Showa Pharmaceutical University.
Central Institute for Experimental Animals.
J Toxicol Sci. 2019;44(8):543-548. doi: 10.2131/jts.44.543.
Long-term exposure to certain volatile organic compounds is a significant public health concern. A variety of food containers and drinking cups prepared from polystyrene or polystyrene-related plastics could contain styrene monomer. In the current study, the concentrations of styrene in plasma and liver were surveyed and determined after oral doses of 25 mg/kg to rats and 200 mg/kg to control and humanized-liver mice. Plasma concentrations of styrene in rats were still detected 2 hr after 10-25 mg/kg oral doses. In contrast, after an order of magnitude higher oral dose of styrene (200 mg/kg) to mice, styrene in mouse plasma was rapidly cleared within 15 min to the limit-of-detection level. However, unmetabolized styrene was detected in mouse liver 24 hr after oral treatment. A simple physiologically based pharmacokinetic (PBPK) model capable of estimating blood and liver concentrations of styrene was established for rats. A human PBPK model was then set up for styrene by using the same intrinsic hepatic clearances in rats and humans and by applying allometric scaling to rat parameters obtained from the plasma concentrations of styrene in rats. By reverse dosimetry analysis (from concentrations to doses), we found that the 95th percentile values of styrene concentrations (0.132 ng/mL) reported in United States biomonitoring data of more than 1000 human blood samples may imply exposure to repeated oral doses of styrene of 2.89 µg/kg/day. These results suggest that styrene biomonitoring data in human blood samples imply exposures roughly similar to or lower than the established tolerable daily intake level of 7.7 μg/kg/day.
长期暴露于某些挥发性有机化合物是一个重大的公共卫生问题。各种由聚苯乙烯或聚苯乙烯相关塑料制成的食品容器和饮料杯都可能含有苯乙烯单体。在当前的研究中，对大鼠口服 25mg/kg 和对照及人源化肝脏小鼠口服 200mg/kg 剂量后，检测并确定了血浆和肝脏中苯乙烯的浓度。大鼠口服 10-25mg/kg 剂量后 2 小时仍能检测到苯乙烯的血浆浓度。相比之下，对小鼠口服更高剂量（200mg/kg）的苯乙烯后，小鼠血浆中的苯乙烯在 15 分钟内迅速清除至检测限以下。然而，在口服处理后 24 小时，仍能检测到小鼠肝脏中未代谢的苯乙烯。建立了一个能够估计大鼠血液和肝脏中苯乙烯浓度的简单生理基于药代动力学（PBPK）模型。然后通过使用大鼠和人类相同的内在肝脏清除率，并对从大鼠血浆中苯乙烯浓度获得的大鼠参数进行种属间比例缩放，为苯乙烯建立了一个人体 PBPK 模型。通过反向剂量分析（从浓度到剂量），我们发现，美国对超过 1000 个人类血液样本的生物监测数据中报告的苯乙烯浓度的第 95 百分位数（0.132ng/mL）可能意味着每天重复口服 2.89μg/kg 的苯乙烯。这些结果表明，人类血液样本中的苯乙烯生物监测数据暗示的暴露水平大致与或低于已确定的可耐受日摄入量 7.7μg/kg/天相当。
