Federal Institute for Risk Assessment (BfR), Thielallee 88-92, 14195 Berlin, Germany.
Toxicol Lett. 2011 Apr 25;202(2):100-10. doi: 10.1016/j.toxlet.2011.01.022. Epub 2011 Feb 1.
Coumarin (1,2-benzopyrone) is occurring in food, and is also used in cosmetics. In order to perform a risk assessment for both oral and dermal exposure, we applied a physiologically based approach to model kinetics in humans by simulating both routes of exposure. The concentration-time profile in liver revealed a higher peak concentration (C(max-hep)) for the oral when compared to the dermal route. The area under the concentration-time curve in the liver (AUC(hep)) was found the same for both routes if the same extent of absorption is assumed. Dose response information from published rat studies were used to identify the metric relevant for liver toxicity. Liver exposure levels resulting from doses and durations as outlined in the studies were simulated in a rat model. We obtained 31 data pairs of C(max-hep) and AUC(hep). Liver toxicity was observed at doses which resulted in simulated C(max-hep) values exceeding a certain liver concentration whereas we could not identify a clear cut off value of AUC(hep). Our findings support the notion that liver toxicity of coumarin in rats is related to C(max-hep) rather than to AUC(hep). If these findings can be transferred to the situation in humans, the result demonstrates that route specific differences in organ peak concentrations have to be considered when performing route-to-route extrapolation.
香豆素（1,2-苯并吡喃）存在于食物中，也用于化妆品。为了对口服和皮肤暴露进行风险评估，我们应用基于生理学的方法通过模拟两种暴露途径来模拟人体动力学。肝脏中的浓度-时间曲线显示，与皮肤途径相比，口服途径的峰值浓度（C(max-hep)）更高。如果假设相同的吸收程度，则肝脏中的浓度-时间曲线下面积（AUC(hep)）在两种途径中是相同的。使用来自已发表的大鼠研究的剂量反应信息来确定与肝脏毒性相关的度量标准。在大鼠模型中模拟了研究中概述的剂量和持续时间导致的肝脏暴露水平。我们获得了 31 对 C(max-hep)和 AUC(hep)的数据。在模拟的 C(max-hep)值超过肝脏特定浓度的剂量下观察到肝脏毒性，而我们无法确定 AUC(hep)的明确截止值。我们的发现支持这样的观点，即大鼠香豆素的肝脏毒性与 C(max-hep)有关，而与 AUC(hep)无关。如果这些发现可以转化为人类的情况，那么结果表明，在进行途径间外推时，必须考虑器官峰浓度的途径特异性差异。
