**3.2 Systemic contact dermatitis**

*Trace Metals in the Environment - New Approaches and Recent Advances*

and oxygen reactive species (ROS). Cr(III) as the real allergen is bound to certain proteins to form the hapten, while ROS induces the releasing of interleukin-1β (IL-1β) which then activates antigen-presenting cells (Langerhans cells (LC)). Activated antigen-presenting cells bind with the hapten, mature, travel to the regional lymph nodes, and stay in paracortical T-cell areas. After that, activated antigen presenting cells-hapten complex activates naïve T cells by helping in vigorous blast formation and proliferation to become chromium-specific T cells. Activated chromium-specific T cells then travel through blood stream and recirculate to give hypersensitivity effect detecting a lower concentration of hapten in different parts of the skin. Treatment of chromium-induced contact dermatitis could be conducted in several approaches including avoiding direct contact to chromium source and topical application of chelating agent and barrier creams to prevent any cutaneous permeation, corticosteroid to relieve inflammation, and antioxidant to reduce oxidative stress [36, 50]. Various antioxidants have been tested in treating chromium-induced contact dermatitis such as *N*-acetylcysteine [51], ascorbic acid [52], pine bark extract (pycnogenol®) [53], and pterostilbene [54]. Two chelating agents, ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), also have been examined for preventing contact dermatitis, but both of these ligands showed a low effectiveness as a protecting agent [55, 56]. The developments in

*Simplified elicitation mechanism of chromium-induced contact dermatitis adapted from several references [48, 49].*

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**Figure 2.**

Systemic contact dermatitis is a kind of dermatitis elicited by systemic administration of certain allergen that previously sensitizes the skin through direct dermal contact [57]. Several groups of allergens have been identified to cause this inflammatory disease such as metals, medications, food, plants and herbals, and certain chemicals [57, 58]. Systemic administration of these allergens is also described in various routes including oral, subconjunctival, intramuscular, pulmonary inhalation, intranasal, intrauterine, endocardial, arthroplastic, intravenous, intraarticular, subcutaneous, intradermal, dental, intratubal, and endovascular [59]. The pathophysiology of this disease still remains unclear, but several mechanisms have been proposed [60–65]. Moreover, the theory suggesting type 3 immune response (antigen-antibody complexes) involved in systemic contact dermatitis (SCD) has not fully been proven [58].

Chromium as a metal allergen has been found to cause systemic contact dermatitis either through oral, dental, or arthroplastic routes [13, 66, 67]. Consumption of Cr(III)-based supplements in the form of chromium picolinate [68] and chromium chloride [69] has been shown to cause SCD. Oral ingestion of potassium dichromate previously used as a homeopathic drug also induces dermatitis as clinical manifestation of SCD [70, 71]. In certain case, SCD is also induced by various metal alloys applied in orthopaedical, cardiac, neurological, and abdominal associated devices [72]. In these cases, chromium-containing alloys such as stainless steel SAE 316 L, cobalt-chromium-molybdenum steel, and Vitalium™ release metal ion [73] are reported to cause SCD [74–79]. These reported SCD cases are identified with the presence of several manifestations including erythroderma [74], and localized/generalized eczema or urticarial [76–78]. These findings suggested that any chromium sources applied in systemic routes could elicit SCD with certain clinical manifestations and degrees of severity.

Treatment of chromium-induced systemic contact dermatitis may be conducted in several approaches including managing diets and lifestyles by gut remediation and avoiding the food and sources that contain chromium; systemic or topical treatment using immune-suppressants such as corticosteroid; phototherapy; and hyposensitization therapy [80, 81]. Sharma developed a guideline for the preparation of low chromate diet that could help in controlling daily chromium consumption from food and ameliorating skin condition [82]. In case of SCD from arthroplastic routes, revision or removal of implant needs to be conducted by considering the time of hypersensitivity incidence after surgery and degree of severity [74]. Revision of implant could be conducted by using less allergenic implant such as titanium-based implant or chromium-based implant coated with certain biocompatible materials such as polytetrafluoroethylene, ZrN multilayers, diamond-like carbon, titanium nitride, graphite-like carbon, and tantalum [74, 79, 83]. Revision or removal of implants may not produce rapid disappearance [76] probably due to the presence of soluble or particulate debris of implant that produce inflammations [84, 85].

#### **3.3 Skin cancer**

Chromium, especially Cr(VI), is a potent human carcinogen. In a human cell, carcinogenesis of chromium(VI) (**Figure 3**) occurs through the penetration of chromium(VI) species into the cell via sulphate/phosphate anion transport system, reduction of chromium(VI) by endogenous antioxidant to produce ROS and chromium(III), and alteration of DNA directly by chromium(VI) or indirectly by ROS [86]. The alteration of DNA then produces different types of products including Cr-DNA adducts, DNA–protein and DNA interstrand cross-links, DNA breaks, and DNA base damage [87]. Carcinogenicity of chromium(VI) has induced lung cancer in workers from various chromium-based industries [88–90] and has been associated to incidence of other cancers [91]. However, the meta-analysis study showed that the correlation between exposure of chromium(VI) and the high mortality in skin cancer is not significant [91]. This study indicated that there is no supporting data confirming the chromium species as carcinogen in inducing skin cancer in human.

Several studies, however, showed that chromium species could induce skin cancer in rats and mice either as single carcinogen or cocarcinogen. Oral administrations of drinking water containing sodium dichromate dehydrate to male F344/N rats for 2 years showed that the sample developed various types of skin cancer [92]. Two other studies using hairless SK1-hrBR mice also exhibited that chromium(VI) could act as cocarcinogen in promoting UV-induced skin tumor [93, 94]. Davidson and co-workers [93] showed that oral administration of chromium(VI)-containing drinking water and UV irradiation to hairless mice have synergistic effect in promoting skin tumor. Exposure of chromium(VI) or UV radiation alone did not induce skin tumors [93]. Uddin and co-worker also conducted the same experiment and found that systemic administration of exogenous antioxidant (vitamin E and selenomethionine) did not improve skin condition [94]. It indicated that chromium(VI) cocarcinogenicity may be occurred in different mechanisms without involving ROS [94]. These three studies indicate that acute or chronic oral administration of chromium(VI) species has a great potency in promoting skin cancer in mammals including humans.

**129**

*Dermatologic Toxicities and Biological Activities of Chromium*

Irritation and chemical burn are caused by dermal exposure of chromium(VI) particle, solution, or mist in large quantities. Solid deposition of chromium(VI) would develop to "chromium ulcers" or "chrome holes" [67], while high concentration of chromium(VI) solution would lead to chromium burn. A mechanism for this ulcer formation is still unclear, but it may be related to the disruption of actin cytoskeleton by chromium(VI) leading to mitochondria-dependent apoptosis in skin fibroblasts cells [96]. Several reports exhibited these irritation and burning effects from different chromium species such as solid CrO3 [97], chromic acid solution [98–100], hot chromium(III) sulphate solution [101, 102], and chromium acid

Management of irritation is conducted by considering preventive and treatment approaches. Prevention of irritation is conducted by using barrier creams, moisturizers, etc., while treatment could be done by using moisturizers and corticosteroids [50]. For chromium burn, treatment is conducted by combining mechanical excision, hemofiltration, and systemic administration of chelating agent and antioxi-

Human hair is naturally exposed to a certain amount of chromium [104] that come from various sources [105–107]. Excessive and repeated exposures of chromium in certain environmental condition cause discoloration of blond, dyed-blond, and white hair (to become green) [108–110] and cause rapid hair fall [111, 112]. The mechanisms of these two effects are still unclear. Hair discoloration is probably the result of interaction between chromium ions (and also copper and nickel) and protein in hair (keratin) [113], while rapid hair fall may be related to several mechanisms such as promoting premature end of hair cycle [114] or disruption of

Acne vulgaris is a common dermatological condition that affects physical and psychological aspects of patients [116]. Several diseases that show the presence of a certain degree of acne also relate with depression and emotional stress such as type-2 diabetes, rheumatoid arthritis, and polycystic ovarian syndrome (PCOS) [117–119]. Pathophysiology of this disease involves several key mechanisms including excessive sebum production due to hormonal and environmental conditions, alteration of fatty acids composition due to sebum metabolism by *Cutibacterium acnes*, hyperkeratinization within the follicle that clogs up the pore in the form of whitehead or blackhead comedones, inflammation induced by bacterial colonization, and malfunction of locale innate and adaptive immune system [120]. The presence of acne vulgaris is also correlated to the clinical depression in patients [116]. In this case, depression or stress can influence the regulation of sebaceous gland as the main part in sebum production [121]. Catecholamines (epinephrine and norepinephrine) as the main stress hormones also affect the growth of certain *Cutibacterium acnes* strains [122–124]. Catecholamine-treated *C. acnes* strain also can stimulate a limited but significant increase of lipid production in sebaceous

*DOI: http://dx.doi.org/10.5772/intechopen.90347*

**3.4 Irritation and chromium burn**

mist [103].

dant [100].

**3.5 Hair disorders**

hair shaft formation [115].

**4.1 Acne vulgaris (antiacne)**

**4. Biological activities of chromium**
