Kacew Sam, Demir Esref
McLauglin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Medical Laboratory Techniques Program, Department of Medical Services and Techniques, Vocational School of Health Services, Antalya Bilim University, Antalya 07190, Türkiye.
Toxics. 2025 Jun 6;13(6):482. doi: 10.3390/toxics13060482.
In South Korea, issues have been raised regarding exposure to humidifier disinfectant products containing certain chemicals postulated to induce lung diseases in consumers. Several rodent studies utilizing whole-body inhalation, which comprises freely moving animals breathing through the nares, and intranasal instillation involving restraint, were conducted by various Korean Governmental Agencies on these products to investigate whether there is a causal relationship between these products and the development of lung diseases. In particular, the humidifier disinfectant product Kathon, containing chloromethylisothiazolinone and methylisothiazolinone (CMIT and MIT), when directly introduced into inhalation chambers at varying concentrations for up to 13 weeks, produced no significant histopathological alterations and no marked changes in pulmonary function parameters. Further, there was no evidence of cytotoxicity; total and differential cell counts did not differ from control. In addition, the levels of cytokine markers of inflammation were not markedly altered. In contrast to published papers utilizing intratracheal and intranasal instillation, where the animal is anesthetized and chemical bypasses the defense mechanisms in the respiratory tract, then reaches the pulmonary region, ignoring recommended dose levels was found to initiate fibrotic responses in mice and rats. However, the usefulness of experimental results to extrapolate to humans obtained following intratracheal and intranasal instillation studies is of limited value because the data generated did not use a realistic design and appropriate dosimetry. Therefore, these findings have significant drawbacks in their use to characterize an inhalation risk for pulmonary fibrosis in humans and cannot be used for the extrapolation of such risk to humans. It is thus evident that the inhalation data generated by the Korean Regulatory Agencies are more realistic and show that exposure to CMIT and MIT does not initiate pulmonary fibrosis. Although inhalation studies still do not fully replicate real-world human exposure scenarios and have limitations for direct extrapolation to humans, they are nevertheless more appropriate than intratracheal or intranasal instillation models.
在韩国，人们对接触含有某些据推测会导致消费者肺部疾病的化学物质的加湿器消毒产品提出了质疑。韩国多个政府机构针对这些产品开展了多项啮齿动物研究，其中包括让自由活动的动物通过鼻孔呼吸的全身吸入法，以及涉及约束动物的鼻内滴注法，以调查这些产品与肺部疾病的发生之间是否存在因果关系。特别是，含有氯甲基异噻唑啉酮和甲基异噻唑啉酮（CMIT和MIT）的加湿器消毒产品卡松，当以不同浓度直接引入吸入室长达13周时，并未产生明显的组织病理学改变，肺功能参数也未出现显著变化。此外，没有细胞毒性的证据；总细胞计数和分类细胞计数与对照组无差异。另外，炎症细胞因子标志物的水平也没有明显改变。与使用气管内和鼻内滴注法的已发表论文不同，在气管内和鼻内滴注法中，动物被麻醉，化学物质绕过呼吸道的防御机制，然后到达肺部区域，研究发现忽视推荐剂量水平会在小鼠和大鼠中引发纤维化反应。然而，气管内和鼻内滴注研究所得出的实验结果外推至人类的有效性价值有限，因为所产生的数据未采用实际可行的设计和适当的剂量测定法。因此，这些研究结果在用于描述人类肺纤维化的吸入风险方面存在重大缺陷，不能用于将此类风险外推至人类。由此可见，韩国监管机构生成的吸入数据更为实际，表明接触CMIT和MIT不会引发肺纤维化。尽管吸入研究仍不能完全复制现实世界中的人类接触场景，且直接外推至人类存在局限性，但它们仍然比气管内或鼻内滴注模型更为合适。
