National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands; email:
Current affiliation: Reckitt Benckiser, 1118 BH Schiphol, The Netherlands.
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:203-223. doi: 10.1146/annurev-pharmtox-101419-100049. Epub 2020 Apr 13.
The Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO, which may be decreased if its mechanism of action becomes clearer. Here we consider adverse outcome pathways and present the available information on each of the key events (KEs). Inhalation exposure to TiO can induce lung tumors in rats via a mechanism that is also applicable to other poorly soluble, low-toxicity particles. To reduce uncertainties regarding human relevance, we recommend gathering information on earlier KEs such as oxidative stress in humans. For oral exposure, insufficient information is available to conclude whether TiO can induce intestinal tumors. An oral carcinogenicity study with well-characterized (food-grade) TiO is needed, including an assessment of toxicokinetics and early KEs.
欧洲化学品管理局风险评估委员会就将二氧化钛（TiO）归类为吸入性疑似人类致癌物一事发表了意见。最近的动物研究表明，TiO 可能通过口服途径致癌。TiO 的致癌性存在相当大的不确定性，如果其作用机制更加明确，其致癌性可能会降低。在这里，我们考虑了不良结局途径，并提供了有关每个关键事件 (KE) 的可用信息。TiO 的吸入暴露可通过一种也适用于其他难溶性、低毒性颗粒的机制在大鼠中诱导肺肿瘤。为了降低对人类相关性的不确定性，我们建议收集有关人类氧化应激等早期 KE 的信息。对于口服暴露，目前尚无足够信息来确定 TiO 是否可以诱导肠道肿瘤。需要进行一项具有良好特性（食品级）TiO 的口服致癌性研究，包括毒代动力学和早期 KE 的评估。
