**1. Introduction**

Chromium is a unique transition metal with relatively high abundance on earth crust (1.4 × 10<sup>−</sup><sup>2</sup> %). Chromium can form several species with different oxidation states from −4 to +6. Chromium with 0, +3, and +6 oxidation states are most commonly found and utilized in ambient conditions [1]. In industrial sectors, chromium-based materials have been used as coating material for corrosion resistant, pigments and dyes, wood preservatives, tanning agent, catalyst, and medical apparatus [1]. Chromium, especially for chromium(III), also showed certain biological activity especially in regulating carbohydrates and lipid metabolism [2, 3]. As an essential micronutrient, a low dietary of chromium will exhibit several adverse effects such as glucose intolerance, growth disorders, diminished longevity, etc. [3, 4].

Chromium toxicity has been a controversial problem due to its status as an essential micronutrient [5]. Various studies have shown that numerous acute and chronic adverse effects can be caused by any dermal or systemic exposure of chromium species in human organ systems [6]. The toxicity and biological activity of chromium seem to be correlated directly with the concentration of corresponding chromium species [7]. In this case, chromium species have its optimum concentration to produce beneficial effects. Meanwhile, accumulation of less toxic chromium species in relatively high concentration will still produce a negative effect in the accumulation site [8, 9]. Chromium picolinate, for instance, has been mainly used as food supplement. Chromium(III) in this compound tend to accumulate in male

Sprague-Dawley rats' cells over the period of investigation [10] and may be oxidized to more carcinogenic chromium(V) and chromium(VI) within the cells [11].

As the outermost organ that protects the human body from various pollutants, the skin is usually exposed to various sources of chromium, and it causes many dermatological acute and chronic negative effects such as contact dermatitis [12], systemic contact dermatitis [13], and possibly skin cancer [14]. In the same way, any topical or systemic administration of chromium compounds also can exhibit a beneficial effect for the skin such as antiacne [15], rapid wound healing [16], and anti-aging [17]. In this chapter, both toxicity and biological activity of chromium species in the skin are described starting from the source and route of exposure, toxicity and its possible treatment, and biological activity.

## **2. Source and exposure route of chromium in the skin**

In modern life, chromium has been used in many forms and applications with Cr(0), Cr(III), and Cr(VI) as the main oxidation states. Various sources of chromium that affect or may affect the skin have been identified and tabulated in several review [12, 18, 19]. In general, exposure route of chromium that comes from these sources can be classified into two pathways including dermal and systemic pathways. In these cases, direct dermal exposure would cause contact dermatitis, irritation, and skin cancer, while systemic administration would elicit systemic contact dermatitis and skin tumor.

Dermal exposure (**Figure 1**) is initiated from direct contact of chromium sources on the skin. Chromium species are then accumulated on the skin surface or penetrated into the skin layers mediated by sweat or other biological fluids. The penetration of chromium species either as particulate or soluble forms occurred via three possible routes including transcellular by crossing the cell, intercellular by partitioning into the lipid matrix, and transappendageal by entering hair follicle and sebaceous glands [20, 21]. There are many factors involved in the penetration process including concentration of chromium species, medium (solvent and pH), intrinsic properties of chromium species (molecular volume of chromium species, counter ion, nature of chemical bond and polarity, solubility, and valence), reactivity towards protein, previous penetration or accumulation, skin characteristics (gender and race, age skin, density of sebaceous gland, thickness of skin, and anatomy of skin), and environmental factors (temperature, humidity, and UV radiation) [21, 22]. In a normal skin condition, Cr(VI) ions tend to have higher solubility [23] and percutaneous permeability than Cr(III) ions [24, 25]. However, Cr(III) have higher protein affinity to form metal-protein complex which tends to make it retain in the skin epidermis [26]. After penetrating the skin, Cr(VI) species are reduced by proteins or endogenous antioxidants to form Cr(III) [27] which then react further with any DNA or protein to form Cr(III)-protein complex as the actual allergen (haptens) [28].

In systematic exposure, chromium mostly enter the human body via oral consumption of certain chromium sources such as food or food supplement [29], foodstuff [30], and drinking water [31] or from applications of chromium-based implants [32]. In the digestive system, most of Cr(III) consumed are excreted to feces and some of it (~2%) is absorbed by epithelial cells covering the stomach and enterocytes covering the intestines through passive absorption (diffusion) [33]. This absorption was affected (increased or decreased) by the presence of various ligand such as amino acids, vitamins, carbohydrates, plasma proteins, certain metals, and other chelating agents [34]. After the absorption, Cr(III) complex would be accumulated inside the cells or actively transported to the blood stream by still an

**125**

*Dermatologic Toxicities and Biological Activities of Chromium*

unknown transporter. Cr(III) ions then bound to transferrin (siderophilin) or other

Contact dermatitis is a common skin disease caused by repeated dermal contact with certain allergens (haptens) leading to delayed-type hypersensitivity effect [35]. Many haptens have been identified to cause contact dermatitis such as metals, fragrances, and flavors, preservatives, plastics, rubber, pharmaceutical, cosmetics, woods and plants, textile, etc. [35]. Chromium-induced contact dermatitis is characterized by the presence of certain clinical manifestations in feet and hands. Acute dermatitis is usually indicated by the formation of erythema, oedema, papules, vesicles, and weeping, while chronic dermatitis tends to form scaly, dry, and fissured skin [36]. Various chromium-induced contact dermatitis cases have been reported involving different chromium sources such as cement [37, 38], leather [38–43], tattoo ink [44], cellular phone [45, 46], etc. Concentration threshold for soluble chromium in each chromium-containing product should not exceed 1 ppm

In general, chromium-induced contact dermatitis is formed through several steps which can be described as the following (**Figure 2**) [48, 49]: initially, after penetrating the skin, Cr(VI) ions are reduced by endogenous antioxidant to form Cr(III)

plasma proteins in the blood stream and travel to the whole body [33, 34].

*Several pathways of dermal exposure: (A) deposition of Cr(VI) in the skin surface causes irritation or chemical burn; (B) penetration of Cr(VI) through transcellular and intercellular pathways induces cell apoptosis and contact dermatitis, while Cr(III) tend to suspended in the skin surface due to strong affinity to skin protein; (C) deeper penetration to blood stream causes organ disruptions, (D) Cr species from systemic administration trigger systemic contact dermatitis, (E) deposition of Cr species on hair causes hair discoloration; (F) penetration of Cr species into hair follicle induces rapid hair fall. Figure is drawn using* 

**3. Toxicities of chromium**

*ChemBioDraw Ultra version 14.0 software.*

to minimize elicitation of contact dermatitis [47].

**3.1 Contact dermatitis**

**Figure 1.**

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

*Dermatologic Toxicities and Biological Activities of Chromium DOI: http://dx.doi.org/10.5772/intechopen.90347*

#### **Figure 1.**

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

toxicity and its possible treatment, and biological activity.

contact dermatitis and skin tumor.

allergen (haptens) [28].

**2. Source and exposure route of chromium in the skin**

Sprague-Dawley rats' cells over the period of investigation [10] and may be oxidized

As the outermost organ that protects the human body from various pollutants, the skin is usually exposed to various sources of chromium, and it causes many dermatological acute and chronic negative effects such as contact dermatitis [12], systemic contact dermatitis [13], and possibly skin cancer [14]. In the same way, any topical or systemic administration of chromium compounds also can exhibit a beneficial effect for the skin such as antiacne [15], rapid wound healing [16], and anti-aging [17]. In this chapter, both toxicity and biological activity of chromium species in the skin are described starting from the source and route of exposure,

to more carcinogenic chromium(V) and chromium(VI) within the cells [11].

In modern life, chromium has been used in many forms and applications with Cr(0), Cr(III), and Cr(VI) as the main oxidation states. Various sources of chromium that affect or may affect the skin have been identified and tabulated in several review [12, 18, 19]. In general, exposure route of chromium that comes from these sources can be classified into two pathways including dermal and systemic pathways. In these cases, direct dermal exposure would cause contact dermatitis, irritation, and skin cancer, while systemic administration would elicit systemic

Dermal exposure (**Figure 1**) is initiated from direct contact of chromium sources on the skin. Chromium species are then accumulated on the skin surface or penetrated into the skin layers mediated by sweat or other biological fluids. The penetration of chromium species either as particulate or soluble forms occurred via three possible routes including transcellular by crossing the cell, intercellular by partitioning into the lipid matrix, and transappendageal by entering hair follicle and sebaceous glands [20, 21]. There are many factors involved in the penetration process including concentration of chromium species, medium (solvent and pH), intrinsic properties of chromium species (molecular volume of chromium species, counter ion, nature of chemical bond and polarity, solubility, and valence), reactivity towards protein, previous penetration or accumulation, skin characteristics (gender and race, age skin, density of sebaceous gland, thickness of skin, and anatomy of skin), and environmental factors (temperature, humidity, and UV radiation) [21, 22]. In a normal skin condition, Cr(VI) ions tend to have higher solubility [23] and percutaneous permeability than Cr(III) ions [24, 25]. However, Cr(III) have higher protein affinity to form metal-protein complex which tends to make it retain in the skin epidermis [26]. After penetrating the skin, Cr(VI) species are reduced by proteins or endogenous antioxidants to form Cr(III) [27] which then react further with any DNA or protein to form Cr(III)-protein complex as the actual

In systematic exposure, chromium mostly enter the human body via oral consumption of certain chromium sources such as food or food supplement [29], foodstuff [30], and drinking water [31] or from applications of chromium-based implants [32]. In the digestive system, most of Cr(III) consumed are excreted to feces and some of it (~2%) is absorbed by epithelial cells covering the stomach and enterocytes covering the intestines through passive absorption (diffusion) [33]. This absorption was affected (increased or decreased) by the presence of various ligand such as amino acids, vitamins, carbohydrates, plasma proteins, certain metals, and other chelating agents [34]. After the absorption, Cr(III) complex would be accumulated inside the cells or actively transported to the blood stream by still an

**124**

*Several pathways of dermal exposure: (A) deposition of Cr(VI) in the skin surface causes irritation or chemical burn; (B) penetration of Cr(VI) through transcellular and intercellular pathways induces cell apoptosis and contact dermatitis, while Cr(III) tend to suspended in the skin surface due to strong affinity to skin protein; (C) deeper penetration to blood stream causes organ disruptions, (D) Cr species from systemic administration trigger systemic contact dermatitis, (E) deposition of Cr species on hair causes hair discoloration; (F) penetration of Cr species into hair follicle induces rapid hair fall. Figure is drawn using ChemBioDraw Ultra version 14.0 software.*

unknown transporter. Cr(III) ions then bound to transferrin (siderophilin) or other plasma proteins in the blood stream and travel to the whole body [33, 34].

## **3. Toxicities of chromium**

#### **3.1 Contact dermatitis**

Contact dermatitis is a common skin disease caused by repeated dermal contact with certain allergens (haptens) leading to delayed-type hypersensitivity effect [35]. Many haptens have been identified to cause contact dermatitis such as metals, fragrances, and flavors, preservatives, plastics, rubber, pharmaceutical, cosmetics, woods and plants, textile, etc. [35]. Chromium-induced contact dermatitis is characterized by the presence of certain clinical manifestations in feet and hands. Acute dermatitis is usually indicated by the formation of erythema, oedema, papules, vesicles, and weeping, while chronic dermatitis tends to form scaly, dry, and fissured skin [36]. Various chromium-induced contact dermatitis cases have been reported involving different chromium sources such as cement [37, 38], leather [38–43], tattoo ink [44], cellular phone [45, 46], etc. Concentration threshold for soluble chromium in each chromium-containing product should not exceed 1 ppm to minimize elicitation of contact dermatitis [47].

In general, chromium-induced contact dermatitis is formed through several steps which can be described as the following (**Figure 2**) [48, 49]: initially, after penetrating the skin, Cr(VI) ions are reduced by endogenous antioxidant to form Cr(III)

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

**Figure 2.**

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

**127**

**3.3 Skin cancer**

*Dermatologic Toxicities and Biological Activities of Chromium*

chromium-induced contact dermatitis are still widely opened. These developments could be focused on finding natural antioxidant and chelating agents that effectively relieve oxidative stress and reduce the reactivity of chromium ions, respectively.

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

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 manifesta-

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].

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,

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

**3.2 Systemic contact dermatitis**

not fully been proven [58].

tions and degrees of severity.

chromium-induced contact dermatitis are still widely opened. These developments could be focused on finding natural antioxidant and chelating agents that effectively relieve oxidative stress and reduce the reactivity of chromium ions, respectively.
