Abstract：
Despite two decades of research on silver nanoparticle (AgNP) toxicity, a safe threshold for exposure has not yet been established, albeit being critically needed for risk assessment and regulatory decision-making. Traditionally, a point-of-departure (PoD) value is derived from dose response of apical endpoints in animal studies using either the no-observed-adverse-effect level (NOAEL) approach, or benchmark dose (BMD) modeling. To develop new approach methodologies (NAMs) to inform human risk assessment of AgNPs, we conducted a concentration response modeling of the transcriptomic changes in hepatocytes derived from human induced pluripotent stem cells (iPSCs) after being exposed to a wide range concentration (0.01-25 μg/ml) of AgNPs for 24 h. A plausible transcriptomic PoD of 0.21 μg/ml was derived for a pathway related to the mode-of-action (MOA) of AgNPs, and a more conservative PoD of 0.10 μg/ml for a gene ontology (GO) term not apparently associated with the MOA of AgNPs. A reference dose (RfD) could be calculated from either of the PoDs as a safe threshold for AgNP exposure. The current study illustrates the usefulness of in vitro transcriptomic concentration response study using human cells as a NAM for toxicity study of chemicals that lack adequate toxicity data to inform human risk assessment.
摘要：
尽管对银纳米粒子（AgNP）毒性进行了二十年的研究，尚未建立暴露的安全阈值，尽管对于风险评估和监管决策至关重要。传统上,使用未观察到的不良反应水平（NOAEL）方法，从动物研究中顶端终点的剂量反应得出起点（PoD）值，或基准剂量（BMD）建模。为了开发新的方法方法(NAM)，为AgNPs的人类风险评估提供信息，我们在暴露于广泛浓度（0.01-25μg/ml）的AgNPs24小时后，对来自人诱导多能干细胞（iPSCs）的肝细胞的转录组变化进行了浓度响应建模。对于与AgNPs的作用模式（MOA）相关的途径，得出了0.21μg/ml的合理转录组PoD，对于与AgNPs的MOA没有明显关联的基因本体论（GO）术语，更保守的PoD为0.10μg/ml。参考剂量(RfD)可以从PoD中的任一个计算,作为AgNP暴露的安全阈值。当前的研究说明了使用人类细胞作为NAM的体外转录组浓度响应研究对于缺乏足够的毒性数据来告知人类风险评估的化学物质的毒性研究的有用性。
