Ingestion of titanium dioxide as an excipient in medicines and the risk of cancer: a nationwide study within the French National health data system.

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.