Product Safety, Syngenta Crop Protection LLC, Greensboro, NC, 27409, USA.
Product Safety, Syngenta Crop Protection LLC, Greensboro, NC, 27409, USA.
Environ Pollut. 2024 Nov 1;360:124765. doi: 10.1016/j.envpol.2024.124765. Epub 2024 Aug 20.
Ecological risk assessments of agrochemicals have traditionally depended on in vivo guideline tests using northern bobwhite and mallard to provide relevant endpoints for avian species. However, these studies have limitations, including animal welfare concerns, the time and cost involved, limited potential for extrapolation to more realistic exposure conditions, and the lack of mechanistic understanding. The proof-of-concept work presented a case study for thiamethoxam in three avian species, demonstrating the potential of physiologically based kinetic (PBK) modeling to enable dosimetry extrapolations that inform hazard characterization in risk assessment, and reduce the use of avian testing. The model structure for northern bobwhite and mallard contained ten compartments, while an additional ovulation model was included for chicken in the physiological state of egg-laying. The model was first parameterized and evaluated for chicken and northern bobwhite using in vitro kinetic measurements and in vivo toxicokinetic (TK) data. The chicken model was then extrapolated to mallard based on allometric scaling. The models were then used to map the TK profiles across species by simulating internal dose metrics in different avian toxicology studies. These metrics, including peak blood concentrations (C) and area under the curve (AUC) for blood concentration, were determined for acute, subacute, or chronic toxicity endpoints for mallard and northern bobwhite, enabling a quantitative cross-species and cross-route comparison of dosimetry. The results suggested that the chronic toxicological response of birds exposed to thiamethoxam is highly dependent on internal exposure, while mallard appeared to be more dynamically sensitive to thiamethoxam on an acute oral exposure basis. The case study increases the confidence in using new approach methodologies (NAMs) for interpreting avian toxicity studies and facilitating in vitro-in silico-based ecological risk assessments of agrochemicals.
农药的生态风险评估传统上依赖于使用北方鹌鹑和野鸭进行体内指导方针测试，以提供鸟类物种的相关终点。然而，这些研究存在局限性，包括动物福利问题、所涉及的时间和成本、向更现实的暴露条件外推的有限潜力，以及缺乏对机制的理解。概念验证工作为三种鸟类中的噻虫嗪提供了案例研究，展示了生理相关动力学 (PBK) 建模的潜力，可实现剂量测定外推，为风险评估中的危害特征提供信息，并减少对鸟类测试的使用。北方鹌鹑和野鸭的模型结构包含十个隔室，而在产卵生理状态下的鸡中则包含一个额外的排卵模型。该模型首先使用体外动力学测量和体内毒代动力学 (TK) 数据对鸡和北方鹌鹑进行参数化和评估。然后基于比例缩放将鸡模型外推到野鸭。然后，通过模拟不同鸟类毒理学研究中的内部剂量指标，使用这些模型来绘制跨物种的 TK 谱。这些指标包括野鸭和北方鹌鹑急性、亚急性或慢性毒性终点的血液浓度峰值 (C) 和血液浓度下的面积 (AUC)，可实现跨物种和跨途径的剂量测定定量比较。结果表明，鸟类暴露于噻虫嗪的慢性毒理学反应高度依赖于内部暴露，而在急性口服暴露的基础上，野鸭似乎对噻虫嗪更为动态敏感。该案例研究增加了对使用新方法 (NAM) 解释鸟类毒性研究和促进农药体外-计算生态风险评估的信心。
