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

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).This research was funded by the Portuguese Foundation for Science and Technology FCT/MCTES through national funds (PIDDAC), PTDC/SAU-PUB/29481/2017 and co-funded by UIDB/00009/2020 (Centre for Toxicogenomics and Human Health—ToxOmics (UIDP/00009/2020; UIDB/00009/2020), iMed.ULisboa (UIDB/04138/2020+UIDP/04138/2020), CESAM (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020), and BioISI (UID/MULTI/04046/2019). N.V. thanks the Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia, e Ensino Superior, for her PhD grant 2020.07168.BD. L.G. was supported by FCT Individual CEEC as a Principal Researcher Grant (CEECIND/03143/2017) and R.A. as an Assistant Researcher Grant (CEECIND/01570/2018).