Adverse Outcome Pathways Associated with the Ingestion of Titanium Dioxide Nanoparticles—A Systematic Review

Abstract

Titanium dioxide nanoparticles (TiO2-NPs) are widely used, and humans are exposed through food (E171), cosmetics (e.g., toothpaste), and pharmaceuticals. The oral and gastrointestinal (GIT) tract are the first contact sites, but it may be systemically distributed. However, a robust adverse outcome pathway (AOP) has not been developed upon GIT exposure to TiO2-NPs. The aim of this review was to provide an integrative analysis of the published data on cellular and molecular mechanisms triggered after the ingestion of TiO2-NPs, proposing plausible AOPs that may drive policy decisions. A systematic review according to Prisma Methodology was performed in three databases of peer-reviewed literature: Pubmed, Scopus, and Web of Science. A total of 787 records were identified, screened in title/abstract, being 185 used for data extraction. The main endpoints identified were oxidative stress, cytotoxicity/apoptosis/cell death, inflammation, cellular and systemic uptake, genotoxicity, and carcinogenicity. From the results, AOPs were proposed where colorectal cancer, liver injury, reproductive toxicity, cardiac and kidney damage, as well as hematological effects stand out as possible adverse outcomes. The recent transgenerational studies also point to concerns with regard to population effects. Overall, the findings further support a limitation of the use of TiO2-NPs in food, announced by the European Food Safety Authority (EFSA).

Toothpaste ingestion—evaluating the problem and ensuring safety: systematic review and meta-analysis

“…Recent studies investigating transgenerational effects have raised additional concerns regarding the potential impact on populations. These findings reinforce the European Food Safety Authority's decision to restrict the use of TiO2, emphasizing the need for caution in their application (12); Abrasives such as hydrated silica or calcium carbonate are used to help remove stains and plaque. Excessive or aggressive brushing with abrasive toothpaste can potentially harm tooth enamel; Artificial Colors are often on a list of ingredients in toothpaste to enhance their appearance.…”

Impact of nano-titanium dioxide extracted from food products on Caco-2 cells using three-phase digestion model

“…9,11,12 The nanomaterial has also been evidenced to cause DNA strand breaks, chromosomal damage, and gene mutation, and can induce epigenetic modifications. 8,10,[12][13][14] At higher concentrations, TiO 2 nanoparticles cause reproductive toxicity in both females and males, [15][16][17] and induce oxidative stress that leads to cell damage, inflammation, and adverse immune responses. 9,11,12,17 Systematic review and metaanalysis have demonstrated that TiO 2 nanoparticles disrupt the mammalian cell cycle in vitro, 18 and disturb glucose and lipid homeostasis in mice and rats.…”

“…8,10,[12][13][14] At higher concentrations, TiO 2 nanoparticles cause reproductive toxicity in both females and males, [15][16][17] and induce oxidative stress that leads to cell damage, inflammation, and adverse immune responses. 9,11,12,17 Systematic review and metaanalysis have demonstrated that TiO 2 nanoparticles disrupt the mammalian cell cycle in vitro, 18 and disturb glucose and lipid homeostasis in mice and rats. 11,12 The nanomaterial has also been found to impact the digestive tract, increasing chronic intestinal inflammation and disorders of the intestinal barrier, and disrupting the normal functions of the gastrointestinal tract.…”

“…13,16,[19][20][21] Epidemiological data on the impact of TiO 2 nanoparticles remains lacking. 9,12,14,17 Despite this body of evidence, the mechanism(s) of nanoparticle toxicity remain inconclusive and contested. [9][10][11][12]18 It has been suggested that observed toxicities may be a result of either direct or indirect interaction with DNA, 10 or may be caused by reactive oxygen species (ROS) generated by the nanoparticles themselves and activated by UV or during particle-elicited inflammation.…”

Investigate the constituents of commercially available toothpastes

“…It has been discovered that titanium dioxide, which is accepted to be ingested orally by young children between the ages of 2 and 6, is absorbed via the intestines and causes biological harm at the cellular and molecular level (Rompelberg et al 2016). Since the concentration of titanium dioxide, which can be ingested not only through toothpaste but also through numerous food products (milk, cream, coffee, gum, sauce), can reach very high levels in the body, it is advantageous to avoid using it in toothpastes in order to minimize exposure (Rolo et al 2022). It is notable that this substance is present in nearly two-thirds of toothpastes marketed in our country.…”