Read-across is one of the most frequently used alternative tools for hazard assessment, in particular for complex endpoints such as repeated dose or developmental and reproductive toxicity. Read-across extrapolates the outcome of a specific toxicological in vivo endpoint from tested (source) compounds to “similar” (target) compound(s). If appropriately applied, a read-across approach can be used instead of de novo animal testing. The read-across approach starts with structural/physicochemical similarity between target and source compounds, assuming that similar structural characteristics lead to similar human hazards. In addition, similarity also has to be shown for the toxicokinetic and toxicodynamic properties of the grouped compounds. To date, many read-across cases fail to demonstrate toxicokinetic and toxicodynamic similarities. New concepts, in vitro and in silico tools are needed to better characterise these properties, collectively called new approach methodologies (NAMs). This white paper outlines a general read-across assessment concept using NAMs to support hazard characterization of the grouped compounds by generating data on their dynamic and kinetic properties. Based on the overarching read-across hypothesis, the read-across workflow suggests targeted or untargeted NAM testing also outlining how mechanistic knowledge such as adverse outcome pathways (AOPs) can be utilized. Toxicokinetic models (biokinetic and PBPK), enriched by in vitro parameters such as plasma protein binding and hepatocellular clearance, are proposed to show (dis)similarity of target and source compound toxicokinetics. Furthermore, in vitro to in vivo extrapolation is proposed to predict a human equivalent dose, as potential point of departure for risk assessment. Finally, the generated NAM data are anchored to the existing in vivo data of source compounds to predict the hazard of the target compound in a qualitative and/or quantitative manner. To build this EU-ToxRisk read-across concept, case studies have been conducted and discussed with the regulatory community. These case studies are briefly outlined.

交叉读取是用于危险评估的最常用替代工具之一，特别是对于复杂的终点（例如重复剂量或发育毒性和生殖毒性）而言。跨读将特定的毒理学体内终点结果从测试的（来源）化合物推断为“相似的”（目标）化合物。如果适当地应用，可以使用交叉阅读法代替从头进行动物试验。交叉读取方法始于目标化合物与源化合物之间的结构/物理化学相似性，前提是假定相似的结构特征会导致相似的人类危害。另外，还必须显示分组化合物的毒代动力学和毒动力特性相似。迄今为止，许多交叉阅读案例未能证明毒物动力学和毒物动力学的相似性。新概念 需要使用体外和计算机模拟工具来更好地表征这些特性，这些特性统称为新方法（NAM）。本白皮书概述了使用NAM的通用交叉评估概念，以通过生成有关其动态和动力学特性的数据来​​支持分组化合物的危险性表征。基于总体交叉阅读假设，交叉阅读工作流程建议进行有针对性的或无针对性的NAM测试，还概述了如何利用机械知识（例如不良结局途径（AOP））。提出了通过体外参数（例如血浆蛋白结合和肝细胞清除率）丰富的毒代动力学模型（生物动力学和PBPK），以显示靶标和源化合物的毒代动力学（不相似）。此外，建议进行体外到体内外推以预测人等效剂量，作为风险评估的潜在出发点。最后，将生成的NAM数据锚定到源化合物的现有体内数据中，以定性和/或定量的方式预测目标化合物的危害。为了构建这种跨欧盟的“ ToxRisk风险”概念，已经进行了案例研究并与监管机构进行了讨论。简要概述了这些案例研究。