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Dermal Toxicity of Zno Nanoparticles: A Worrying Feature of Sunscreen?

2012; Future Medicine; Volume: 7; Issue: 4 Linguagem: Inglês

10.2217/nnm.12.23

1748-6963

Stephan Hackenberg, Norbert Kleinsasser,

Indoor Air Quality and Microbial Exposure

NanomedicineVol. 7, No. 4 EditorialFree AccessDermal toxicity of ZnO nanoparticles: a worrying feature of sunscreen?Stephan Hackenberg & Norbert KleinsasserStephan HackenbergDepartment of Oto-Rhino-Laryngology, Plastic, Aesthetic & Reconstructive Head & Neck Surgery, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany & Norbert Kleinsasser* Author for correspondenceDepartment of Oto-Rhino-Laryngology, Plastic, Aesthetic & Reconstructive Head & Neck Surgery, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany. Published Online:4 Apr 2012https://doi.org/10.2217/nnm.12.23AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: nanoparticlesskinsunscreentoxicityultravioletzinc oxidePhotodamage of the skinAcute and chronic exposure to UV irradiation can induce sunburn, dermal carcinogenesis and photoaging of the skin, and the application of sunscreens is an effective method to protect the human skin against such UV-induced damage. Sunscreens can reduce the occurrence of squamous cell carcinoma and actinic keratoses [1], and their use remains the most prevalent UV-protection strategy used by the public [2]. Recently, however, concerns regarding possible hazardous biological effects from sunscreen ingredients have emerged. In particular, the use of nanomaterials is the primary focus of controversies over the safety of sunscreen formulas since scientific knowledge on the cyto- and genotoxicity of nanoparticles (NPs) is still quite limited.NPs in sunscreensBesides titanium dioxide (TiO2), zinc oxide (ZnO) is also one of the most important inorganic UV filters used in sunscreens. Due to their high photostability and low photoallergic potential, TiO2 and ZnO are often preferred as ingredients in sunscreens over organic UV filters [3]. However, major disadvantages of TiO2 and ZnO include their poor dispersive properties and thus their skin-occlusive effects. Novel technologies could overcome these shortcomings by reducing the particle size to the nanoscale level (<100 nm). NPs exhibit different physicochemical properties compared with their bulk substances. With respect to ZnO NPs, minimized particle size and enhanced dispersibility compared with standard-sized ZnO lead to relevant cosmetic improvements such as increased transparency of the formula without impairment of UV protection efficiency. However, information about the negative health implications and the toxicological impact of nanoscale ZnO particles is still incomplete, although the processing and use of nanomaterials in everyday products is booming. Major questions regarding the safety of ZnO NPs in sunscreens are their toxic potential in viable human keratinocytes and their ability to penetrate the skin, resulting in possible local and systemic distribution.Cytotoxicity of ZnO NPs in vitroSeveral investigations have demonstrated the toxic and mutagenic effects of ZnO NPs in human keratinocytes. Sharma et al. described the genotoxic potential of 30 nm ZnO NPs in a human epidermal cell line (A431) at a concentration of 0.8 µg/ml, as well as in primary human epidermal cells at 14 µg/ml [4]. Oxidative stress seemed to play a crucial role in the DNA-damaging processes, and was measured by the depletion of glutathione, catalase and superoxide dismutase. ZnO NPs were shown by Kocbek et al. to decrease mitochondrial activity, to change cellular morphology, and to disturb the cell cycle distribution in human keratinocytes at a concentration of 10 µg/ml [5]. Genotoxicity was also demonstrated in other human cell systems like skin fibroblasts [6], neural cells (U87) [7] and nasal mucosa cells, as shown by our own research group [8]. Furthermore, we demonstrated the cytotoxicity of ZnO NPs (100 nm) at 20 µg/ml with and without UVA-1 irradiation in human primary oral mucosa cells, whereas squamous cell carcinoma cell lines were more vulnerable to the photocatalytic reaction. Tumor cells were eliminated at a concentration of 0.2 µg/ml ZnO NPs in combination with 15 min of UVA-1 treatment, whereas UV irradiation did not influence toxicity of ZnO NPs in oral mucosa cells [9]. Dufour et al. described chromosomal damage at high concentrations of ZnO NPs in nonmalignant Chinese hamster ovary cells, but did not observe photogenotoxicity under preliminary or simultaneous UV irradiation [10]. Summarizing the current literature, there seems to be evidence of a DNA damaging potential of ZnO NPs in viable human cells, although nanotoxicological in vitro data are not directly transferrable to the in vivo situation. Particularly, the cellular uptake mechanisms of nanomaterials into human cells are different in the in vitro setting. The use of high concentrations of insoluble NPs induces physiological particle uptake via endocytosis, resulting in extremely high intracellular particle concentrations. This subsequently provokes the generation of reactive oxygen species, finally leading to DNA damage in the form of genotoxicity [2]. Thus, molecular mechanisms of ZnO NP-induced toxicity should be investigated using low particle concentrations.Skin penetration by NPsA distinct feature of the human skin is its multilayer structure, which builds up an effective barrier against xenobiotics. The stratum corneum represents the outermost layer of the skin and plays a crucial role in protecting the human organism against penetration by chemicals. Thus, studies on ZnO NP-induced skin toxicity should predominantly focus on the potential of the particles to penetrate the stratum corneum and to reach viable keratinocytes in the deeper layers of the epidermis. Several studies have been performed to elucidate this important question. Skin penetration investigations demonstrated that ZnO NPs do not infiltrate the epidermis [11–13]. Furthermore, these studies showed that ZnO NPs were not able to penetrate healthy and intact human or porcine skin in vitro or in vivo. NPs can be retained in the hair follicle ostium or skin folds, but are usually eliminated by sebum flow [14]. Some authors contend that a diameter of 5 nm is the critical particle size that allows for skin penetration [15]. However, it is not only the diameter of particles that seems to influence their ability to penetrate the stratum corneum, but also the condition of the skin in experimental settings in vitro and in vivo, resulting from different sources and storage modalities, as well as the surface properties and aggregation status of the tested NPs [16]. In summary, an intact stratum corneum sufficiently prevents particle contact with keratinocytes. However, little is known about skin penetration by NPs in sunburned or inflamed skin, despite the fact that sunscreens are likely to be applied to compromised skin areas. Theoretically, a damaged stratum corneum may allow contact of NPs with viable keratinocytes. A recent study by Monteiro-Riviere et al. analyzed the invasion of TiO2 and ZnO NPs into porcine UVB-damaged skin in vivo and in vitro[17]. Both TiO2 and ZnO NPs penetrated only into the superficial layers of the epidermis. The authors used NPs similar to those applied in commercial sunscreens. Although penetration was enhanced as compared with healthy skin, only the upper layers of the epidermis were affected. In comparison to TiO2 NPs, ZnO NPs invaded the stratum corneum even less. Recently, Lin et al. did not observe any skin penetration of ZnO NPs in intact and tape-stripped human skin as analyzed by time-correlated single-photon counting [18]. In general, the likelihood of NP contact with basal keratinocytes depends on the extent of the stratum corneum defect and increases in cases of severe skin damage. In the opinion of the authors, exposure of ZnO NPs to damaged skin should still not be proclaimed as being safe, since there is a lack of studies investigating severely injured skin.ConclusionThe stratum corneum seems to prevent ZnO NP contact with viable skin cells sufficiently. However, although one has to acknowledge the beneficial protective effects of sunscreens against UV-induced skin damage, including malignancies, there is also evidence from in vitro data that ZnO NPs have geno- and cytotoxic, as well as immunogenic, potential in viable keratinocytes. This is why subsequent investigations on the dermal toxicity of ZnO NPs should primarily address skin penetration mechanisms. Future studies should also concentrate on the relationship between particle size and skin penetration, taking into account specific NP surface properties in order to define detailed risk profiles for sunscreen ingredients. More data must also be acquired about NP skin penetration in compromised and severely damaged – for example, sunburned – skin, since reports in this area are very limited.Future perspectiveNP invasion into healthy and compromised tissue as well as penetration into cellular compartments will be a focus of nanotoxicological studies in the years to come. Advanced 3D cell culture models for the skin may help to perform detailed in vitro studies.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Green A, Williams G, Neale R et al. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download