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

Abstract

Nano-sized titanium dioxide (TiO 2 ) particles are used in sunscreen formulations to protect against skin lesions caused by exposure to UV light (Gelis et al., 2003;Rouabhia et al., 2002;Suzuki, 1987). Nano and larger scale titanium dioxide particles are known to be carcinogenic to the rat lung (Baan et al., 2006;Baan, 2007). Recently, we demonstrated a promoting effect on rat lung carcinogenesis by nano-size TiO 2 particles administered by a novel intrapulmonary spraying method (Xu et al., 2010). The mechanism of promotion of lung carcinogenesis involved the induction of MIP1α protein expression by ncTiO 2 -laden alveolar macrophages (Xu et al., 2010).We also examined the carcinogenic effect of TiO 2 (mean manufacturer's particulate diameter of 20 nm) on the skin in a UVB-initiated two-stage rat carcinogenesis model and found that topical application of TiO 2 did not promote skin carcinogenesis in this model. This result is probably due to the inability of TiO 2 to penetrate through 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.

Titanium dioxide nanoparticles: a review of current toxicological data

“…However, no details were given regarding the fate of the particles that did penetrate. TiO 2 NPs were also found to have no skin carcinogenesis promoting effects due to lack of penetration through the epidermis [70,71] (details given in the section on carcinogenecity). Another study utilizing the time of flight secondary ion mass spectrometry (TOF-SIMS) showed the presence of silica coated TiO 2 NPs (rutile; 14–16 nm) within epidermis and superficial dermis [72].…”

“…The same conclusion was reached by Sagawa et al . [70] who studied the promoting effect of silicone coated TiO 2 NPs (35 nm; 5 times a week for 8 and 40 weeks; 0, 10, or 20 mg) suspended in silicone oil and non-coated TiO 2 NPs (20 nm; twice a week for 28 or 40 weeks; 0, 50, or 100 mg) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model. Analysis of skin indicated that silicone coated TiO 2 NPs and non-coated TiO 2 NPs did not penetrate though either healthy or damaged skin.…”

A Case Study

“…Although the sunscreens are meant to provide protection against cutaneous cancer, acute dermal toxicity of TiO 2 has only been tested once in five male and five female rats in a study of Croda company. The lack of promoting effect of nano-sized TiO 2 particles on chemically induced skin carcinogenesis in rats and mice has also been investigated and proven by Sagawa et al [155]. No deaths were recorded after 24 h dermal occlusive administration of 2000 mg/kg ultrafine TiO 2 in peanut oil as vehicle.…”

Safety of titanium dioxide nanoparticles in cosmetics

“…Three studies performed in mice ( N = 1), rats ( N = 1) or both ( N = 1) were evaluated in detail by the SCCS in 2013–2014 . In mice, no carcinogenic promoter activity was observed with uncoated nano‐TiO 2 in both studies . Likewise, no carcinogenic promoter activity was observed with alumina‐coated or stearic acid‐coated nano‐TiO 2 .…”

“…Likewise, no carcinogenic promoter activity was observed with alumina‐coated or stearic acid‐coated nano‐TiO 2 . However, an increase in the number of tumours was found among mice treated with silica‐coated nano‐TiO 2 . Nevertheless, as this increase was not significant and positive controls were lacking, no conclusion could be drawn.…”