Review of potential health risks associated with nanoscopic calcium phosphate.

Calcium phosphate is applied in many products in biomedicine, but also in toothpastes and cosmetics. In some cases, it is present in nanoparticulate form, either on purpose or after degradation or mechanical abrasion. Possible concerns are related to the biological effect of such nanoparticles. A thorough literature review shows that calcium phosphate nanoparticles as such have no inherent toxicity but can lead to an increase of the intracellular calcium concentration after endosomal uptake and lysosomal degradation. However, cells are able to clear the calcium from the cytoplasm within a few hours, unless very high doses of calcium phosphate are applied. The observed cytotoxicity in some cell culture studies, mainly for unfunctionalized particles, is probably due to particle agglomeration and subsequent sedimentation onto the cell layer, leading to a very high local particle concentration, a high particle uptake, and subsequent cell death. There is no risk from an oral uptake of calcium phosphate nanoparticles due to their rapid dissolution in the stomach. The risk from dermal or mucosal uptake is very low. Calcium phosphate nanoparticles can enter the bloodstream by inhalation, but no adverse effects have been observed, except for a prolonged exposition to high particle doses. Calcium phosphate nanoparticles inside the body (e.g. after implantation or due to abrasion) do not pose a risk as they are typically resorbed and dissolved by osteoclasts and macrophages. There is no indication for a significant influence of the calcium phosphate phase or the particle shape (e.g. spherical or rod-like) on the biological response. In summary, the risk associated with an exposition to nanoparticulate calcium phosphate in doses that are usually applied in biomedicine, health care products, and cosmetics is very low and most likely not present at all. STATEMENT OF SIGNIFICANCE: Calcium phosphate is a well-established biomaterial. However, there are occasions when it occurs in a nanoparticulate form (e.g. as nanoparticle or as nanoparticulate bone substitution material) or after abrasion from a calcium phosphate-coated metal implant. In the light of the current discussion on the safety of nanoparticles, there have been concerns about potential adverse effects of nano-calcium phosphate, e.g. in a statement of a EU study group from 2016 about possible dangers associated with non-spherical nano-hydroxyapatite in cosmetics. In the US, there was a discussion in 2016 about the dangers of nano-calcium phosphate in babyfood. In this review, the potential exposition routes for nano-calcium phosphate are reviewed, with special emphasis on its application as biomaterial.