Titanium dioxide dust, when inhaled, has been classified by the International Agency for Research on Cancer (IARC) as an IARC Group 2B carcinogen, meaning it is possibly carcinogenic to humans.[55] The findings of the IARC are based on the discovery that high concentrations of pigment-grade (powdered) and ultrafine titanium dioxide dust caused respiratory tract cancer in rats exposed by inhalation and intratracheal instillation.[56] The series of biological events or steps that produce the rat lung cancers (e.g. particle deposition, impaired lung clearance, cell injury, fibrosis, mutations and ultimately cancer) have also been seen in people working in dusty environments. Therefore, the observations of cancer in animals were considered, by IARC, as relevant to people doing jobs with exposures to titanium dioxide dust. For example, titanium dioxide production workers may be exposed to high dust concentrations during packing, milling, site cleaning and maintenance, if there are insufficient dust control measures in place. However, the human studies conducted so far do not suggest an association between occupational exposure to titanium dioxide and an increased risk for cancer. The safety of the use of nano-particle sized titanium dioxide, which can penetrate the body and reach internal organs, has been criticized.[57] Studies have also found that titanium dioxide nanoparticles cause inflammatory response and genetic damage in mice.[58][59] The mechanism by which TiO
2 may cause cancer is unclear. Molecular research suggests that cell cytotoxicity due to TiO
2 results from the interaction between TiO
2 nanoparticles and the lysosomal compartment, independently of the known apoptotic signalling pathways.[60]
The body of research regarding the carcinogenicity of different particle sizes of titanium dioxide has led the US National Institute for Occupational Safety and Health to recommend two separate exposure limits. NIOSH recommends that fine TiO
2 particles be set at an exposure limit of 2.4 mg/m3, while ultrafine TiO
2 be set at an exposure limit of 0.3 mg/m3, as time-weighted average concentrations up to 10 hours a day for a 40 hour work week.[61] These recommendations reflect the findings in the research literature that show smaller titanium dioxide particles are more likely to pose carcinogenic risk than the larger titanium dioxide particles.
There is some evidence the rare disease yellow nail syndrome may be caused by titanium, either implanted for medical reasons or through eating various foods containing titanium dioxide.
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