![]() The ARE-Nrf2 Luciferase KeratinoSens TM test, representing the second key event, can discriminate between skin sensitizers and non-sensitizers under the United Nations Globally Harmonized System of Classification and Labelling of Chemicals ( OECD, 2018a). The second key event occurs within the keratinocytes and includes inflammatory responses as well as changes in gene expression associated with specific cell signaling pathways, such as the antioxidant/electrophile response element (ARE)-dependent pathways ( OECD, 2014). The first key event involves the initial covalent reaction of electrophilic chemicals in the irritant with nucleophilic thiol and primary amines in skin proteins. According to Cho et al., 2012, the toxicity of fast-dissolving metal oxide NPs is closely related to the intrinsic toxicity of its constituent metal ions.Ĭurrent knowledge regarding the chemical and biological mechanisms associated with skin sensitization has been summarized in the form of an adverse outcome pathway (starting with the molecular initiating event, through intermediate events, to the adverse effect), namely allergic contact dermatitis ( OECD, 2018a). Dissolution of such NMs causes toxicity different from that caused by NMs that do not dissolve well, possibly due to the released ions. NPs, in most cases, are minimally soluble under normal physiological conditions however, some have been shown to be soluble in certain media, such as lysosomal fluid ( Cho et al., 2012 Cho et al., 2013). The physicochemical properties of NPs form the key determinants of its toxic potential ( Donaldson et al., 2013 Braakhuis et al., 2014). However, since these guidelines are based on chemical substances, development of alternative test methods reflecting the properties of nanomaterials are also imperative. In recent cosmetic tests, the importance of alternative test methods considering animal welfare and the 3R principles has been emphasized ( Rusche, 2003 Kaluzhny et al., 2011). With an exponential increase in the commercialization of NPs in cosmetics and relevant safety concerns, evaluation of NP safety has become important ( Katz et al., 2015). While the major NP-exposure pathways include inhalation, ingestion, and absorption into the skin, the latter can cause lesions such as local inflammation, contact allergy, and skin sensitization ( Oberdörster et al., 2005 Maynard and Kuempel, 2005). ![]() With an increase in the number and production volume of NPs, concerns about their toxicity have increased exponentially in the recent years. Metal oxide nanoparticles (NPs) constitute one of the major types of nanomaterials (NMs) that are used in industrial, biomedical, and cosmetic applications. Based on ion chelation data, metal ion release was confirmed as the major “factor” for skin sensitization. However, further investigations are required to elucidate the mechanism underlying NP-induced skin sensitization. Collectively, the results implied fast-dissolving metal oxide (CuO and CoO) NPs release their metal ion, inducing skin sensitization. The results showed that CuO and CoO NPs induce a similar pattern of positive luciferase induction and cytotoxicity compared to the respective metal chlorides Co 3O 4, NiO, and TiO 2 induced no such response. In addition, the response of metal oxide NPs was confirmed in lymph node of BALB/C mice via an in vivo method. The materials were applied to KeratinoSens TM cells for imitated skin-environment setting, and luciferase induction and cytotoxicity were evaluated at 48 h post-incubation. We selected five metal oxide NPs, containing copper oxide, cobalt monoxide, cobalt oxide, nickel oxide, or titanium oxide, and two types of metal chlorides (CoCl 2 and CuCl 2), to compare the skin sensitization abilities between NPs and the constituent metals. In this study, we evaluated the skin sensitization of nanomaterials comparing metal haptens in vivo and in vitro. Nanomaterials comprising metal haptens raises concerns about the skin sensitization to nanomaterials. Human skins are exposed to nanomaterials in everyday life from various sources such as nanomaterial-containing cosmetics, air pollutions, and industrial nanomaterials. Division of Toxicological Research, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, South Korea.Sung-Hyun Kim Jin Hee Lee Kikyung Jung Jun-Young Yang Hyo-Sook Shin Jeong Pyo Lee Jayoung Jeong Jae-Ho Oh* Jong Kwon Lee*
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