Recent studies reported adverse liver effects and intestinal tumor formation after oral exposure to titanium dioxide (TiO₂). Other oral toxicological studies, however, observed no effects on liver and intestine, despite prolonged exposure and/or high doses. In the present assessment, we aimed to better understand whether TiO₂ can induce such effects at conditions relevant for humans. Therefore, we focused not only on the clinical and histopathological observations, but also used Adverse Outcome Pathways (AOPs) to consider earlier steps (Key Events). In addition, aiming for a more accurate risk assessment, the available information on organ concentrations of Ti (resulting from exposure to TiO₂) from oral animal studies was compared to recently reported concentrations found in human postmortem organs. The overview obtained with the AOP approach indicates that TiO₂ can trigger a number of key events in liver and intestine: Reactive Oxygen Species (ROS) generation, induction of oxidative stress and inflammation. TiO₂ seems to be able to exert these early effects in animal studies at Ti liver concentrations that are only a factor of 30 and 6 times higher than the median and highest liver concentration found in humans, respectively. This confirms earlier conclusions that adverse effects on the liver in humans as a result of (oral) TiO₂ exposure cannot be excluded. Data for comparison with Ti levels in human intestinal tissue, spleen and kidney with effect concentrations were too limited to draw firm conclusions. The Ti levels, though, are similar or higher than those found in liver, suggesting these tissues may be relevant too.

最近的研究报道了口服二氧化钛（TiO ₂）后对肝脏的不利影响和肠道肿瘤的形成。然而，其他口服毒理学研究表明，尽管长时间暴露和/或高剂量服用对肝脏和肠道没有影响。在本评估中，我们旨在更好地了解TiO ₂在与人类相关的条件下是否可以诱导此类效应。因此，我们不仅关注临床和组织病理学观察，还使用不良结果途径（AOP）考虑了较早的步骤（关键事件）。此外，为了更准确地进行风险评估，可获得关于钛器官浓度的现有信息（由于暴露于TiO ₂将来自口腔动物研究的）与最近报道的人体死后器官中发现的浓度进行了比较。通过AOP方法获得的概述表明，TiO ₂可以触发肝脏和肠道中的许多关键事件：活性氧（ROS）的产生，氧化应激的诱导和炎症。在动物肝脏研究中，TiO ₂似乎能够在Ti肝浓度上发挥这些早期作用，而Ti肝浓度仅分别是人体中最高和最高肝脏浓度的30倍和6倍。这证实了先前的结论，即（口服）TiO ₂对人类肝脏的不利影响不能排除暴露。与人肠道组织，脾脏和肾脏中Ti含量进行比较并得出有效浓度的数据太有限，无法得出明确的结论。但是，钛的含量与肝脏中的钛含量相似或更高，表明这些组织也可能是相关的。