Abstract
Concerns about the safety of titanium dioxide (TiO2), including potential carcinogenicity, have prompted its ban in foods in the European Union, while remaining allowed as pharmaceutical excipient. We aimed to evaluate whether ingesting increasing quantities of TiO2 through medicines is associated with higher cancer risk. Data were derived from the French National Health Data System, a nationwide medico-administrative database. A case-control study was nested within two cohorts: users of metformin (all doses) and users of 200 mg acebutolol, both available in TiO2-containing and TiO2-free formulations. During 2013–2021, 293,101 cancer cases were identified and matched to 2,930,633 controls. TiO2 exposure through metformin and acebutolol consumption was calculated based on drug claims from 2006 up to five years before the index date. Conditional logistic regression models estimated linear associations between TiO2 exposure and cancer risk. RRs of overall cancer per 1000 TiO2-containing tablets and per 10,000 mg of TiO2 increments were both 1.00 (95% CI: 0.99–1.01). Analyses by cancer site also yielded RRs very close to 1.00 or slightly different but not statistically significant, except for breast (RR per 10,000 mg: 1.03, 95% CI:1.00-1.07) and lymphoid/hematopoietic (RR per 1000 tablets: 0.97, 95% CI: 0.95-1.00) cancers, which however lost significance after Bonferroni correction. There was a suggestion of non-linear positive association for central nervous system cancers. This first epidemiological study on TiO2 ingestion and cancer found no meaningful linear association between increasing TiO2 exposure through medicines and overall or site-specific cancer risk. Non-linear associations cannot be excluded.
Introduction
Food-grade titanium dioxide (TiO2) is widely used as pharmaceutical excipient for its ability to enhance whiteness and opacity, improve contrast with colorants, and protect photosensitive active ingredients from light degradation [1]. In France, 57% of oral pharmaceutical specialties on the market in 2020 contained TiO2 [2]. In foods, TiO2 is used as a whitening and brightening agent, for example in candies, chewing gums, baked goods, skimmed milk, white sauces and icings [3]. The comparison between estimated daily TiO2 intake from drug consumption in France and realistic estimates of dietary intake in European populations suggests that TiO2 exposure from pharmaceuticals is lower than dietary exposure in adults aged 20–59, but may reach comparable levels in older individuals [2].
In May 2021, the European Food Safety Authority (EFSA) concluded that, based on the available evidence and associated uncertainties, TiO2 could no longer be considered safe for use in foods. That conclusion was supported by findings from experimental studies suggesting immunotoxicity, inflammation and neurotoxicity, and potential genotoxicity [3]. Furthermore, in one study, TiO2 ingestion promoted preneoplastic lesions expansion in the colon of rats [4]. TiO2 could be carcinogenic through mechanisms such as oxidative stress, inflammation, and genotoxicity [5]. Food-grade TiO2 contains nanoparticles, characterized by their small size and large surface area, in varying proportions (approximately 10 to 50%) [6]. These nanoparticles may contribute to the potential health effects of TiO2, given their ability to cross biological barriers and induce oxidative stress, DNA damage, apoptosis and inflammatory responses [7, 8].
In January 2022, based on EFSA’s assessment—particularly the unresolved concern regarding genotoxicity and the many uncertainties—the European Commission decided to ban the use of TiO2 as a food additive [9, 10]. Since EFSA did not identify an immediate health risk and to allow for a smooth transition, foods containing TiO2 were permitted to be placed on the market until August 2022 and to be sold until their date of minimum durability or ‘use by’ date.
Although banned in foods, TiO2 remains provisionally authorized in medicines in the European Union [9, 10]. That decision was based on the European Medicines Agency’s scientific analysis regarding the technical purpose of the use of TiO2 in medicinal products and the feasibility and timelines for its replacement [1], and aimed to avoid shortages, as the replacement of TiO2 would require investigation and testing of suitable alternatives. A review clause in the Regulation stipulates that the European Commission must assess whether to maintain or remove TiO2 as an excipient in pharmaceuticals within three years of the Regulation’s entry into force —that is, in 2025—based on an updated analysis by the European Medicines Agency.
However, there is a lack of epidemiological studies examining the long-term health effects of TiO2 ingestion in humans, including on cancer risk. We thus performed an epidemiological study to investigate whether the ingestion of increasing quantities of TiO2 through medicines is associated with higher cancer risk, on the assumption that any increase in TiO2 exposure would cause a monotonic variation in cancer risk.
Download the full article as PDF here Ingestion of titanium dioxide as an excipient in medicines and the risk of cancer
or read it here
Materials and methods
Data sources
This study used the French National Health Data System (SNDS, Système National des Données de Santé), which contains, for over 99% of the French population, individual-level medico-administrative data on outpatient services reimbursed by the National Health Insurance as well as hospital discharge diagnoses and long-term diseases (LTD) registrations (e.g., for cancer) [11, 12]. Drug claim data include dispensing dates for reimbursed medications together with their French presentation identification codes. The SNDS also provides demographic information such as sex, dates of birth and death, and place of residence. Hospital discharge diagnoses include “main” (e.g. myocardial infarction, chemotherapy) and “related” (e.g. breast cancer) diagnoses, as well as “associated” diagnoses, i.e. patient’s comorbidities involving a higher burden of care. All data can be linked using a pseudonymized identifier. The SNDS integrates data from several insurance schemes, the “General scheme” for salaried workers covering 75% of the population with data recorded since 2006. Smaller schemes have been progressively incorporated.
We also used data from the French Theriaque database (https://www.theriaque.org) as of 2021, which provides, for all pharmaceutical products ever marketed in France, detailed information including presentation identification codes, the list of excipients—including TiO2—, pharmaceutical form, strength, Anatomical Therapeutic Chemical (ATC) codes, and package dispensing unit numbers. Data on exact TiO2 quantities, obtained from the French medicines safety agency (ANSM) as of 2021, were available for 42% of TiO2-containing pharmaceutical specialties [2].
Cairat, M., Severi, G., Huybrechts, I. et al. Ingestion of titanium dioxide as an excipient in medicines and the risk of cancer: a nationwide study within the French National health data system. Eur J Epidemiol (2025). https://doi.org/10.1007/s10654-025-01263-4
Read more interesting articles on studys on Titanium Dioxide – TiO2 here:
- Concerns regarding Calcium Carbonate as an alternative Excipient for Titanium Dioxide
- Compliant, Customisable Consistant – SheffCoat™ TF Plus
- Revolutionizing White Coatings: A Titanium-Free Approach
