Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics

This review focuses on outlining the toxicity of titanium dioxide (TiO₂) particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO₂ particles is vital as it enables risk assessments to be conducted, by combining this information with knowledge on the likely exposure levels of humans. This review has concentrated on the toxicity of TiO₂, due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO₂, in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO₂) and due to its widespread application within consumer products (such as sunscreens). The pulmonary and dermal hazards of TiO₂ have been a particular focus of the available studies, due to the past use of TiO₂ as a (negative) control when assessing the pulmonary toxicity of particulates, and due to its incorporation within consumer products such as sunscreens. Mechanistic processes that are critical to TiO₂ particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO₂ exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO₂ that have been identified as being most likely to drive the observed toxicity include particle size (and therefore surface area), crystallinity (and photocatalytic activity), surface chemistry, and particle aggregation/agglomeration tendency. The experimental set up also influences toxicological outcomes, so that the species (or model) used, route of exposure, experiment duration, particle concentration and light conditions are all able to influence the findings of investigations. In addition, the applicability of the observed findings for particular TiO₂ forms, to TiO₂ particulates in general, requires consideration. At this time it is inappropriate to consider the findings for one TiO₂ form as being representative for TiO₂ particulates as a whole, due to the vast number of available TiO₂ particulate forms and large variety of potential tissue and cell targets that may be affected by exposure. Thus emphasising that the physicochemical characteristics are fundamental to their toxicity.