Ducrot Virginie, Ashauer Roman, Bednarska Agnieszka J, Hinarejos Silvia, Thorbek Pernille, Weyman Gabriel
INRA, UMR0985 Ecologie et Santé des Ecosystèmes, Equipe Ecotoxicologie et Qualité des Milieux Aquatiques, Rennes, France.
Environment Department, University of York, York, United Kingdom.
Integr Environ Assess Manag. 2016 Jan;12(1):32-45. doi: 10.1002/ieam.1641. Epub 2015 Jun 11.
Recent guidance identified toxicokinetic-toxicodynamic (TK-TD) modeling as a relevant approach for risk assessment refinement. Yet, its added value compared to other refinement options is not detailed, and how to conduct the modeling appropriately is not explained. This case study addresses these issues through 2 examples of individual-level risk assessment for 2 hypothetical plant protection products: 1) evaluating the risk for small granivorous birds and small omnivorous mammals of a single application, as a seed treatment in winter cereals, and 2) evaluating the risk for fish after a pulsed treatment in the edge-of-field zone. Using acute test data, we conducted the first tier risk assessment as defined in the European Food Safety Authority (EFSA) guidance. When first tier risk assessment highlighted a concern, refinement options were discussed. Cases where the use of models should be preferred over other existing refinement approaches were highlighted. We then practically conducted the risk assessment refinement by using 2 different models as examples. In example 1, a TK model accounting for toxicokinetics and relevant feeding patterns in the skylark and in the wood mouse was used to predict internal doses of the hypothetical active ingredient in individuals, based on relevant feeding patterns in an in-crop situation, and identify the residue levels leading to mortality. In example 2, a TK-TD model accounting for toxicokinetics, toxicodynamics, and relevant exposure patterns in the fathead minnow was used to predict the time-course of fish survival for relevant FOCUS SW exposure scenarios and identify which scenarios might lead to mortality. Models were calibrated using available standard data and implemented to simulate the time-course of internal dose of active ingredient or survival for different exposure scenarios. Simulation results were discussed and used to derive the risk assessment refinement endpoints used for decision. Finally, we compared the "classical" risk assessment approach with the model-based approach. These comparisons showed that TK and TK-TD models can bring more realism to the risk assessment through the possibility to study realistic exposure scenarios and to simulate relevant mechanisms of effects (including delayed toxicity and recovery). Noticeably, using TK-TD models is currently the most relevant way to directly connect realistic exposure patterns to effects. We conclude with recommendations on how to properly use TK and TK-TD model in acute risk assessment for vertebrates.
最近的指南将毒代动力学-毒效动力学（TK-TD）建模确定为改进风险评估的一种相关方法。然而，与其他改进选项相比，其附加值并未详细说明，且未解释如何恰当地进行建模。本案例研究通过两个假设植物保护产品的个体水平风险评估示例来解决这些问题：1）评估作为冬季谷物种子处理单次施用对小型食谷鸟类和小型杂食性哺乳动物的风险，以及2）评估在农田边缘区域脉冲处理后对鱼类的风险。利用急性试验数据，我们按照欧洲食品安全局（EFSA）指南进行了第一阶段风险评估。当第一阶段风险评估突出显示存在问题时，讨论了改进选项。强调了应优先使用模型而非其他现有改进方法的情况。然后，我们以两个不同模型为例实际进行了风险评估改进。在示例1中，使用一个考虑云雀和林鼠毒代动力学及相关摄食模式的TK模型，根据作物内情况下的相关摄食模式预测个体中假设活性成分的内部剂量，并确定导致死亡的残留水平。在示例2中，使用一个考虑黑头呆鱼毒代动力学、毒效动力学及相关暴露模式的TK-TD模型，针对相关的FOCUS SW暴露情景预测鱼类存活的时间进程，并确定哪些情景可能导致死亡。使用可用的标准数据对模型进行校准，并实施以模拟不同暴露情景下活性成分内部剂量或存活的时间进程。对模拟结果进行了讨论，并用于得出用于决策的风险评估改进终点。最后，我们将“经典”风险评估方法与基于模型的方法进行了比较。这些比较表明，TK和TK-TD模型通过研究现实暴露情景和模拟相关效应机制（包括延迟毒性和恢复）的可能性，可为风险评估带来更多现实性。值得注意的是，目前使用TK-TD模型是将现实暴露模式直接与效应联系起来的最相关方式。我们最后就如何在脊椎动物急性风险评估中正确使用TK和TK-TD模型提出了建议。
