Skin is an important barrier, protecting against insult from the environment. The skin is structured in three layers: the epidermis, the dermis and the subcutaneous layer. The outer layer of the epidermis, the stratum corneum (SC), covers the entire outside of the body and only contains dead cells, which are strongly keratinized. For most chemicals the SC is the rate-limiting barrier to percutaneous absorption (penetration). The skin of most mammalian species is, on most parts of the body, covered with hair. At the sites, where hair follicles grow, the barrier capacity of the skin differs slightly from the "normal" stratified squamous epidermis. Most studies concerning penetration of materials into the skin have focussed on whether or not drugs penetrate through the skin using different formulations containing chemicals and/or particulate materials as a vehicle. The main types of particulate materials commonly used are: liposomes; solid poorly soluble materials such as TiO2 and polymer particulates and submicron emulsion particles such as solid lipid nanoparticles. The penetration of these particulate carriers has not been studied in detail.
TiO2 particles are often used in sunscreens to absorb UV light and therefore to protect skin against sunburn or genetic damage. It has been reported by Lademann et al
] that micrometer-sized particles of TiO2 get through the human stratum corneum and even into some hair follicles – including their deeper parts. However, the authors did not interpret this observation as penetration into living layers of the skin, since this part of the follicular channel (the acroinfundibulum) is covered with a horny layer barrier too [82
]. A different interpretation has been suggested in a recent review by Kreilgaard [83
], who argued that "very small titanium dioxide particles (e. g. 5–20 nm) penetrate into the skin and can interact with the immune system". Tinkle et al [84
] demonstrated that 0.5- and 1.0 micron particles, in conjunction with motion, penetrate the stratum corneum of human skin and reach the epidermis and, occasionally, the dermis. The authors hypothesised that the lipid layers within the cells of the stratum corneum form a pathway by which the particles can move [85
] into the skin and be phagocytized by the Langerhans cells. In this study the penetration of particles is limited to particle diameter of 1 micron or less. Nevertheless, other studies reported penetration through the skin using particles with diameters of 3–8 micron [86
] but only limited penetration was found often clustered at the hair follicle (see above).
Penetration of non-metallic solid materials such as biodegradable poly(D,L-lactic-co-glycolic acid (PLGA) microparticles, 1 to 10 micron with a mean diameter of 4.61 ± 0.8 micron was studied after application on to porcine skin. The number of microparticles in the skin decreased with the depth (measured from the airside towards the subcutaneous layer). At 120 micron depth (where viable dermis present) a relatively high number of particles was found, at 400 micron (dermis) some micro-particles were still seen. At a depth of 500 micron no microparticles were found [88
]. In the skin of individuals, who had an impaired lymphatic drainage of the lower legs, soil microparticles, frequently 0.4–0.5 micron but as larger particles of 25 micron diameter, were found in the in the dermis of the foot in a patient with endemic elephantiasis. The particles are seen to be in the phagosomes of macrophages or in the cytoplasm of other cells. The failure to conduct lymph to the node produces a permanent deposit of silica in the dermal tissues (a parallel is drawn with similar deposits in the lung in pneumoconiosis). This indicates that soil particles penetrate through (damaged) skin, most probably in every individual, and normally are removed via the lymphatic system [89
]. Liposomes penetrate the skin in a size dependent manner. Micro-sized, and even submicron sized, liposomes do not easily penetrate into the viable epidermis, while liposomes with an average diameter of 272 nm can reach into the viable epidermis and some are found in the dermis. Smaller sized liposomes of 116 and 71 nm were found in higher concentration in the dermis.
Emzaloid™ particles, a type of submicron emulsion particle such as liposomes and nonionic surfactant vesicles (niosomes), with a diameter of 50 nm to 1 micron, were detected in the epidermis in association with the cell membranes after application to human skin [91
]. The authors suggested that single molecules, which make up the particles, may penetrate the intercellular spaces and, at certain regions in the stratum corneum, are able to accumulate and reform into micro spheres. In a subsequent experiment, it was shown that the used formulation allowed penetration of the spheres into melanoma cells, even to the nucleus [92
A recent review by Hostynek [93
] stated that the uptake of metals through the skin is complex, because of both exogenous factors (e.g. dose, vehicle, protein reactivity, valence) and endogenous factors (e.g. age of skin, anatomical site, homeostatic control). Attempts to define rules governing skin penetration to give predictive quantitative structure-diffusion relationships for metallic elements for risk assessment purposes have been unsuccessful, and penetration of the skin still needs to be determined separately for each metal species, either by in vitro or in vivo assays.
Only limited literature on nanoparticles penetrating the skin is available, but some conclusions can already be drawn. Firstly, penetration of the skin barrier is size dependent, nano-sized particles are more likely to enter more deeply into the skin than larger ones. Secondly, different types of particles are found in the deeper layers of the skin and at present it is impossible to predict the behaviour of a particle in the skin. And finally, materials, which can dissolve or leach from a particle (e.g. metals), or break into smaller parts (e.g. Emzaloid™ particles), can possibly penetrate the skin. We did not find any direct indication that particles, that had penetrated the skin, also entered the systemic circulation. The observation that particles in the skin can be phagositized by macrophages, Langerhans cells or other cells is a possible road towards skin sensitisation. Tinkle et al
] have shown that topical application of beryllium, to C3H mice, generated beryllium-specific sensitisation. These data are consistent with the development of a hapten-specific, cell-mediated immune response.
5.1 Mechanical irritation of skin
Glass fibres and Rockwool fibres are widely distributed man-made mineral fibres because of their multiple applications, mainly as insulation materials, which have become important for replacing asbestos fibres. In contact with the skin, these fibres can induce dermatitis through the mechanical irritation. Why these fibres are such strong irritant has not been examined in detail. In occlusion irritant patch tests in humans it was found that Rockwool fibres with a diameter of 4.20 ± 1.96 micron were more irritating than those with a mean diameter of 3.20 ± 1.50 micron. The fact that "small" fibres can cause strong skin irritation has been known for a long time, e.g. itching powder. It is also commonly accepted that some types of man made fibres can easily induce non-allergic dermatitis. Although this is common knowledge, it is not clear what makes these fibres irritants. In search for reports on skin irritation caused by fibres with a diameter of < 100 nm no information could be found, indicating that more research is needed.