Institute of Occupational Medicine (IOM), Edinburgh, UK.
National Institute for Public Health and the Environment - RIVM, Bilthoven, The Netherlands.
Part Fibre Toxicol. 2023 Feb 9;20(1):5. doi: 10.1186/s12989-023-00516-y.
Toxicity assessment for regulatory purposes is starting to move away from traditional in vivo methods and towards new approach methodologies (NAM) such as high-throughput in vitro models and computational tools. For materials with limited hazard information, utilising quantitative Adverse Outcome Pathways (AOPs) in a testing strategy involving NAM can produce information relevant for risk assessment. The aim of this work was to determine the feasibility of linking in vitro endpoints to in vivo events, and moreover to key events associated with the onset of a chosen adverse outcome to aid in the development of NAM testing strategies. To do this, we focussed on the adverse outcome pathway (AOP) relating to the onset of pulmonary fibrosis.
We extracted in vivo and in vitro dose-response information for particles known to induce this pulmonary fibrosis (crystalline silica, specifically α-quartz). To test the in vivo-in vitro extrapolation (IVIVE) determined for crystalline silica, cerium dioxide nanoparticles (nano-CeO) were used as a case study allowing us to evaluate our findings with a less studied substance. The IVIVE methodology outlined in this paper is formed of five steps, which can be more generally summarised into two categories (i) aligning the in vivo and in vitro dosimetry, (ii) comparing the dose-response curves and derivation of conversion factors.
Our analysis shows promising results with regards to correlation of in vitro cytokine secretion to in vivo acute pulmonary inflammation assessed by polymorphonuclear leukocyte influx, most notable is the potential of using IL-6 and IL-1β cytokine secretion from simple in vitro submerged models as a screening tool to assess the likelihood of lung inflammation at an early stage in product development, hence allowing a more targeted investigation using either a smaller, more targeted in vivo study or in the future a more complex in vitro protocol. This paper also highlights the strengths and limitations as well as the current difficulties in performing IVIVE assessment and suggestions for overcoming these issues.
为了监管目的，毒性评估开始从传统的体内方法转向新的方法，如高通量体外模型和计算工具。对于危害信息有限的材料，在涉及新方法的测试策略中利用定量的不良结局途径（AOP）可以提供与风险评估相关的信息。本工作的目的是确定将体外终点与体内事件联系起来的可行性，并且与所选不良结局相关的关键事件联系起来，以帮助开发新方法测试策略。为此，我们专注于与肺纤维化发生相关的不良结局途径（AOP）。
我们提取了已知会引起这种肺纤维化的颗粒（结晶二氧化硅，特别是α-石英）的体内和体外剂量反应信息。为了测试为结晶二氧化硅确定的体内-体外外推（IVIVE），我们使用了二氧化铈纳米颗粒（纳米 CeO）作为案例研究，使我们能够用一种研究较少的物质来评估我们的发现。本文概述的 IVIVE 方法由五个步骤组成，可以更一般地分为两类：（i）对齐体内和体外剂量学，（ii）比较剂量-反应曲线和推导转换因子。
我们的分析显示，体外细胞因子分泌与体内多形核白细胞流入评估的急性肺炎症之间具有良好的相关性，最值得注意的是，使用简单的体外浸泡模型中 IL-6 和 IL-1β细胞因子分泌作为早期产品开发中肺炎症可能性的筛选工具的潜力，从而允许使用更小、更有针对性的体内研究或在未来更复杂的体外方案进行更有针对性的调查。本文还强调了进行 IVIVE 评估的优势和局限性以及当前存在的困难，并提出了克服这些问题的建议。
