Abstract：
In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a \"data-derived\" adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of ∼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.
摘要：
在农用化学品的风险评估中，历史上一直缺乏使用数据来完善默认调整因子，即使大型数据集可支持这一点。解决动物对人类外推（AFA）不确定性的科学现状是开发一个“数据衍生”调整因子（DDEF）来量化这种差异，如果数据可用。物种之间的毒物动力学（TK）和毒物动力学（TD）差异可用于DDEF，人类数据集是理想而罕见的。我们确定了一个目前注册的除草剂的案例，mesotrione,其中人类TK和TD是可用的。此案例研究概述了使用人类和动物比较数据并基于抑制4-羟基苯酚丙酮酸双加氧酶（HHPD）的不良结果途径（AOP）开发DDEF的方法。对于动力学（AFAK=2.5）的大鼠到人的外推（AFA）的计算DDEF乘以动力学的AFA（AFAD=0.3），导致复合DDEF为〜1（AFA=0.75）。这反映了AOP和现有的科学证据，即人类对HPPD抑制剂的作用不如大鼠敏感。利用来自肝细胞和肝细胞溶胶的体外数据集进行进一步分析，并使用体外至体内外推（IVIVIVE）外推至整个动物，以支持毒性动力学外推。体外数据集产生与体内数据衍生的相同的AFAD(AFAD=0.3)。这些分析表明，大多数物种差异与毒理学有关。其他HPPD抑制剂和细胞类型的其他体外/体内数据集的未来工作将进一步支持这一结果。这项工作证明了利用所有可用的毒物动力学和毒物动力学数据来代替农业化学人体健康风险评估的默认不确定性因素。
