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Abstract：
Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.
摘要：
下一代风险评估被定义为以暴露为主导，假设驱动的风险评估方法，集成了新的方法方法（NAM），以确保安全，而不使用动物试验。这些原则适用于面霜和润肤露中0.1%香豆素的假设安全性评估。为了评估NAM的使用，现有的动物和人类关于香豆素的数据被排除在外.使用用于皮肤施用的香豆素的基于生理学的动力学模型来估计内部浓度(血浆Cmax)。使用一系列体外NAM评估系统毒性，以确定各种生物学效应的出发点（PoDs），例如受体介导的和免疫调节效应（EurofinsSafetyScreen44和BioMap多样性8小组，分别)，和一般生物活性(ToxCast数据，体外细胞应激小组和高通量转录组学)。此外,使用ToxTracker工具跟踪遗传毒性的计算机警报。将来自体外测定的PoD针对计算的体内暴露作图,以计算具有相关不确定性的安全裕度。面霜和润肤露的预测Cmax值低于所有安全裕度高于100的PoD。此外，香豆素没有遗传毒性,未与所测试的44种受体中的任何一种结合，并且在与消费者相关的暴露中未显示任何免疫调节作用。总之,这个案例研究证明了整合曝光科学的价值，计算建模和体外生物活性数据，在没有动物数据的情况下做出安全决定。
