title: Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice.
abstract: Nano-sized titanium dioxide particles (TiO(2)) are widely used in cosmetics, sunscreens and food additives. We previously reported that topical application of non-coated rutile type TiO(2) 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 TiO(2) into the epidermis. In the present study, we examined the promoting effect of silicone coated TiO(2 )(sTiO(2)) suspended in silicone oil and non-coated TiO(2 )(ncTiO(2)) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model: sTiO(2) suspended in silicon oil forms smaller particles than ncTiO(2) 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 TiO(2). Animals were initially treated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) and then with 0, 10, or 20 mg sTiO(2) (mice) or 0, 50, or 100 mg ncTiO(2) (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 sTiO(2) and ncTiO(2) did not penetrate though either healthy or damaged skin. Furthermore sTiO(2) did not penetrate an in vitro human epidermis model. Our results indicate that treatment with sTiO(2) or ncTiO(2) did not promote skin carcinogenesis in mice or rats, probably due to lack of penetration through the epidermis.
authors.affiliation: Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sagawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: Jiegou
authors.initials: J
authors.lastname: Xu
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fukamachi
authors.forename: Yuto
authors.initials: Y
authors.lastname: Sakai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nishimura
authors.forename: Masumi
authors.initials: M
authors.lastname: Suzui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.forename: Akimichi
authors.initials: A
authors.lastname: Morita
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012828:Silicones / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D012869:Skin Absorption; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism; D014025:Titanium / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D002273:Carcinogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012828:Silicones; C009495:titanium dioxide; D015127:9,10-Dimethyl-1,2-benzanthracene; D014025:Titanium