Sunscreens have become a quasi-exclusive mode of protection used by the public when engaged in outdoor activities (42,43), even though seeking shade and wearing protective clothing provide more protection. The popularity may be attributed to the recommendation from physicians (44) and marketing actions from the sun care and cosmetic industry (45). Nevertheless, routine use has been shown to reduce skin cancers and slow the photoaging process. Sunscreen is effective in decreasing the number of actinic keratoses (46) and squamous cell cancers (SCCs) (47). In a subsequent study with more than 8 years of follow up, a more dramatic preventive benefit in the reduction of SCC was observed (48). As for basal cell carcinomas (BCCs), the protective benefit is not conclusive. A statistically significant reduction of BCCs with routine use of sunscreens has not been demonstrated. However, there is an overall trend showing a decreased incidence of BCCs (47,48). As for the protective role of sunscreens in melanoma, there have been intense scientific discussions that periodically spill over and land in the headlines of the general media. The major controversy centers on the debate about whether sunscreen use can lead to an increase in melanoma. Epidemiologic studies are mixed with some showing preventive benefit, whereas others showing an increased risk for developing melanoma. A recent meta-analysis concluded that sunscreens use is safe, and sunscreens use does not increase the risk for developing melanoma (49). Many confounding factors may explain the lack of protective effect with routine sunscreen use. Diffey et al. summarized this well in suggesting that most sunscreens in the past offered no or little UVA protection (50). It is foreseeable that future studies involving the use of sunscreen with more balanced coverage may show the protective benefit for melanoma and BCCs.
Aside from skin cancer prevention, sunscreens offer other medical and cosmetic benefits. Many tell-tale signs of aging, such as the formation of wrinkles, appearance of pigmentations, dilation of blood vessels, and loss of collagen, are accelerated by UV exposure. Routine use of sunscreen can attenuate and slow down this process (51). In addition, many first line treatments of photodermatoses involve the use of sunscreens. For example, it is recommended that patients with polymorphic light eruption use broad spectrum sunscreens to reduce the frequency of flares (52). Similarly, broad spectrum sunscreens can attenuate the immunosuppressive effects of UV rays (53) and reduce the severity of cutaneous lupus erythematosus (54).
In the United States, sunscreens are regulated by the Food and Drug Administration (FDA). At the moment of completing this review, there are only 16 active ingredients that are approved (Table 4), and it is expected that additional actives, and new combinations of actives, may be accepted once the much anticipated sunscreen monograph is passed by the FDA. For ease of understanding, the discussion on sunscreen actives is divided into two groups: inorganic and organic.
Inorganic sunscreens work by both scattering and absorbing UV rays. Currently, in the United States, there are only two inorganic filters, titanium dioxide (TiO2) and zinc oxide (ZnO), approved by the FDA. Compared with the organic actives, TiO2 and ZnO offer a number of advantages. Both actives are photostable, yielding sunscreen products with predictable degrees of photoprotection after UV exposure. By contrast, some organic actives, such as avobenzone, are photolabile and may lose 50% of photoprotective property after 1 hour of UV exposure if not stabilized properly. Both TiO2 and ZnO have low allergenic potential and low rates of sensitization. Finally, ZnO offers protection extending to the UVA I (up to 380 nm) range (55), but the magnitude of UV protection from ZnO is low compared with other organic UV filters.
Despite these advantages, the public has always resisted embracing inorganic sunscreens, especially the early generation of these products. The reluctance is largely caused by the large particle size and high refractive indices of both TiO2 (refractive index = 2.6) and ZnO (refractive index = 1.9), which result in unsatisfactory whitening appearance. With a higher refractive index, TiO2 products appear whiter than ZnO products when applied to the skin. Aside from the cosmetic shortcomings, large particles and poor dispersion also create a gritty sensation when the sunscreens dry. Lastly, the opaque nature and occlusive qualities of these products are comedogenic.
To address these shortcomings, enormous progress has been made in the past decade to reduce the particle size of the ZnO and TiO2. Decreasing the size leads to less scattering of visible light and improvement in the cosmetic appearance. However, in the progress toward micronizing these particles, there is a growing trend to incorporate nano-scaled TiO2 and ZnO in the sunscreens. Conventionally, nanoparticles are defined as particles with dimensions less than 100 nm. Partially because of the massive increase in surface area-to-volume ratio, nanomaterials exhibit new optical, mechanical and electrical properties that are vastly different from their conventional-sized counterparts. These new properties can also lead to unpredictable outcomes when they interact with biological tissues. For this very reason, there is a growing concern regarding the safety profile of personal care products containing nanomaterials.
In the case of sunscreen, nano-sized ZnO and TiO2 provide superior UV protection while further eliminating the unsightly white residues. Titanium dioxide particles with size in the 20- to 30-nm range provide the optimal UV absorption/scattering properties, whereas zinc oxide particles with size from 60 to 120 nm offer the most favorable UV protection. Each year, thousands of tons of these nanomaterials are produced for sunscreen formulation. Along with the rising popularity, there is also an increased scrutiny from the nonprofit organizations, scientific communities, and governmental regulatory agencies regarding safety issues, specifically relating to the skin penetration and toxicity profiles of these newer formulations.
Regarding the issue of penetration, the major concern is that these nanoparticles can penetrate the skin barrier with relative ease and interact with living cells in the lower portion of the epidermis. However, a large number of in vitro and in vivo studies using murine, porcine, or human skin have shown that the nano-sized TiO2 and ZnO remain at the stratum corneum level (56–65). There is no increased level of penetration when compared to the macro-sized counterparts. In studies that showed penetration of these nanoparticles, most of these nanomaterials are found in the pilosebaceous openings and superficial portion of the follicles. A number of factors may explain the poor penetration through the stratum corneum. From research in the field of transdermal drug delivery, it is known that the penetration of molecules through the stratum corneum depends on a number of factors, such as the concentration and molecule size. Small compounds with a molecular weight between 163 and 357 Da (molecular size between 0.8 and 1.6 nm) can penetrate the skin barrier with ease. Nanoparticles often form larger aggregates and conglomerates once incorporated in the final sunscreen formulation. The sizes of these aggregates often exceed 100nm, which is 10–100 times larger than the desired 1.6 nm (molecular weight 163 to 357 Da). Lastly, it is worth mentioning that most studies are focused on healthy skin with intact stratum corneum. There may be an increase in penetration of nanomaterials through compromised or diseased skin. However, to date, a review of the literature suggests that there is no conclusive evidence showing compromised skin always lead to greater penetration (66). In some diseases, such as psoriasis, hyperkeratosis leads to reduced penetration.
The toxicity profile of nanoparticles after topical application depends on exposure to living cells and intrinsic toxicity of TiO2 and ZnO. From the discussion earlier, there is no evidence of showing increased penetration into living cells with the use of nanoparticles in sunscreens. TiO2 and ZnO have low intrinsic toxicity profile. Both compounds have been on the market for many decades, and both have low or no incidence of adverse skin or systemic effects. Furthermore, Zn is considered as an essential nutrient with known health benefits, and Ti has been used in many food additives. The toxicity concern for nanoparticle TiO2 and ZnO arose following a study showing TiO2 were photogenotoxic in mouse lymphoma and Chinese hamster lung cells (67). The presumed mechanism is the production of hydroxyl radicals from TiO2 after UV exposure, which leads to DNA strand breakage (68). To demonstrate the safety profile, producers of TiO2-based sunscreens tested 10 different sunscreen grade TiO2, including nano- and micro-sized particles, for genotoxicity (Ames test, clastogenicity in mammalian cells), photo-genotoxicity (photo-Ames test in mammalian cells), and cytotoxicity (CHO and V-79 cells). Their conclusion suggested these TiO2 particles were not cytotoxic, phototoxic, genotoxic, or photogenotoxic. Furthermore, there was no significant difference between the nano- and micro-sized particles (69). The toxicity issue was also examined by the European Commission where sunscreen preparations containing nano-sized TiO2 and ZnO were reviewed. The results suggested that these materials are not toxic, irritating, sensitizing or photosensitizing after topical application (70,71).
In summary, inorganic sunscreens with nano- or micro-sized TiO2 and ZnO are effective in providing UV protection while preserving the cosmetic elegance. Current studies suggest that these nanoparticles do not show an increased penetration and have a good safety profile. Currently, there is no regulation in the United States regarding the testing and labeling standards for sunscreens with nano-TiO2 and ZnO. This deficiency will not be addressed in the new FDA sunscreen monograph scheduled to be released in the end of 2009.