A toxicokinetic model for thiamethoxam in rats: implications for higher-tier risk assessment

Risk assessment for mammals is currently based on external exposure measurements, but effects of toxicants are better correlated with the systemically available dose than with the external administered dose. So for risk assessment of pesticides, toxicokinetics should be interpreted in the context of potential exposure in the field taking account of the timescale of exposure and individual patterns of feeding. Internal concentration is the net result of absorption, distribution, metabolism and excretion (ADME). We present a case study for thiamethoxam to show how data from ADME study on rats can be used to parameterize a body burden model which predicts body residue levels after exposures to LD50 dose either as a bolus or eaten at different feeding rates. Kinetic parameters were determined in male and female rats after an intravenous and oral administration of 14C labelled by fitting one-compartment models to measured pesticide concentrations in blood for each individual separately. The concentration of thiamethoxam in blood over time correlated closely with concentrations in other tissues and so was considered representative of pesticide concentration in the whole body. Body burden model simulations showed that maximum body weight-normalized doses of thiamethoxam were lower if the same external dose was ingested normally than if it was force fed in a single bolus dose. This indicates lower risk to rats through dietary exposure than would be estimated from the bolus LD50. The importance of key questions that should be answered before using the body burden approach in risk assessment, data requirements and assumptions made in this study are discussed in detail

(Z)-N-{3-[(6-Chloro­pyridin-3-yl)meth­yl]-1,3-thia­zolidin-2-yl­idene}cyanamide

The asymmetric unit of the title compound, C10H9ClN4S, common name thia­cloprid, comprises two mol­ecules. In both mol­ecules, the thia­zolidine rings are almost planar (with r.m.s. deviations of 0.016 and 0.065 Å) and form dihedral angles of 73.36 (6) and 70.25 (8)° with the 2-chloro­pyridine rings. In the crystal, inter­molecular C—H⋯N hydrogen bonds links the mol­ecules into chains propagating in [01]

Ethyl 2-{3-[(2-chloro-1,3-thia­zol-5-yl)meth­yl]-4-nitro­imino-1,3,5-triazinan-1-yl}acetate

In the title compound, C11H15ClN6O4S, which belongs to the neonicotinoid class of insecticidally active heterocyclic compounds, the six-membered triazine ring adopts an opened envolope conformation. The planar nitro imine group [dihedral angle between nitro and imine groups = 1.07 (7)°] and the thia­zole ring are oriented at a dihedral angle of 69.62 (8)°. A classical intra­molecular N—H⋯O hydrogen bond is found in the mol­ecular structure. Moreover, one classical inter­molecular N—H⋯N and four non-classical C—H⋯O and C—H⋯N hydrogen bonds are also present in the crystal structure. Besides inter­molecular hydrogen bonds, the Cl atom forms an inter­molecular short contact [3.020 (2) Å] with one of the nitro O atoms

Spiroindolines Identify the Vesicular Acetylcholine Transporter as a Novel Target for Insecticide Action

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family

Field efficacy and persistence of synthetic pesticidal dusts on stored maize grain under contrasting agro-climatic conditions

Grain storage trials were conducted in two districts of Zimbabwe with contrasting agro-climatic conditions (mean annual temperature of 18–30 °C and 28–42 °C; total rainfall of 750–1000 mm per annum and <450 mm per annum; respectively) to determine the comparative efficacy of commercially-available grain storage synthetic pesticides under contrasting climatic conditions. The five grain protectants, namely Shumba super dust® (fenitrothion 1% + deltamethrin 0.13%), Actellic gold dust® (pirimiphos-methyl 1.6% + thiamethoxam 0.36%), Super guard® (pirimiphos-methyl 1.6% + permethrin 0.4%), Chikwapuro® (pirimiphos-methyl 2.5% + deltamethrin 0.1%) and Ngwena yedura® (pirimiphos-methyl 2.5% + deltamethrin 0.2%) were evaluated at manufacturer's rates on stored shelled maize. The trials were conducted for a 40 week-long storage season in 2014/15 and again in 2015/16. Samples were analysed for insect grain damage, total insects per kilogram, grain weight loss, insect feeding dust and chaff as well as grain moisture content. Temperature and relative humidity within stores were recorded using data loggers. The results highlighted the generally poor efficacy of the synthetic pesticides under both cooler and hotter climatic test conditions. The pesticides failed to prevent insect grain damage or suppress insect pest numbers. Only Actellic gold dust®, introduced in the 2015/16 storage season was effective under both the agro-climatic conditions. The current study suggests that only Actellic gold dust® can be recommended for smallholder farm grain protection under both cooler and hotter climatic conditions. The findings confirm the frequent claims of smallholder farmers in east and southern Africa regarding poor storage pesticide performance, and emphasize the need to develop alternative effective storage insect pest control options

Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin

Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR–neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH–π interactions in the Ls-AChBP–CTD complex than in the Ls-AChBP–IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs