The daily requirement for zinc in men and women is 11 and 8 mg day−1, respectively (Table 1). Interestingly, approximately 11% of the body's Zn is associated with the epidermis . From a biochemical point of view, Zn represents a dominant cofactor for many enzymes (Table 2) [38, 39], including those involved in wound healing , and most recently has been hypothesized to function as a non-traditional antioxidant .
Although Zn appears to be safe and effective in many topical applications, it is not totally innocuous. For example, in wound-healing studies, topical application of ZnCl2 and ZnSO4 were not only irritating, but also delayed barrier repair . However, despite several exceptions, Zn compounds appear to offer the greatest therapeutic potential of all the metal minerals as evidence by the number of FDA-approved usages . Table 3 lists the four product categories and zinc compounds approved for over-the-counter (OTC) uses [42-47].
Table 3. Use of Zinc salts and compounds approved by the FDA for over- the-counter human use
|Anti-fungal||Zn undecylenate||For the treatment of athlete's foot, jock itch and ringworm||10–25|||
|Dandruff and Seborrhoea Dermatitis||Zn pyrithione||For the control or relief of dandruff and/or seborrhoeic dermatitis. To control flakes and scalp itch||0.1–2.0|||
|Skin Protection||Zn acetate|
Promotes healing of minor skin irritation and sunburn
|Zn carbonate||Protects chafed skin associated with diaper rash and helps protect from wetness||0.2–2.0|||
|Zn oxide||Dries the oozing and weeping of poison ivy, oak, and sumac, insect bites.||1.0–25|||
|Sun Protection||Zn Oxide||Helps to prevent sunburn…||Up to 25|||
In the United States, the FDA recognizes three Zn compounds: zinc acetate (0.1–2%), zinc carbonate (0.2–2%) and zinc oxide (1–25%), as safe and effective for use as topical skin protectants . However, despite the opportunity to use the carbonate and acetate salts of zinc, almost all skin protectants are based on ZnO, probably because it is cost-effective, easily formulated and stable under aerobic conditions.
According to Lansdown et al. , the medicinal properties of zinc, in the form of calamine, were first documented more than 2000 years ago in the Ebers Papyrus. Calamine is a mixture of ZnO with approximately 0.5% Fe2O3 . As noted earlier, zinc is an essential micronutrient. Requirements are satisfied by a well-balanced diet, leading to an average daily intake of 10–15 mg day−1, consistent with a recommended daily allowance of 8 mg day−1 and 11 mg day−1 for women and men, respectively (Table 1). Clinical deficiencies of Zn were first reported in 1961 . However, from a public health perspective, this deficiency appears to be limited to developing countries.
Approximately 50% of the available Zn is localized to the cytoplasm, 30–40% in the nucleus, and the remainder is associated with the plasma membrane . Within the cytoplasm, approximately 20% is associated with the zinc-binding protein, metallothioneins (MTs); MTs are low molecular weight proteins (6–7 Kd) with a high (approximately 30%) cysteine content that appear to function as Zn and copper (Cu) storage molecules . Although the MTs are expressed constitutively in skin cells, expression is significantly up-regulated in cells exhibiting high mitotic activity such as those found in wound margins. Importantly, Zn is a cofactor in numerous biochemical reactions. Indeed, the prevalence of genes encoding zinc proteins is estimated at over 3% of the 32 000 identified genes . According to Schwartz et al. , over 300 Zn-dependent enzymes have been identified and characterized. Table 2 lists several examples. Since the early phases of wound healing requires the action of metalloproteases, it is believed that MTs function as a source of Zn++ and Cu++ necessary for metalloenzyme synthesis .
In human skin, the Zn concentration in the epidermis (50–70 μg g−1 dry weight) is higher than in the dermis (10–15 μg g−1 dry weight) . Within the epidermis, the Zn++ concentration gradient is inverted to Ca++, with higher levels localized to metabolically active basal cell layer and much less at the stratum corneum . This is not surprising because low Ca++ and high Zn++ stimulate keratinocyte proliferation [10, 11].
Studies in experimental wound models suggest that supplemental Zn enhances wound healing [40, 49]. In the rat model, Zn levels in the wound margin increase 15–20% within 24 h and increase to 30% by the time re-epithelialization begins. Although zinc's anti-microbial activity may accelerate healing, this hypothesis is not universally accepted. As noted above, proliferating cells require Zn++ and metallothioneins for the production of the Zn-requiring metalloproteinases (MMPs), RNA and DNA polymerases and many other Zn-containing enzymes. Some wound healing research suggests that the manner in which Zn is presented to the tissue may be important. Agren et al.  found ZnO to be superior to ZnSO4 in terms of mitigating inflammation and enhancing re-epithelialization of partial thickness porcine skin. The authors attributed the efficacy of ZnO to its lower water solubility, and ability to provide sustained release of Zn++ to the wound site at non-toxic levels. It is worth noting that the aqueous solubility of ZnO is much lower than almost any other Zn salt with the exception of ZnCO3 (ZnO Ksp = 3.86 × 10−10 vs. ZnCO3 Ksp = 1.4 × 10−11) . In a double-blind, placebo-controlled human clinical study, topically applied ZnO significantly promoted healing of leg ulcers . Others investigators recognize ZnO as a topical debriding agent for pressure ulcer [53, 54] and as an occlusive dressing for diabetic foot ulcers . In smaller clinical studies, investigators claim ZnO enhances healing of burn wounds , suction-blister wounds , superficial (i.e. 1 mm deep) small incisions  and the epithelialization donor graft sites . However, as noted by Lansdown  larger-scale trials are urgently required to verify the benefits of topical zinc oxide in acute human wounds.
The percutaneous penetration of ZnO has been studied [60, 61]. Although the FDA accepts the concept that penetration of ZnO through intact skin is extremely low , abrogation of the stratum corneum barrier enhances the penetration of Zn because of increased hydration. Most recently, Newman et al.  reviewed the safety of nanosized titanium dioxide and zinc oxide particles, as it relates to sunscreen products, and concluded ‘Although we found no evidence of significant penetration of titanium dioxide and zinc oxide nanosized particles beyond the stratum corneum, further studies must be carried out to simulate real-world conditions particularly in sunburned skin and under ultraviolet exposure’.
ZnO has been used in topical products for quite some time. As noted previously, one of the first FDA-approved usages of ZnO is as a skin protectant . Accordingly, products containing between 1% and 25% ZnO can claim on their label to be a ‘poison ivy, oak, sumac protectant’ and ‘to dry the oozing and weeping of poison ivy, oak, sumac’. Additionally, ZnO is approved as a broad-spectrum sunscreen agent . Unlike the organic sunscreens, the mineral sunscreens such as ZnO and TiO2 not only reduce skin penetration by UVB radiation, but also provide protection against UVA radiation. As noted in Table 3, ZnO can be used in topical sunscreen formulations up to 25% . Interestingly, consumer interest in sunscreen products based on ZnO and TiO2 has grown in recent years because of heightened consumer awareness of the damage to skin caused by increasing exposure to solar radiation and has led to the marketing of several commercial sunscreen products based solely on these mineral sunscreens. Clearly, ZnO has a long history of safe and effective use and is recognized for skin rashes such as diaper rash, prickly heat and skin conditions such as eczema, impetigo, ringworm, ulcers, pruritus and psoriasis .
Iron is one of the most abundant trace metals in the body and functions largely in oxygen transport and oxidation–reduction reactions, especially in respiration [64, 65]. As can be seen in Table 2, Fe plays a role in various oxygenases, including the skin-relevant procollagen-proline dioxygenase. One estimate suggests that 70% of the body's Fe is associated with haemoglobin . Levels in normal epidermis and psoriatic epidermis vary over a broad range [66, 67]. Much like calcium, the body's requirement for iron varies with gender and age (Table 1). For adult males, the daily iron requirement is 8 mg. Actively menstruating women require 15–18 mg day−1, whereas post-menopausal women require significantly less, only 8 mg day−1 .
Toxicity of Fe appears route specific. Higdon and Drake  note that accidental overdose of iron-containing products is the single largest cause of poisoning fatalities in children <6 year of age. In contrast to this, colour cosmetics containing iron oxide have been applied to the facial skin to beautify and/or camouflage minor imperfections since antiquity [68, 69]. Although there are few reports on the topical toxicity of iron or iron compounds, there is significant evidence from experimental animal models implicating the release of Fe from haemoglobin by UVR in the induction of cutaneous oxidative stress [70, 71]. Interestingly, iron analysis of epidermis derived from sun-exposed and unexposed skin revealed that the sun-exposed skin exhibited significantly higher levels of free iron than unexposed skin (53.0 vs. 17.8 ppm), respectively . In subsequent work, Bissett and McBride showed in guinea pig and mouse models that topical application of an iron chelator (2-furildioxime) significantly delayed UVB-induced tumour onset . To the best of our knowledge, we are unaware of any specific therapeutic usage of topical iron delivery.
Copper is an important trace mineral found throughout the body where it serves as a cofactor for several enzymes, including lysyl oxidase, the enzyme involved in cross-linking collagen, and tyrosinase, the enzyme involved in skin pigmentation . Indeed, at least one study reports the benefits of dietary supplementation on this enzyme in skin . The recommended daily allowance for Cu for healthy adult men and women over the age of 19 is 900 μg day−1 (Table 1). Although deficiencies of Cu appear rare, conditions that give rise to intestinal malabsorption (i.e. coeliac disease, bowel resection, etc.) or defective transport of Cu is frequently diagnosed because of the visible changes in skin pigmentation and/or hair growth (i.e. Menke's kinky hair syndrome) . Conversely, excessive exposure to Cu compounds is easily diagnosed by the characteristic green hue it produces in hair .
In 1973, Pickard and Thaler  isolated a tripeptide–copper complex from serum that enhanced collagen formation in cultured cells. Several commercial cosmetic products are based on a proprietary copper–peptide complex (Cu-GHK, Cu-AHK). According to a website managed by Loren Pickart, PhD, copper–peptides have been proven to calm irritated skin, improve skin elasticity and firmness, repair photodamaged skin, reduce fine lines and wrinkles, accelerate wound healing and a host of other benefits . Recently, Mazurowska and Mojski  reported on the ability of GHK-Cu and GSH-Cu to penetrate liquid crystalline liposomal membranes. Interestingly, using the same tripeptides, but with manganese as the metal ion, Hussain and Goldberg  report that topical application of a serum formulation twice daily for 12 weeks, significantly improved the visual signs of photoaged skin, especially hyperpigmentation.
Other applications of Cu compounds are related to their well-known antibacterial, anti-fungal and antiviral activities . Borkow et al. recently reported a more provocative use of Cu . In a 4-week double-blinded, randomized study involving 57 volunteers, this team observed that subjects sleeping on pillowcases containing 0.4% copper oxide exhibited significantly reduced facial wrinkles, crow's feet/lines and a global improvement in appearance. The authors attribute the improvement in skin appearance to copper's ability to penetrate the skin and stimulate the formation of extracellular matrix proteins.
Topical use of Cu appears limited because of its potential to induce oxidation–reduction reactions and general toxicity. However, one cosmetic company recently created a bimineral complex composed of copper and zinc that is claimed to generate a galvanic signal capable of reducing inflammation . In a double-blind, placebo-controlled study, Chantalat et al. [82, 83] compared the performance of a placebo formula (gel + activating moisturizer) to an active system (bimineral complex gel + activating moisturizer) to improve the appearance of individuals with photoaged skin. Although both treatments significantly (P < 0.05) improved visual signs of ageing from baseline, the bimineral complex formulation provided significantly greater improvement than the vehicle control (P < 0.05) for attributes such as skin tone and colour, skin texture, fine lines, crow's feet wrinkles, wrinkles and dark circles around the eyes. Despites its attractiveness from a marketing perspective, we believe more rigorous clinical studies are necessary to establish the value of ‘galvanic’ treatments.
Selenium is commonly found in the soil, particularly, in Western United States, where it accumulates in plants as selenomethionine and selenocysteine . In humans, these two amino acids are key components of antioxidant enzymes such as glutathione peroxidase and thioredoxin reductase . Although deficiencies in humans are rare, animal studies have implied a possible link between selenium deficiency and cancer . Oral administration of Se to mice has been shown to mitigate UVR-induced inflammation, pigmentation, hyperkeratosis and carcinogenesis [87, 88]. In a small human clinical study with 8 subjects, topical application of lotions containing selenomethionine (0.002–0.05%) – the most effective way of delivering selenium into the skin – for 2 weeks was shown to mitigate the acute effects of UV exposure . In addition to inhibiting photodamage, research in animal models suggests that selenomethionine may also reverse photoageing . However, in a recently published Cochrane Review, Dennert et al.  systematically reviewed 55 studies involving more than one million participants and was not able to establish reliable conclusions regarding a causal relationship between low selenium exposure and increased the risk of cancer and the benefits of selenium supplementation in reducing the incidence of cancer in humans.
Mechanistically, Se is believed to protect the skin and other organs through its involvement in antioxidant enzymes, especially glutathione peroxidase and thioredoxin reductase . Rafferty et al. have shown that human fibroblasts, keratinocytes and melanocytes express between 10 and 15 selenoproteins. Supplementation of culture media with either selenium or selenomethionine significantly reduced UV-induced death of keratinocytes and melanocytes . In a more recent study, Sengupta et al. used a mouse model where the Sec tRNA (the unique tRNA that codes for selenocysteine) was knocked out, limiting the animal's ability to make selenoproteins. The results of this deficiency included epidermal hyperplasia, aberrant hair follicle development progressing to alopecia and ultimately to premature death . Taken together, these results support the crucial role of selenium and selenoproteins in the well-being of skin.
In the United States, topical application of selenium sulphide is approved in rinse-off products for the treatment of dandruff and seborrhoeic dermatitis .