some hydrogen bonding or π-π stacking interactions with insect acetylcholine binding protein (AChBP). In addition, the bee-toxicity bioassay also showed that compounds I-01, II-05 and II-11 were with much lower contact bee-toxicity than imidacloprid. The possible mechanism of the bee toxicity of the novel butenolide compounds was explored based on the nAChR function subunit AmeIα8/ratβ2. This study will provide rational guidance on novel butenolide compounds as low-bee-toxicity candidates based on their molecular hydrophobic properties.

Preliminary Evidence That Fiji Water Has Protective Effects against Aluminum Toxicity in Honey Bees (Apis mellifera).

Researchers have determined that bioavailable aluminum chloride (AlCl3) may affect honey bee behavior (e.g., foraging patterns and locomotion) and physiology (e.g., abdominal spasms). The purpose of these experiments was to determine if Fiji water reduces the impacts of AlCl3 toxicity in bees by measuring circadian rhythmicity (number of times bees crossed the centerline during the day and night), average daily activity (average number of times bees crossed the centerline per day), and mortality rates (average number of days survived) using an automated monitor apparatus. Overall, the AlCl3 before and after Fiji groups had significantly higher average daily activity and rhythmicity rates compared to their respective AlCl3 before and after deionized water (DI) groups. One of the AlCl3 before DI groups exhibited no difference in rhythmicity rates compared to its respective AlCl3 after Fiji group. Overall, these results suggest that Fiji water might exert protective effects against AlCl3. The AlCl3 groups paired with Fiji water had higher activity and rhythmicity levels compared to the AlCl3 groups paired with DI. It is important for researchers to continue to study aluminum and possible preventatives for aluminum uptake.

The fungicide azoxystrobin causes histopathological and cytotoxic changes in the midgut of the honey bee Apis mellifera (Hymenoptera: Apidae).

Apis mellifera is an important bee pollinating native and crop plants but its recent population decline has been linked to the use of pesticides, including fungicides that have been commonly classified as safe for bees. However, many pesticides, in addition to direct mortality cause sublethal effects, including damage to target selective honey bee organs. The midgut is the organ responsible for the digestion and absorption of nutrients and the detoxification of ingested substances, such as pesticides. This study evaluated the histopathological and cytotoxic changes in the midgut of A. mellifera workers caused by the pesticide azoxystrobin. The limit-test was performed, and a 100 µg a.i./bee dose was administered orally and midgut analyzed with light and transmission electron microscopies after 24 h and 48 h of pesticide exposure. The midgut of the control bees has a single layer of digestive cells, with spherical nuclei, nests of regenerative cells, and the lumen coated with the peritrophic matrix. The bees fed on azoxystrobin showed morphological changes, including intense cytoplasm vacuolization and cell fragments released into the gut lumen. The protein detection test showed greater staining intensity in the nests of regenerative cells after 24 h of exposure to azoxystrobin. The occurrence of damage to the midgut in A. mellifera exposed to azoxystrobin indicates that although this fungicide has been classified as low toxicity for bees, it has sublethal effects in the midgut, and effects in other organs should be investigated.

Design, synthesis, and biological activity of novel spiro-pyrazolo[1,5-a]quinazolines derivatives as potential insecticides.

Arylpyrazole insecticides display broad-spectrum insecticidal activity against insect pests. However, the high toxicity toward honeybees associated with fipronil prohibits its agronomic utility. To explore reducing the toxicity of aryl pyrazole analogs to bees, a series of new spiro-pyrazolo[1,5-a]quinazoline derivatives were designed and synthesized. Bioassay results showed that these compounds exhibited good insecticidal activity. In particular, the insecticidal activity of compound 5f against Plutella xylostella larvae (median lethal contentration, LC50 =1.43 mg L-1 ) was equivalent to that of fipronil. Moreover, some compounds also showed good insecticidal activity against Solenopsis invicta. Importantly, the bee toxicity study confirmed that compound 5f had much lower acute oral toxicity, with a median lethal dose (LD50 ) = 1.15 μg bee-1 that was three to four orders of magnitude greater than that of fipronil (0.0012 μg bee-1 ). Electrophysiological studies were conducted using honeybee γ-aminobutyric acid receptor heterologously expressed in Xenopus oocytes to explain the reduced bee toxicity of compound 5f. The inhibitory effect of compound 5f (16.29 μmol L-1 ) was determined to be approximately 700-fold lower than that of fipronil (0.023 μmol L-1 ). These spiro-pyrazolo[1,5-a]quinazoline derivatives could be potential candidates and lead structures for the discovery of novel insecticides with low bee toxicity. © 2022 Society of Chemical Industry.

Does IPPM bear fruit? Evaluating reduced‐risk insecticide programmes on pests, pollinators and marketable yield

Abstract Integrated pest and pollinator management (IPPM) has been touted as a novel approach to control pests while mitigating negative effects of insecticides on pollinators. In addition to non‐chemical approaches, IPPM programmes focus on insecticide treatments with low bee toxicity, threshold‐based applications and restricted timings to avoid sprays during pollinator foraging. However, the singular and combined effect of this approach on pollination services and pest management is understudied and generally lacks field validation. In two field studies, we evaluated the effect of IPPM insecticide programmes on striped cucumber beetle (Acalymma vittatum) management, pollination and watermelon yield. The first trial (2020) featured insecticide treatments representing a factorial combination of (1) products varying in bee toxicity (bifenthrin, cyclaniliprole and acetamiprid), (2) application frequencies (weekly vs. threshold‐based) and (3) application timings (AM vs. PM), as well as an untreated control. These data were then used to inform a second trial (2021) that applied two insecticide treatments (IPPM based or grower standard) to commercial‐scale (20–30 acres) fields in collaboration with regional watermelon farms. Weekly beetle densities, pollinator visitation and yield data were collected to determine programme efficacy. Overall, beetle infestations were successfully managed with all insecticide treatments, none of which compromised marketable yield. In 2020, threshold‐based insecticide programmes offered statistically similar levels of pest control but required 20%–80% fewer applications compared to a weekly programme. Furthermore, pollinator visitation was increased in threshold‐based programmes by ~42% across all products. The on‐farm validation trial in 2021 upheld these findings; IPPM fields had effective beetle control but with 1–7 fewer insecticide applications compared to grower standard fields. IPPM fields also had 62% greater pollinator visitation and 49% more melons during harvest compared to grower standard fields. Synthesis and applications. Our study demonstrates the capacity of IPPM programmes to manage pests while mitigating negative effects on pollinators. In particular, administering insecticide applications by pest thresholds led to the greatest enhancement in pollinator function. These findings also suggest that growers can benefit from this approach with reduced insecticide costs while encouraging pollination in pollinator‐dependent crops.

Acute toxicity of pesticide mixtures to honey bees is generally additive, and well predicted by Concentration Addition

Understanding the frequency of non-additive effects of pesticides (synergism and antagonism) is important in the context of risk assessment. The goal of this study was to investigate the prevalence of non-additive effects of pesticides to honey bees (Apis mellifera). We investigated a large set of mixtures including insecticides and fungicides of different chemical modes of action and classes. The mixtures included represent a relevant sample of pesticides that are currently used globally. We investigated whether the experimental toxicity of the mixtures could be predicted based on the Concentration Addition (CA) model for acute contact and oral adult bee toxicity tests. We measured the degree of deviation from the additivity predictions of the experimental toxicity based on the well-known Mixture Deviation Ratio (MDR). Further, we investigated the appropriate MDR thresholds that should be used for the identification of non-additive effects based on acceptable rates for false positive (alpha) and true positive (beta) findings. We found that a deviation factor of MDR = 5 is a sound reference for labeling potential non-additive effects in acute adult bee experimental designs when assuming a typical Coefficient of Variation (CV%) = 100 in the determination of the LD50 of a pesticide (a factor of 2× deviation in the LD 50 resulting from inter-experimental variability). We found that only 2.4 % and 9 % of the mixtures evaluated had an MDR > 5 and MDR < 0.2, respectively. The frequency and magnitude of deviation from additivity found for bees in this study are consistent with those of other terrestrial and aquatic taxa. Our findings suggest that additivity is a good baseline for predicting the toxicity of pesticide mixtures to bees, and that the rare cases of synergy of pesticide mixtures to bees are not random but have a mechanistic basis.

BeeGUTS-A Toxicokinetic-Toxicodynamic Model for the Interpretation and Integration of Acute and Chronic Honey Bee Tests.

Understanding the survival of honey bees after pesticide exposure is key for environmental risk assessment. Currently, effects on adult honey bees are assessed by Organisation for Economic Co‐operation and Development standardized guidelines, such as the acute and chronic oral exposure and acute contact exposure tests. The three different tests are interpreted individually, without consideration that the same compound is investigated in the same species, which should allow for an integrative assessment. In the present study we developed, calibrated, and validated a toxicokinetic–toxicodynamic model with 17 existing data sets on acute and chronic effects for honey bees. The model is based on the generalized unified threshold model for survival (GUTS), which is able to integrate the different exposure regimes, taking into account the physiology of the honey bee: the BeeGUTS model. The model is able to accurately describe the effects over time for all three exposure routes combined within one consistent framework. The model can also be used as a validity check for toxicity values used in honey bee risk assessment and to conduct effect assessments for real‐life exposure scenarios. This new integrative approach, moving from single‐point estimates of toxicity and exposure to a holistic link between exposure and effect, will allow for a higher confidence of honey bee toxicity assessment in the future. Environ Toxicol Chem 2022;41:2193–2201. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Mechanism of the distinct toxicity level of imidacloprid and thiacloprid against honey bees: An in silico study based on cytochrome P450 9Q3

The honey bee, Apis mellifera, shows variation in sensitivity to imidacloprid and thiacloprid, which does not reside at the target site but rather in the rapidly oxidative metabolism mediated by P450s (such as a single P450, CYP9Q3). An in silico study was conducted to investigate the various metabolism of imidacloprid and thiacloprid. The binding potency of thiacloprid was stronger and a stable π-π interaction with Phe121 and the N–H⋯N hydrogen bond with Asn214 are found in the CYP9Q3-thiacloprid system but absent in imidacloprid, which might affect the potential metabolic activity. Moreover, the values of highest occupied molecular orbit (HOMO) energy and the vertical ionization potential (IP) of two compounds demonstrated that thiacloprid is more likely to oxidation. The findings revealed the probable binding modes of imidacloprid and thiacloprid with CYP9Q3 and might facilitate future design of the low bee toxicity neonicotinoid insecticides.

A novel bee-friendly peptidomimetic insecticide: Synthesis, aphicidal activity and 3D-QSAR study of insect kinin analogs at Phe2 modification.

As one of the most abundant and destructive pests in agriculture, aphids cause significant damage to crops due to their sap-taking and as virus vectors. Chemical insecticides are the most effective method to control aphids, but they bring insecticide resistance problems and harm nontarget organisms, especially bees, therefore the search for novel eco-friendly aphid control agents with low bee toxicity is urgent. Insect kinins are a class of small neuropeptides that control important functions in insects. In our previous study, we found insect kinin analog IV-3 has good aphicidal activity and the location of the aromatic ring on the side chain of Phe2 is the key to the formation of the β-turn resulting in the biological activity of insect kinin analogs. However, there are few studies on insect kinin Phe2 substitution and modification, and its structure-activity relationship is still unclear. In this project, 44 insect kinin analogs with the Phe2 modification, replacing it with different natural or unnatural amino acids, were designed and synthesized based on the lead IV-3 to explore the role of the Phe2 residues. Bioassays with soybean aphids of Aphis glycines indicated that nine analogs have better aphicidal activity than the lead IV-3. In particular, compound L25 exhibits excellent aphicidal activity (LC50 =0.0047 mmol L-1 ) and has low toxicity to bees. Furthermore, a reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) was established to produce a helpful clue that introducing hydrophobic groups away from the backbone chain is beneficial to improve aphicidal activity. The residue Phe2 of insect kinin analogs is the key position and has a significant impact on the activity. L25 has a high toxicity for aphids, while a low toxicity to bees, and therefore can be considered as a lead compound to develop new biosafe aphid control agents. Finally, we provide a useful 3D-QSAR model as theoretical guidance for further structural optimization. © 2022 Society of Chemical Industry.