Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice

Abstract

Nano-sized titanium dioxide particles (TiO₂) are widely used in cosmetics, sunscreens and food additives. We previously reported that topical application of non-coated rutile type TiO₂ did not exhibit a promoting effect on ultraviolet B-initiated skin carcinogenesis in rats, and that this was likely due to lack of penetration of TiO₂ into the epidermis. In the present study, we examined the promoting effect of silicone coated TiO₂ (sTiO₂) suspended in silicone oil and non-coated TiO₂ (ncTiO₂) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model: sTiO₂ suspended in silicon oil forms smaller particles than ncTiO₂ suspended in Pentalan because of the smaller sizes of aggregates formed. The model used skin carcinogenesis-sensitive human c-Ha-ras proto-oncogene transgenic mice (rasH2) and rats (Hras128) and their wild-type counterparts and CD-1 mice to test the effects of topical application of TiO₂. Animals were initially treated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) and then with 0, 10, or 20 mg sTiO₂ (mice) or 0, 50, or 100 mg ncTiO₂ (rats). The incidence and multiplicity of skin tumors (squamous cell papilloma and carcinoma) did not increase over DMBA alone controls in skin carcinogenesis-sensitive mice or rats or wild-type animals. Analysis of rat skin indicated that sTiO₂ and ncTiO₂ did not penetrate though either healthy or damaged skin. Furthermore sTiO₂ did not penetrate an in vitro human epidermis model. Our results indicate that treatment with sTiO₂ or ncTiO₂ did not promote skin carcinogenesis in mice or rats, probably due to lack of penetration through the epidermis.