Yanagiba Yukie, Ono Megumi, Toyooka Tatsushi, Wang Rui-Sheng
Research Center for Chemical Information and Management, National Institute of Occupational Safety and Health, Kawasaki, Japan.
PLoS One. 2024 Dec 30;19(12):e0316150. doi: 10.1371/journal.pone.0316150. eCollection 2024.
A potential link has been reported between skin exposure to aromatic amines, such as ortho-toluidine (OT) and 3,3'-dichloro-4,4'-diaminodiphenylmethane (MOCA), and bladder cancer cases observed in Japanese chemical factories. To evaluate this association, we explored the permeability of OT and MOCA through pig skin and investigated the subsequent changes in plasma and urine concentrations in rats following percutaneous exposure. Employing Yucatan micropig skin, we first executed a permeability test by affixing the skin to a diffusion cell and applying 14C-labeled OT or MOCA. The receptor fluid's radioactivity was quantified at intervals of 1, 3, 6, 8, 24, and 48 h after application using a liquid scintillation counter. Next, we applied lint cloths drenched in OT and MOCA solutions to the backs of 7-week-old male F344 rats and monitored plasma and urine concentrations over time. Additionally, we investigated the pharmacokinetics of 14C-labeled OT or MOCA solutions for 8 h following percutaneous administration. Both OT and MOCA demonstrated high skin penetration; in particular, plasma concentrations significantly rose at 6 h for OT and 8 h for MOCA after exposure. However, OT was rapidly absorbed into the bloodstream and swiftly excreted into the urine, indicating quick absorbability. In contrast, MOCA penetrated the skin quickly but exhibited delayed bloodstream entry and urinary excretion, suggesting slower absorbability. Pharmacokinetic findings revealed the rapid urinary excretion of OT, whereas MOCA was excreted in the urine and potentially in the feces as well via bile. These findings indicate that implementing measures based on chemical absorbability could significantly enhance the management of industrial chemicals where percutaneous absorbability is a concern.
据报道，皮肤接触芳香胺，如邻甲苯胺（OT）和3,3'-二氯-4,4'-二氨基二苯甲烷（MOCA），与日本化工厂观察到的膀胱癌病例之间可能存在联系。为了评估这种关联，我们研究了OT和MOCA通过猪皮肤的渗透性，并调查了大鼠经皮暴露后血浆和尿液浓度的后续变化。我们使用尤卡坦微型猪的皮肤，首先通过将皮肤固定在扩散池上并应用14C标记的OT或MOCA进行渗透性测试。使用液体闪烁计数器在应用后1、3、6、8、24和48小时的间隔对受体液的放射性进行定量。接下来，我们将浸有OT和MOCA溶液的绒布应用于7周龄雄性F344大鼠的背部，并随时间监测血浆和尿液浓度。此外，我们研究了经皮给药后14C标记的OT或MOCA溶液8小时的药代动力学。OT和MOCA均表现出高皮肤渗透性；特别是，暴露后OT在6小时时血浆浓度显著升高，MOCA在8小时时血浆浓度显著升高。然而，OT迅速被吸收进入血液并迅速排泄到尿液中，表明吸收迅速。相比之下，MOCA迅速穿透皮肤，但进入血液和尿液排泄的过程延迟，表明吸收较慢。药代动力学研究结果显示OT迅速经尿液排泄，而MOCA经尿液排泄，也可能通过胆汁经粪便排泄。这些发现表明，基于化学物质吸收性采取措施可以显著加强对经皮吸收性是一个问题的工业化学品的管理。
