Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure

Abstract

Recent studies reported adverse liver effects and intestinal tumor formation after oral exposure to titanium dioxide (TiO 2). 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 TiO 2 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 TiO 2) from oral animal studies was compared to recently reported concentrations found in human postmortem organs. The overview obtained with the AOP approach indicates that TiO 2 can trigger a number of key events in liver and intestine: Reactive Oxygen Species (ROS) generation, induction of oxidative stress and inflammation. TiO 2 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) TiO 2 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.

Issues currently complicating the risk assessment of synthetic amorphous silica (SAS) nanoparticles after oral exposure

“…For titanium dioxide (TiO 2 ) we recently postulated that high dose levels could negatively affect the uptake and subsequent effects (Brand et al 2020). We also postulated administration via the diet could negatively affect the uptake of TiO 2 , in contrast to the impression given by SAS in the present study.…”

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

“…Over the last years, an increasing number of studies investigated the behavior and effects of E171 and nano-sized TiO 2 after ingestion and discovered potential adverse effects, including the induction of inflammation, the formation of reactive oxygen species (ROS), and co-genotoxic effects [13]. Sub-acute and sub-chronic studies also revealed the induction of epithelial hyperplasia and preneoplastic lesions in the colon of rats and mice after the ingestion of E171, while other oral toxicological studies did not confirm such effects [14][15][16][17][18].…”

“…However, if toxicokinetic information based on internal organ concentration and accumulation over time of TiO 2 nanoparticles was included, the potential additional risk for liver and testis was identified [1]. Additional work of Heringa et al (2018) and Brand et al (2020) showed that post-mortem collected human liver (median 0.03 mg/kg), jejunum (median 0.14 mg/kg), ileum (median (0.26 mg/kg), kidney (median 0.06 mg/kg) and spleen (median 0.04 mg/kg) contain titanium particles and that they accumulated both micro-and nanosized TiO 2 [13,76]. The quantities detected in these organs were partially higher than levels that are considered safe for humans, after applying conventional safety factors [76].…”

“…These processes potentially increase E171 absorption over time and worsen the conditions or accelerate the adverse health effects [94]. A decrease in intestinal barrier integrity and the consequent increase in E171 absorption elevates the systemic TiO 2 levels and eventually increases the risk for organ-specific toxicity e.g., neurotoxicity, cardiac toxicity, hepatotoxicity, and reprotoxicity [13,94,108,109,113,[145][146][147][148].…”

Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19

“…For example, Abderrahim Nemmar et al concluded that iron oxide nanoparticles can caused thrombosis, cardiac oxidative and DNA damage through acute intravenous administration [ 145 ]. There are also reports that titanium dioxide nanoparticles and others nanoparticles are harmful to kidney [ 146 , 147 ]. Tungsten trioxide nanoparticles and iron oxide nanoparticles can cause liver toxicity in mice [ 148 , 149 ].…”