With fungal diseases posing a major threat to agricultural production, the application of fungicides to control related diseases is often considered necessary to ensure the world\'s food supply. The search for new bioactive agents has long been a priority in crop protection due to the continuous development of resistance against currently used types of active compounds. Heterocyclic compounds are an inseparable part of the core structures of numerous lead compounds, these rings constitute pharmacophores of a significant number of fungicides developed over the past decade by agrochemists. Among heterocycles, nitrogen-based compounds play an essential role. To date, diazole (imidazole and pyrazole) and diazine (pyrimidine, pyridazine, and pyrazine) derivatives make up an important series of synthetic fungicides. In recent years, many reports have been published on the design, synthesis, and study of the fungicidal activity of these scaffolds, but there was a lack of a comprehensive classified review on nitrogen-containing scaffolds. Regarding this issue, here we have reviewed the published articles on the fungicidal activity of the diazole and diazine families. In current review, we have classified the molecules synthesized so far based on the size of the ring.

Food safety is closely linked to human health. Thiabendazole is widely used as a fungicide and deodorant on agricultural products like vegetables and fruits to prevent fungal infections during transport and storage. This study aims to investigate the toxicity and potential mechanisms of Thiabendazole using novel network toxicology and molecular docking techniques. First, the ADMETlab2.0 and ADMETsar databases, along with literature, predicted Thiabendazole\'s potential to induce cancer and liver damage. Disease target libraries were constructed using GeneCards and TCMIP databases, while Thiabendazole target libraries were constructed using Swiss Target Prediction and TCMIP databases. The Venn database identified potential targets associated with Thiabendazole-induced cancer and liver injury. Protein-protein interaction (PPI) networks were derived from the STRING database, and gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways were obtained from the DAVID database. Molecular docking assessed the binding affinity between Thiabendazole and core targets. The study revealed 29 potential targets for Thiabendazole-induced cancer and 30 potential targets for liver injury. PPI identified 5 core targets for Thiabendazole-induced cancers and 4 core targets for induced liver injury. KEGG analysis indicated that Thiabendazole might induce gastric and prostate cancer via cyclin-dependent kinase 2 (CDK2) and epidermal growth factor receptor (EGFR) targets, and liver injury through the same targets, with the p53 signaling pathway being central. GO analysis indicated that Thiabendazole-induced cancers and liver injuries were related to mitotic cell cycle G2/M transition and DNA replication. Molecular docking showed stable binding of Thiabendazole with core targets including CDK1, CDK2, EGFR, and checkpoint kinase 1 (CHEK1). These findings suggest Thiabendazole may affect the G2/M transition of the mitotic cell cycle through the p53 signaling pathway, potentially inducing cancer and liver injury. This study provides a theoretical basis for understanding the potential molecular mechanisms underlying Thiabendazole toxicity, aiding in the prevention and treatment of related diseases. Additionally, the network toxicology approach accelerates the elucidation of toxic pathways for uncharacterized agricultural chemicals.

Pethoxamid, a member of the chloroacetamide herbicide family, is a recently approved chemical for pre- or post-emergence weed control; however, toxicity data for sublethal effects in aquatic organisms exposed to pethoxamid are non-existent in literature. To address this, we treated zebrafish embryos/larvae to pethoxamid over a 7-day period post-fertilization and evaluated several toxicological endpoints associated with oxidative stress and neurotoxicity. Continuous pethoxamid exposure did not affect survival nor hatch success in embryos/larvae for 7 days up to 1000 μg L-1. Exposure to pethoxamid did not affect embryonic ATP-linked respiration, but it did reduce non-mitochondrial respiration at the highest concentration tested. We also noted a significant increase in both apoptosis and levels of reactive oxygen species (ROS) in larvae zebrafish following exposure to pethoxamid. Increases in apoptosis and ROS, however, were not correlated with any altered gene expression pattern for apoptotic and oxidative damage response transcripts. To assess neurotoxicity potential, we measured behavior and several transcripts implicated in neural processes in the central nervous system. While locomotor activity of larval zebrafish was affected by pethoxamid exposure (hyperactivity was observed at concentrations below 1 μg L-1, and hypoactivity was noted at higher exposures to 10 and 100 μg L-1 pethoxamid), there were no effects on steady state mRNA abundance for neurotoxicity-related transcripts tested. This data contributes to knowledge regarding exposure risks for chloroacetamide-based herbicides and is the first study investigating sublethal toxicity for this newly registered herbicide.

Bacteria equipped with virulence systems based on highly bioactive small molecules can circumvent their host\'s defense mechanisms. Pathogens employing this strategy are currently threatening global rice production. In the present study, variations in the virulence of the highly destructive Burkholderia plantarii were observed in different rice-producing regions. The environment-linked variation was not attributable to any known host-related or external factors. Co-occurrence analyses indicated a connection between reduced virulence and 5-Amino-1,3,4-thiadiazole-2-thiol (ATT), a non-bactericidal organic compound. ATT, which accumulates in rice plants during metabolization of specific agrochemicals, was found to reduce virulence factor secretion by B. plantarii up to 88.8% and inhibit pathogen virulence by hijacking an upstream signaling cascade. Detailed assessment of the newly discovered virulence inhibitor resulted in mechanistic insights into positive effects of ATT accumulation in plant tissues. Mechanisms of virulence alleviation were deciphered by integrating high-throughput data, gene knockout mutants, and molecular interaction assays. TroK, a histidine protein kinase in a two-component system that regulates virulence factor secretion, is likely the molecular target antagonized by ATT. Our findings provide novel insights into virulence modulation in an important plant-pathogen system that relies on the host\'s metabolic activity and subsequent signaling interference.

The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.

UNASSIGNED: Pollution has emerged as a significant threat to humanity, necessitating a thorough evaluation of its impacts. As a result, various methods for human biomonitoring have been proposed as vital tools for assessing, managing, and mitigating exposure risks. Among these methods, urine stands out as the most commonly analyzed biological sample and the primary matrix for biomonitoring studies.
UNASSIGNED: This review concentrates on exploring the literature concerning residual pesticide determination in urine, utilizing liquid and gas chromatography coupled with mass spectrometry, and its practical applications.
UNASSIGNED: The examination focused on methods developed since 2010. Additionally, applications reported between 2015 and 2022 were thoroughly reviewed, utilizing Web of Science as a primary resource.
UNASSIGNED: Recent advancements in chromatography-mass spectrometry technology have significantly enhanced the development of multi-residue methods. These determinations are now capable of simultaneously detecting numerous pesticide residues from various chemical and use classes. Furthermore, these methods encompass analytes from a variety of environmental contaminants, offering a comprehensive approach to biomonitoring. These methodologies have been employed across diverse perspectives, including toxicological studies, assessing pesticide exposure in the general population, occupational exposure among farmers, pest control workers, horticulturists, and florists, as well as investigating consequences during pregnancy and childhood, neurodevelopmental impacts, and reproductive disorders.
UNASSIGNED: Such strategies were essential in examining the health risks associated with exposure to complex mixtures, including pesticides and other relevant compounds, thereby painting a broader and more accurate picture of human exposure. Moreover, the implementation of integrated strategies, involving international research initiatives and biomonitoring programs, is crucial to optimize resource utilization, enhancing efficiency in health risk assessment.

Herbicides are often detected in aquatic ecosystems due to residential and agricultural applications and can harm aquatic organisms once deposited into water systems. Pendimethalin is part of the dinitroaniline chemical family and is applied to crops like corn, legumes, potatoes, and soybeans. The potential toxicity of pendimethalin to aquatic species is understudied compared to other widely studied herbicides, like atrazine and glyphosate. The objectives of this review were to (1) collate information on sub-lethal responses to pendimethalin exposure in fish, (2) evaluate how exposure studies relate to environmental concentrations, and (3) identify putative bioindicators for exposure studies. Overall, studies reporting pendimethalin in water systems worldwide indicate a range of 100-300 ng/L, but levels have been reported as high as ~15 µg/g in sediment. In teleost fish, studies demonstrate developmental toxicity, immunotoxicity, and behavioral disruptions. The strongest evidence for pendimethalin-induced toxicity involves oxidative stress, although studies often test toxicity at higher concentrations than environmentally relevant levels. Using the Comparative Toxicogenomics Database, pathway analysis reveals linkages to neurotoxicity and mechanisms of neurodegeneration like \"Ubiquitin Dependent Protein Degradation\", \"Microtubule Cytoskeleton\", \"Protein Oxidation and Aggregation in Aging\", and \"Parkinson\'s Disease\". Other prominent pathways included those related to mTOR signaling and reproduction. Thus, two potential mechanisms underlying pendimethalin-induced toxicity in fish include the neural and reproductive systems. This review synthesizes current data regarding environmental fate and ecotoxicology of pendimethalin in teleost fish and points to some putative physiological and molecular responses that may be beneficial for assessing toxicity of the herbicide in future investigations.

Public concern about the effects of pesticides on non-target organisms has increased in the recent years. Nevertheless, there is a limited number of studies that address the actual toxic effects of herbicides on insects. This study investigated the side effects of herbicides on non-target organisms inhabiting agroecosystems and performing essential ecological and economic functions such as crop pollination. We analysed morphological alterations in the gut, Malpighian tubules and circulating haemocytes of Apis mellifera workers as markers of exposure effects. A commercial formulation of a pendimethalin-based herbicide (PND) was administered orally under laboratory conditions at a realistic concentration admitted in the field (330gL-1 of active ingredient., 4 L ha-1 for cereal and vegetable crops). The worker bees were exposed to a single application of PND for a period of one week, to simulate the exposure that can occur when foraging bees accidentally drink drops of contaminated water upon treatments. Histopathological analyses of the midgut, ileum and Malpighian tubules showed alterations over time (from 24 to 72 h after the beginning of exposure) such as loss of epithelial organisation, cellular vacuolisation and altered pyknotic nuclei as well as disruption of the peritrophic membrane over time. Semiquantitative analyses of the midgut showed a significant increase in the organ injury index 24 and 72 h after the initial exposure in PND-exposed bees compared to control bees. In addition, a change in positivity to Gram staining was observed in the midgut histological sections. A recovery of cytotoxic effects was observed one week after the initial exposure, which was favoured by the periodic renewal of the intestinal epithelium and the herbicide dissipation time. Cytochemical staining with Giemsa of haemocytes from PND-treated workers over 24 and 72 h showed significant nuclear alterations such as lobed or polymorphic nuclei and micronuclei compared to bees in the control group. These results show that the dose of PND used to protect crops from weeds can lead to significant cytotoxic and genotoxic effects in non-target organisms such as honey bees. In croplands, the sublethal effects on cell morphology can impair vital physiological processes such as nutrition, osmoregulation, and resistance to pathogens, contributing to the decline in biodiversity and abundance of species that play a prominent ecological role, such as pollinators.

An overview is given on the significance of the oxime moiety in crop protection chemistry. This review focuses on the two most important aspects of agrochemical oximes, which are the occurrence and role of oxime groups in compounds with herbicidal, fungicidal and insecticidal activity, as well as the application of oxime derivatives as intermediates in the synthesis of crop protection agents not bearing any oxime function. Especially noteworthy is the fact, that in the synthesis of agrochemicals, oximes can be cyclized to isooxazoline, isoxazole, oxadiazole, oxazine, pyrrole, isothiazole and imidazole rings. © 2024 Society of Chemical Industry.

Biochars and organoclays have been proposed as efficient adsorbents to reduce the mobility of agrochemicals in soils. However, following their application to soils, these adsorbents undergo changes in their physicochemical properties over time due to their interaction with soil components. In this study, the adsorption capacity of a commercial biochar and a commercial organoclay for the antibiotic sulfamethoxazole (SFMX) and the pesticide ethofumesate (ETFM) was evaluated over aging periods of 3 months in the laboratory and 1 year in the field, subsequent to their application to a Mediterranean soil. The results showed that the adsorption of SFMX and ETFM in the soil amended with the adsorbents was greater than in the unamended soil, but for both chemicals, adsorption decreased with aging of the adsorbents in the soil. Characterization of the adsorbents before and after aging revealed physical blocking of adsorption sites by soil components. The loss of adsorption capacity of the adsorbents upon aging led to higher leaching of SFMX and ETFM in the soil containing field-aged adsorbents, although leaching remained lower than in unamended soil. Our findings reveal that, under the Mediterranean environment studied, the efficacy of the studied materials as adsorbents is maintained to a considerable extent for at least one year after their field application, which would have positive implications in their use for attenuating the dispersion of agricultural contaminants in the environment.