Widespread Use of Toxic Skin Lightening Compounds: Medical and Psychosocial Aspects

Published:October 14, 2010DOI:https://doi.org/10.1016/j.det.2010.08.010

      Keywords

      Disorders of hyperpigmentation and skin lightening treatments have a significant impact on the dermatologic, physiologic, psychologic, economic, social, and cultural aspects of life. Skin lightening compounds or bleaching agents are chemicals used to achieve a lighter skin tone or whiten skin. These compounds are commonly used by individuals with hyperpigmentation disorders, such as melasma and postinflammatory hyperpigmentation (PIH), or those that desire lighter skin for cosmetic reasons. The most commonly used skin lightening products contain hydroquinone, topical corticosteroids (TCs), or mercury. Despite their apparent effectiveness, numerous cutaneous and systemic complications have been associated with these agents (Table 1), resulting in more stringent regulations regarding the preparation and distribution of skin lightening products. In addition to the medical implications and patient safety concerns, the psychosocial aspects of hyperpigmentation disorders are important to consider, particularly their impact on quality of life, to further elucidate the motivations for skin bleaching.
      Table 1Adverse effects of skin lightening compounds
      HydroquinoneMercurialsTopical Corticosteroids
      Allergic contact dermatitisAllergic contact dermatitisAllergic contact dermatitis
      HyperpigmentationHyperpigmentationSkin atrophy/striae atrophica
      Corneal melanosis/degenerationAnxiety/depression/psychosisAcne vulgaris/periooral dermatitis
      Exogenous ochronosisErythrodermaCellulitis/dermatophytosis
      Conjunctival pigmentationAcute tubular necrosisCataracts/glaucoma
      TrimethylaminuriaMembranous nephropathyHypertrichosis
      Impaired wound healingPeripheral neuropathyRosacea/telangiectasia
      Nail discolorationPositive antinuclear antibody testAdrenal suppression/Cushing syndrome
      Squamous cell carcinoma?TremorSquamous cell carcinoma?

      Medical use of topical skin lightening compounds

       Hydroquinone

      The most commonly used over-the-counter (OTC) and prescription skin lightening preparation is a ubiquitous phenol compound known as hydroquinone or 1,4-dihydroxybenzene.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      Topical application of hydroquinone competitively inhibits melanogenesis through suppression of tyrosinase
      • Jimbow K.
      • Obata H.
      • Pathak M.A.
      • et al.
      Mechanism of depigmentation by hydroquinone.
      and subsequent release of semiquinone free radicals, which are toxic to melanosomes.
      • Denton C.R.
      • Lerner A.B.
      • Fitzpatrick T.B.
      Inhibition of melanin formation by chemical agents.
      In rat and human skin in vitro studies, hydroquinone has been shown to penetrate the epidermis and continue into the dermis, subcutaneous tissue, and circulation.
      • Barber E.D.
      • Hill T.
      • Schum D.B.
      The percutaneous absorption of hydroquinone (HQ) through rat and human skin in vitro.
      Hydroquinone’s ability to lighten skin was first reported by Oettel in 1936,
      • Oettel H.
      Hydroquinone poisoning.
      when hydroquinone ingestion caused pigmentation changes in black-haired cats, which was reversible after hydroquinone discontinuation. Shortly after, in 1941, Martin and Ansbacher
      • Martin G.J.
      • Ansbacher S.
      Confirmatory evidence of the chromotrichal activity of p-aminobenzoic acid.
      showed that hydroquinone ingestion induced graying of hair in mice. In the 1950s, hydroquinone was used as a sunscreen in the Southern United States, and users reported skin lightening as a complication.
      • Denton C.R.
      Skin protective agents.
      Since 1956, hydroquinone has been available in various OTC formulations for skin lightening purposes in the United States.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      In 1961, Spencer
      • Spencer M.C.
      Hydroquinone bleaching.
      reported the first clinical trial evaluating hydroquinone as a skin lightener, and since then hydroquinone has remained the preferred treatment for various hyperpigmentation disorders, such as melasma, PIH, and lentigines.

       Topical Corticosteroids

      TCs are subdivided according to strength (class I–VII), with class I (ie, clobetasol) being the most potent and class VII (ie, hydrocortisone) the least potent.
      • Levin C.
      • Maibach H.I.
      Topical corticosteroid-induced adrenocortical insufficiency: clinical implications.
      The strength of TCs is determined by the vasoconstriction assay, in which potency is associated with the degree of blood vessel blanching in the upper dermis.
      • Levin C.
      • Maibach H.I.
      Topical corticosteroid-induced adrenocortical insufficiency: clinical implications.
      • McKenzie A.W.
      • Stoughton R.B.
      Method for comparing percutaneous absorption of steroids.
      TCs have long been used for their skin lightening properties and are often the most commonly used skin lighteners in Africa.
      • Wone I.
      • Tal-Dia A.
      • Diallo O.F.
      • et al.
      Prevalence of the use of skin bleaching cosmetics in two areas in Dakar (Senegal).
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      TCs are believed to bleach the skin through inhibiting pro-opiomelanocortin (POMC), the precursor protein for α-melanocyte-stimulating hormone (α-MSH), which is produced in the intermediate lobe of the pituitary to stimulate epidermal melanin production.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.

       Mercurials

      Mercury exists in three forms: organic, inorganic, and elemental.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      Mercury-containing creams and ointments have been used for centuries to treat infections (ie, syphilis),
      • Cole H.N.
      • Shreiber M.A.
      • Sollman T.
      Mercurial ointments in the treatment of syphilis.
      impetigo,
      • Engler D.E.
      Mercury “bleaching” creams.
      phthiriasis (lice),
      • Vena G.A.
      • Foti C.
      • Grandolfo M.
      • et al.
      Mercury exanthem.
      and inflammatory skin diseases (ie, psoriasis),
      • Gordon B.
      • Inman P.M.
      • Trinder P.
      Mercury absorption and psoriasis.
      but more recently they have been used as skin lighteners.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      Mercurials exert their skin lightening actions through inhibition of sulfhydryl enzymes or mercaptans,
      • Denton C.R.
      • Lerner A.B.
      • Fitzpatrick T.B.
      Inhibition of melanin formation by chemical agents.
      ultimately resulting in suppression of tyrosinase (the rate-limiting enzyme in the melanin pathway) and decreased melanogenesis.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.

      Adverse effects of topical skin lightening compounds

       Hydroquinone

      Although hydroquinone is one of the most effective and popular skin lightening compounds, it has been shown to cause multiple cutaneous and systemic side effects.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      The most common acute complication of hydroquinone use is irritant contact dermatitis (up to 70% of patients) (Fig. 1), followed by PIH, hypopigmentation, and allergic contact dermatitis.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      • Balina L.M.
      • Graupe K.
      The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream.
      • Grimes P.E.
      A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation.
      Chronic complications of hydroquinone exposure include nail discoloration
      • Garcia R.L.
      • White Jr., J.W.
      • Willis W.F.
      Hydroquinone nail pigmentation.
      • Arndt K.A.
      • Fitzpatrick T.B.
      Topical use of hydroquinone as a depigmenting agent.
      • Mann R.J.
      • Harman R.R.
      Nail staining due to hydroquinone skin-lightening creams.
      or “pseudo yellow-nail syndrome,”
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      conjunctival pigmentation,
      • Anderson B.
      Corneal and conjunctival pigmentation among workers engaged in manufacture of hydroquinone.
      corneal melanosis and degeneration,
      • Anderson B.
      Corneal and conjunctival pigmentation among workers engaged in manufacture of hydroquinone.
      • DeCaprio A.P.
      The toxicology of hydroquinone—relevance to occupational and environmental exposure.
      • Naumann G.
      Corneal damage in hydroquinone workers. A clinicopathologic study.
      peripheral neuropathy,
      • Karamagi C.
      • Owino E.
      • Katabira E.T.
      Hydroquinone neuropathy following use of skin bleaching creams: case report.
      decreased skin elasticity,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      impaired wound healing,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      and wound dehiscence,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      particularly after abdominal procedures such as caesarian section or hysterectomy. Another unique complication of chronic hydroquinone use is trimethylaminuria or “fish odor syndrome,”
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Jordaan H.F.
      • Van Niekerk D.J.
      Transepidermal elimination in exogenous ochronosis. A report of two cases.
      characterized by a rotten fish body odor caused by excretion of trimethylamine in the saliva, sweat, urine, and vagina.
      • Ruocco V.
      • Florio M.
      Fish-odor syndrome: an olfactory diagnosis.
      An association between hydroquinone and squamous cell carcinoma has also been suggested, although all reported cases had a history of prior or concomitant TC use.
      • Addo H.
      Squamous cell carcinoma associated with prolonged bleaching.
      • Ly F.
      • Kane A.
      • Deme A.
      • et al.
      First cases of squamous cell carcinoma associated with cosmetic use of bleaching compounds.
      Further studies are needed to properly determine the risk of skin cancer in hydroquinone users.
      Figure thumbnail gr1
      Fig. 1A Senegalese woman with a peculiar reddish hue that some bleaching creams cause.
      The most severe and widely recognized complication of chronic hydroquinone use is exogenous ochronosis,
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      with at least 789 reported cases, 756 of which occurred in Africa.
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      Ochronosis can exist in both endogenous and exogenous form, the former associated with alkaptonuria, an autosomal recessive disorder (1:25,000) characterized by the absence of homogentisic acid oxidase (HGOA),
      • Phornphutkul C.
      • Introne W.J.
      • Perry M.B.
      • et al.
      Natural history of alkaptonuria.
      and the latter typically attributed to hydroquinone-containing compounds.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      Exogenous ochronosis has also been associated with antimalarials,
      • Ludwig G.D.
      • Toole J.F.
      • Wood J.C.
      Ochronosis from Quinacrine (Atabrine).
      • Adler I.
      • Klocker H.
      • Oettel H.J.
      • et al.
      [Problem of the liver function tests in the acute and chronic liver diseases].
      • Bruce S.
      • Tschen J.A.
      • Chow D.
      Exogenous ochronosis resulting from quinine injections.
      ; carbolic acid (phenol) leg ulcer compresses
      • Berry J.L.
      • PeatOchronosis S.
      Report of a case with carboluria.
      • Brogren N.
      Case of exogenetic ochronosis from carbolic acid compresses.
      ; resorcinol
      • Thomas A.E.
      • Gisburn M.A.
      Exogenous ochronosis and myxoedema from resorcinol.
      ; mercury
      • Levin C.Y.
      • Maibach H.
      Exogenous ochronosis. An update on clinical features, causative agents and treatment options.
      ; levodopa
      • Kaufmann B.
      • Wegmann W.
      Exogenous ochronosis after L-dopa treatment.
      ; and picric acid.
      • Levin C.Y.
      • Maibach H.
      Exogenous ochronosis. An update on clinical features, causative agents and treatment options.
      In the inherited form, HGOA enzyme deficiency leads to homogentisic acid accumulation, which polymerizes to form ochre-colored pigments that deposit in the skin, cartilage, and tendons.
      • Phornphutkul C.
      • Introne W.J.
      • Perry M.B.
      • et al.
      Natural history of alkaptonuria.
      • Van Offel J.F.
      • De Clerck L.S.
      • Francx L.M.
      • et al.
      The clinical manifestations of ochronosis: a review.
      Alkaptonuria is classically characterized by the triad of painless cutaneous hyperpigmentation (ochronosis), arthritis, and homogentisic aciduria, in which urine turns black when left standing or on contact with air or an alkali.
      • Phornphutkul C.
      • Introne W.J.
      • Perry M.B.
      • et al.
      Natural history of alkaptonuria.
      • Van Offel J.F.
      • De Clerck L.S.
      • Francx L.M.
      • et al.
      The clinical manifestations of ochronosis: a review.
      Thickening of the cartilage of the pinnae, calcification of the aortic valve and prostate gland, and dark cerumen are also characteristic.
      • Van Offel J.F.
      • De Clerck L.S.
      • Francx L.M.
      • et al.
      The clinical manifestations of ochronosis: a review.
      Although exogenous ochronosis is clinically and histologically similar to its endogenous form, it is not inherited and no systemic symptoms are observed.
      The term ochronosis (“yellow disease” in Greek) was coined by Virchow
      • Virchow R.
      Ein Fall von allgemeiner Ochronose der Knorpel und knorpelahnlichen Theile.
      in 1866, when he described a patient whose cartilage appeared blue-black grossly, but was yellow-brown when viewed microscopically. In 1901, Pick
      • Pick L.
      Uber die ochronosis klin.
      reported the first exogenous form of ochronosis in a patient with prolonged exposure to phenols. In 1975, Findlay and colleagues
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      described the first cases of hydroquinone-induced exogenous ochronosis in 35 South African Bantu women that used high-concentration (3.5%–7%) hydroquinone for several years. In 1979, Dogliotte and Liebowitz
      • Dogliotte M.
      • Leibowitz M.
      Granulomatous ochronosis—a cosmetic-induced skin disorder in blacks.
      classified exogenous ochronosis into three different stages: (1) erythema and mild pigmentation, (2) hyperpigmentation, black colloid milia, and scanty atrophy, and (3) papulonodules with or without surrounding inflammation. The first case in the United States of exogenous ochronosis caused by hydroquinone use was reported in 1983 by Cullison and colleagues,
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      which was followed with reports by Hoshaw and colleagues,
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      Connor and Braunstein,
      • Connor T.
      • Braunstein B.
      Hyperpigmentation following the use of bleaching creams. Localized exogenous ochronosis.
      and Lawrence and colleagues,
      • Lawrence N.
      • Bligard C.A.
      • Reed R.
      • et al.
      Exogenous ochronosis in the United States.
      all in patients using low-concentration (≤3%) hydroquinone for a short duration (≤1 year). Although various theories exist regarding the pathogenesis of exogenous ochronosis, the most accepted is that of Penneys'
      • Penneys N.S.
      Ochronosislike pigmentation from hydroquinone bleaching creams.
      which attributes the condition to hydroquinone’s inhibition of the enzyme HGOA, leading to the accumulation of homogentisic acid, which then polymerizes to form ochre pigments in the papillary dermis.
      Exogenous ochronosis is characterized by gray-brown or blue-black macules coalescing into patches, which are occasionally accompanied by pinpoint, dark brown, caviar-like papules.
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      • Dogliotte M.
      • Leibowitz M.
      Granulomatous ochronosis—a cosmetic-induced skin disorder in blacks.
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      Exogenous ochronosis is typically symmetrically distributed in photoexposed areas, particularly over osseous surfaces in the infraorbital and zygomatic regions,
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      leading some to speculate that ultraviolet exposure might be a risk factor.
      • O’Donoghue M.N.
      • Lynfield Y.L.
      • Derbes V.
      Ochronosis due to hydroquinone.
      Histologically, exogenous ochronosis is characterized by normal epidermis, curved ochre-colored banana-shaped structures in the papillary dermis, dermal solar elastosis, and degeneration of collagen and elastic fibers.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      Occasionally, sarcoid-like granulomas with multinucleated giant cells are seen surrounding the ochronotic particles.
      • Bruce S.
      • Tschen J.A.
      • Chow D.
      Exogenous ochronosis resulting from quinine injections.
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      • Jacyk W.K.
      Annular granulomatous lesions in exogenous ochronosis are manifestation of sarcoidosis.
      On dermoscopy, blue-gray amorphous areas can be seen obliterating follicular openings.
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      The ochronotic pigment stains blue-black with methylene blue and black with Fontana stain; they do not stain with Prussian blue for iron.
      • Connor T.
      • Braunstein B.
      Hyperpigmentation following the use of bleaching creams. Localized exogenous ochronosis.
      • Tidman M.J.
      • Horton J.J.
      • MacDonald D.M.
      Hydroquinone-induced ochronosis—light and electronmicroscopic features.
      Several modalities have been experimentally used to treat exogenous ochronosis, but results have not been reassuring.
      • Levin C.Y.
      • Maibach H.
      Exogenous ochronosis. An update on clinical features, causative agents and treatment options.
      Some reports have noted improvement with carbon dioxide laser,
      • Diven D.G.
      • Smith E.B.
      • Pupo R.A.
      • et al.
      Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser.
      dermabrasion,
      • Diven D.G.
      • Smith E.B.
      • Pupo R.A.
      • et al.
      Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser.
      • Lang Jr., P.G.
      Probable coexisting exogenous ochronosis and mercurial pigmentation managed by dermabrasion.
      Q-switched ruby laser,
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      Q-switched alexandrite laser (755 nm),
      • Bellew S.G.
      • Alster T.S.
      Treatment of exogenous ochronosis with a Q-switched alexandrite (755 nm) laser.
      tetracycline
      • Fisher A.A.
      Tetracycline treatment for sarcoid-like ochronosis due to hydroquinone.
      and retinoic acid,
      • Diven D.G.
      • Smith E.B.
      • Pupo R.A.
      • et al.
      Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser.
      • Howard K.L.
      • Furner B.B.
      Exogenous ochronosis in a Mexican-American woman.
      whereas cryotherapy and trichloroacetic acid have not shown efficacy.
      • Diven D.G.
      • Smith E.B.
      • Pupo R.A.
      • et al.
      Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser.
      Occasionally, hydroquinone discontinuation leads to reversal of the hyperpigmentation, but this can take up to several years.
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.

       Topical Corticosteroids

      Although TCs are frequently used as skin lightening agents,
      • Wone I.
      • Tal-Dia A.
      • Diallo O.F.
      • et al.
      Prevalence of the use of skin bleaching cosmetics in two areas in Dakar (Senegal).
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      they are associated with multiple dermatologic and systemic side effects.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Ly F.
      Skin diseases associated with the use of skin-bleaching products in Africa.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      Common cutaneous complications associated with TC application include acne vulgaris,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      allergic contact dermatitis,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      • Boyle J.
      • Peachey R.D.
      Allergic contact dermatitis to Dermovate and Eumovate.
      • Lutz M.E.
      • el-Azhary R.A.
      Allergic contact dermatitis due to topical application of corticosteroids: review and clinical implications.
      skin atrophy,
      • Keane F.M.
      • Munn S.E.
      • Taylor N.F.
      • et al.
      Unregulated use of clobetasol propionate.
      • Ly F.
      • Soko A.S.
      • Dione D.A.
      • et al.
      Aesthetic problems associated with the cosmetic use of bleaching products.
      • Otley C.C.
      • Sober A.
      Over-the-counter clobetasol propionate.
      perioral dermatitis,
      • Otley C.C.
      • Sober A.
      Over-the-counter clobetasol propionate.
      hypertrichosis,
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      rosacea,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      striae atrophica,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      • Ly F.
      • Soko A.S.
      • Dione D.A.
      • et al.
      Aesthetic problems associated with the cosmetic use of bleaching products.
      and telangiectasias.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      • Keane F.M.
      • Munn S.E.
      • Taylor N.F.
      • et al.
      Unregulated use of clobetasol propionate.
      The skin on the neck seems particularly prone to atrophy, sometimes producing a rippled, “plucked chicken” appearance, otherwise known as pseudo-pseudoxanthoma elasticum.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      Chronic periocular TC use can cause ophthalmologic complications, such as cataracts and glaucoma.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      TC users are also particularly prone to developing infections such as cellulitis,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      dermatophytosis,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      erysipelas,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      folliculitis,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      and scabies.
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      Dermatophyte infections are especially common
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      and include tinea incognito,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      widespread tinea corporis
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      and tinea faciei,
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      which can mimic roseacea
      • Lee S.J.
      • Choi H.J.
      • Hann S.K.
      Rosacea-like tinea faciei.
      or lupus erythematosus.
      • Meymandi S.
      • Wiseman M.C.
      • Crawford R.I.
      Tinea faciei mimicking cutaneous lupus erythematosus: a histopathologic case report.
      • Singh R.
      • Bharu K.
      • Ghazali W.
      • et al.
      Tinea faciei mimicking lupus erythematosus.
      Furthermore, chronic users are more likely to develop viral warts,
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      which tend to appear simultaneously on the neck and upper trunk, a finding that Olumide and colleagues
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      nicknamed the “pseudo Leser-Trélat sign.”
      TC use is also associated with various systemic complications such as hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing syndrome,
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Staughton R.C.
      • August P.J.
      Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate.
      • May P.
      • Stein E.J.
      • Ryter R.J.
      • et al.
      Cushing syndrome from percutaneous absorption of triamcinolone cream.
      diabetes mellitus,
      • Nnoruka E.
      • Okoye O.
      Topical steroid abuse: its use as a depigmenting agent.
      and hypertension.
      • Bwomda P.
      • Sermijn E.
      • Lacor P.
      • et al.
      Glucocorticoid hypertension due to the use of bleaching skin cream, a case report.
      The most worrisome of these complications is HPA dysfunction causing adrenal insufficiency,
      • Levin C.
      • Maibach H.I.
      Topical corticosteroid-induced adrenocortical insufficiency: clinical implications.
      • Staughton R.C.
      • August P.J.
      Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate.
      • Tobin A.M.
      • Barragry J.
      • Kirby B.
      • et al.
      Adrenal suppression following topical use of clobetasol propionate illegally supplied as a bleaching agent.
      • Gilbertson E.O.
      • Spellman M.C.
      • Piacquadio D.J.
      • et al.
      Super potent topical corticosteroid use associated with adrenal suppression: clinical considerations.
      which can be life-threatening. Adrenal suppression has long been regarded as a complication of high-dose TCs (ie, >50 g/wk of clobetasol propionate), but patients taking low doses (ie, 7.5 g/wk) have also experienced adrenal suppression.
      • Ohman E.M.
      • Rogers S.
      • Meenan F.O.
      • et al.
      Adrenal suppression following low-dose topical clobetasol propionate.
      In 2001, Perret and colleagues
      • Perret J.L.
      • Sane M.
      • Gning S.
      • et al.
      Hypothalamo-hypophyseal-adrenal hypofunction caused by the use of bleaching cosmetics in Senegal.
      assessed the functionality of the HPA axis among decade-long TC users in Sénégal and reported significantly lower plasma cortisol levels in response to cosyntropin stimulation compared with controls.
      Another potential adverse effect from chronic daily use of a potent TC is “steroid addiction syndrome,” which is characterized by intense burning and potentially permanent erythema due to withdrawal vasodilatation.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      The irreversible form of pronounced erythema, often referred to as homme rouge, occurs more commonly in male users.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      Other less-common reactions reported with TC use include avascular necrosis of the femoral head
      • Hogan D.J.
      • Sibley J.T.
      • Lane P.R.
      Avascular necrosis of the hips following longterm use of clobetasol propionate.
      and squamous cell carcinoma.
      • Addo H.
      Squamous cell carcinoma associated with prolonged bleaching.
      • Ly F.
      • Kane A.
      • Deme A.
      • et al.
      First cases of squamous cell carcinoma associated with cosmetic use of bleaching compounds.
      Additionally, chronic use of TCs may mask other pathologic conditions, as was observed in a patient with leprosy.
      • Mahe A.
      • Ly F.
      • Badiane C.
      • et al.
      Irrational use of skin-bleaching products can delay the diagnosis of leprosy.
      The risk of these adverse reactions is potentiated when high-potency formulations are used on sites with fragile, thin skin (ie, face, armpit, groin) for prolonged periods or under occlusion, which promotes penetration.
      • Levin C.
      • Maibach H.I.
      Topical corticosteroid-induced adrenocortical insufficiency: clinical implications.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      Individuals particularly at risk for developing adrenal suppression include infants and patients with damaged skin barriers.
      • Levin C.
      • Maibach H.I.
      Topical corticosteroid-induced adrenocortical insufficiency: clinical implications.

       Mercurials

      Mercury-containing skin lightening agents or mercurials usually contain either mercury chloride or calomel and ammoniated mercury chloride, which are inorganic salts.
      • Mire A.
      Skin-bleaching: poison, beauty, power, and the politics of the colour line.
      Mercury, as thimerosal, is also commonly used in the manufacturing of mascara and other cosmetics.
      • de la Cuadra J.
      Cutaneous sensitivity to mercury and its compounds.
      Acute or chronic exposure to topical mercury-containing compounds can cause dermatologic, renal, and neurologic toxicity.
      • Engler D.E.
      Mercury “bleaching” creams.
      • Mire A.
      Skin-bleaching: poison, beauty, power, and the politics of the colour line.
      • de la Cuadra J.
      Cutaneous sensitivity to mercury and its compounds.
      Classically, mercury poisoning was associated with felt hat manufacturers, hence the name “mad hatters disease,” or in patients treated for cutaneous disorders such as syphilis or impetigo. However, skin lightening products have also emerged as a major cause of mercury toxicity.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      • Olumide Y.M.
      • Akinkugbe A.O.
      • Altraide D.
      • et al.
      Complications of chronic use of skin lightening cosmetics.
      • Oliveira D.B.
      • Foster G.
      • Savill J.
      • et al.
      Membranous nephropathy caused by mercury-containing skin lightening cream.
      • Saffer D.
      • Tayob H.
      • Bill P.L.
      • et al.
      Continued marketing of skin-lightening preparations containing mercury.
      Common cutaneous complications of mercury use include allergic contact dermatitis, flushing, erythroderma, purpura, gingivostomatitis, and nail discoloration.
      • Engler D.E.
      Mercury “bleaching” creams.
      • de la Cuadra J.
      Cutaneous sensitivity to mercury and its compounds.
      • Alexander A.M.K.
      Chronishe Quecksilbervertifang durch langdauernden Gebrauch einer Sommersprossensalbe.
      • Bockers M.
      • Wagner R.
      • Oster O.
      Nail dyschromia as the leading symptom in chronic mercury poisoning caused by a cosmetic bleaching preparation [in German].
      Chronic use of mercurial skin lighteners can cause a paradoxic hyperpigmentation, which might be caused by dermal deposition of mercury-containing granules.
      • Goeckermann W.
      A peculiar discolouration of the skin.
      Mercury-induced neuropsychiatric toxicity includes metallic taste, tremor, peripheral neuropathy, erethrism, memory loss, anxiety, depression, and psychosis.
      • Engler D.E.
      Mercury “bleaching” creams.
      • Saffer D.
      • Tayob H.
      • Bill P.L.
      • et al.
      Continued marketing of skin-lightening preparations containing mercury.
      Other complications include positive antinuclear antibody titers
      • Tang H.L.
      • Chu K.H.
      • Mak Y.F.
      • et al.
      Minimal change disease following exposure to mercury-containing skin lightening cream.
      • Silva I.A.
      • Nyland J.F.
      • Gorman A.
      • et al.
      Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in Amazon populations in Brazil: a cross-sectional study.
      and a suggested association with systemic lupus erythematosus (SLE),
      • Cooper G.S.
      • Parks C.G.
      • Treadwell E.L.
      • et al.
      Occupational risk factors for the development of systemic lupus erythematosus.
      as metallic mercury exposure has been shown to accelerate SLE development in lupus-prone mice.
      • Pollard K.M.
      • Pearson D.L.
      • Hultman P.
      • et al.
      Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice.
      Maternal use of mercury-containing soap during pregnancy has resulted in prenatal and postnatal intoxication, as mercury can cross the placenta.
      • Engler D.E.
      Mercury “bleaching” creams.
      In children, inorganic mercury exposure has also been associated with acrodynia.
      • Engler D.E.
      Mercury “bleaching” creams.
      Nephrotoxicity is another potential complication related to mercury use.
      • Oliveira D.B.
      • Foster G.
      • Savill J.
      • et al.
      Membranous nephropathy caused by mercury-containing skin lightening cream.
      • Tang H.L.
      • Chu K.H.
      • Mak Y.F.
      • et al.
      Minimal change disease following exposure to mercury-containing skin lightening cream.
      • Barr R.D.
      • Rees P.H.
      • Cordy P.E.
      • et al.
      Nephrotic syndrome in adult Africans in Nairobi.
      • Barr R.D.
      The mercurial nephrotic syndrome.
      • Soo Y.O.
      • Chow K.M.
      • Lam C.W.
      • et al.
      A whitened face woman with nephrotic syndrome.
      • Tubbs R.R.
      • Gephardt G.N.
      • McMahon J.T.
      • et al.
      Membranous glomerulonephritis associated with industrial mercury exposure. Study of pathogenetic mechanisms.
      • Kibukamusoke J.W.
      • Davies D.R.
      • Hutt M.S.
      Membranous nephropathy due to skin-lightening cream.
      In one report, 50% of young African women in Kenya who used mercury-containing skin lightening creams developed glomerular lesions.
      • Barr R.D.
      • Rees P.H.
      • Cordy P.E.
      • et al.
      Nephrotic syndrome in adult Africans in Nairobi.
      The type of mercury-associated kidney injury depends on the form of mercury and the rate of administration.
      • Oliveira D.B.
      • Foster G.
      • Savill J.
      • et al.
      Membranous nephropathy caused by mercury-containing skin lightening cream.
      Organic and metallic mercury are lipophilic and typically cause neurotoxicity, whereas inorganic mercury typically causes nephrotoxicity.
      • Magos L.
      Mercury and mercurials.
      Still, any form of mercury can cause tubular or glomerular renal disease depending on the length of contact, with acute exposure usually causing tubular injury (acute tubular necrosis) and chronic exposure usually causing glomerular injury (membranous nephropathy, immune complex–mediated glomerulonephritis, minimal change disease).
      • Oliveira D.B.
      • Foster G.
      • Savill J.
      • et al.
      Membranous nephropathy caused by mercury-containing skin lightening cream.
      • Tang H.L.
      • Chu K.H.
      • Mak Y.F.
      • et al.
      Minimal change disease following exposure to mercury-containing skin lightening cream.
      • Barr R.D.
      • Rees P.H.
      • Cordy P.E.
      • et al.
      Nephrotic syndrome in adult Africans in Nairobi.
      • Barr R.D.
      The mercurial nephrotic syndrome.
      • Soo Y.O.
      • Chow K.M.
      • Lam C.W.
      • et al.
      A whitened face woman with nephrotic syndrome.
      • Tubbs R.R.
      • Gephardt G.N.
      • McMahon J.T.
      • et al.
      Membranous glomerulonephritis associated with industrial mercury exposure. Study of pathogenetic mechanisms.
      • Kibukamusoke J.W.
      • Davies D.R.
      • Hutt M.S.
      Membranous nephropathy due to skin-lightening cream.
      Cole and colleagues
      • Cole H.N.
      • Shreiber M.A.
      • Sollman T.
      Mercurial ointments in the treatment of syphilis.
      showed that the amount of mercury applied to the skin is proportional to the amount excreted by the kidneys. Still, mercury-induced membranous nephropathy typically resolves spontaneously after exposure cessation.
      • Barr R.D.
      • Rees P.H.
      • Cordy P.E.
      • et al.
      Nephrotic syndrome in adult Africans in Nairobi.

      Psychosocial aspect

      Although dermatologic disorders are not generally considered to be life-threatening, suicide has been reported in patients with “skin failure.”
      • Monk B.E.
      • Rao Y.J.
      Delusions of parasitosis with fatal outcome.
      • Cotterill J.A.
      Dermatological non-disease: a common and potentially fatal disturbance of cutaneous body image.
      • Cotterill J.
      Skin and the psyche.
      • Cotterill J.A.
      • Cunliffe W.J.
      Suicide in dermatological patients.
      Psychodermatologic problems are more common in women, and facial symptomatology seems to be a particular risk factor for depression and suicidal ideations.
      • Cotterill J.A.
      Dermatological non-disease: a common and potentially fatal disturbance of cutaneous body image.
      Disorders of pigmentation, such as melasma, vitiligo, PIH, lentigo, and idiopathic guttate hypomelanosis, are prevalent and have been shown to significantly impact health-related quality of life (HRQOL) in a deleterious manner.
      • Pawaskar M.D.
      • Parikh P.
      • Markowski T.
      • et al.
      Melasma and its impact on health-related quality of life in Hispanic women.
      • Balkrishnan R.
      • Kelly A.P.
      • McMichael A.
      • et al.
      Improved quality of life with effective treatment of facial melasma: the pigment trial.
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      A recent United States study showed that 80% of randomly selected patients at a private dermatology clinic had pigmentation disorders that significantly affected their quality of life.
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      Approximately 47.3% of patients felt self-conscious about their skin, 32.7% felt unattractive, and 23.6% felt their disorder affected their day-to-day activities, although few patients sought or received treatment for these conditions.
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      Treatment with skin lightening agents has been shown to improve these unfavorable psychosocial and HRQOL issues.
      • Balkrishnan R.
      • Kelly A.P.
      • McMichael A.
      • et al.
      Improved quality of life with effective treatment of facial melasma: the pigment trial.
      The habitual use of skin lightening compounds has long been commonplace in Africa, particularly Ghana
      • Addo H.
      Squamous cell carcinoma associated with prolonged bleaching.
      • Addo H.
      A clinical study of hydroquinone reaction in skin bleaching in Ghana.
      (Fig. 2), Kenya,
      • Barr R.D.
      • Rees P.H.
      • Cordy P.E.
      • et al.
      Nephrotic syndrome in adult Africans in Nairobi.
      Nigeria,
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      • Adebajo S.B.
      An epidemiological survey of the use of cosmetic skin lightening cosmetics among traders in Lagos, Nigeria.
      Sénégal,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      and Zimbabwe,
      • Muchadeyi E.
      • Thompson S.
      • Baker N.
      A survey of the constituents, availability and use of skin lightening creams in Zimbabwe.
      and in India,
      • Verma S.B.
      Obsession with light skin-shedding some light on use of skin lightening products in India.
      but has recently become recognized in other parts of the world, including North America,
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      South America,
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      Central America,
      • Pichardo R.
      • Vallejos Q.
      • Feldman S.R.
      • et al.
      The prevalence of melasma and its association with quality of life in adult male Latino migrant workers.
      Great Britain,
      • Oliveira D.B.
      • Foster G.
      • Savill J.
      • et al.
      Membranous nephropathy caused by mercury-containing skin lightening cream.
      Europe,
      • Petit A.
      • Cohen-Ludmann C.
      • Clevenbergh P.
      • et al.
      Skin lightening and its complications among African people living in Paris.
      Japan,
      • Ashikari M.
      Cultivating Japanese whiteness: the ‘whitening’ cosmetics boom and the Japanese identity.
      Southeast Asia
      • Tan S.K.
      • Sim C.S.
      • Goh C.L.
      Hydroquinone-induced exogenous ochronosis in Chinese—two case reports and a review.
      (Fig. 3), and the Middle East.
      • al-Saleh I.
      • al-Doush I.
      Mercury content in skin-lightening creams and potential hazards to the health of Saudi women.
      • Hamed S.H.
      • Tayyem R.
      • Nimer N.
      • et al.
      Skin-lightening practice among women living in Jordan: prevalence, determinants, and user’s awareness.
      For more than 50 years, the mainstay of therapy for Black, White, Asian, Indian, and Hispanic individuals with hyperpigmentation disorders has been hydroquinone.
      • Toombs E.L.
      Hydroquinone—what is its future?.
      Although traditionally regarded as a female practice, men in Africa commonly use skin lighteners,
      • Mahe A.
      • Ly F.
      • Aymard G.
      • et al.
      Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
      and recent articles suggest that they are becoming popular among men in India,

      Radio NPR. In India, Skin-whitening creams reflect old biases. 2009. Available at: http://www.npr.org/templates/story/story.php?storyId=120340646. Accessed August 20, 2010.

      North America,
      • Saint Louis C.
      Creams offering lighter skin may bring risks.
      and Central America.
      • Pichardo R.
      • Vallejos Q.
      • Feldman S.R.
      • et al.
      The prevalence of melasma and its association with quality of life in adult male Latino migrant workers.
      Figure thumbnail gr2
      Fig. 2Skin lightening agents that are readily available for sale in Ghana.
      Concerns regarding hydroquinone toxicity, particularly exogenous ochronosis and potential carcinogenicity, has led to rigid regulations in Africa, an OTC ban in Europe, abolishment in Japan, and a proposed OTC ban in the United States. Despite these concerns, human exposure to hydroquinone is common, because it is typically found in cosmetics,
      • Hydroquinone I.A.R.C.
      cigarette smoke,
      • Hydroquinone I.A.R.C.
      motor fuels and oils,
      • Hydroquinone I.A.R.C.
      photograph developer,
      • Hydroquinone I.A.R.C.
      and various foods, such as blueberries,
      • Hydroquinone I.A.R.C.
      cranberries,
      • Hydroquinone I.A.R.C.
      pears,
      • Deisinger P.J.
      • Hill T.S.
      • English J.C.
      Human exposure to naturally occurring hydroquinone.
      coffee,
      • Deisinger P.J.
      • Hill T.S.
      • English J.C.
      Human exposure to naturally occurring hydroquinone.
      tea,
      • Deisinger P.J.
      • Hill T.S.
      • English J.C.
      Human exposure to naturally occurring hydroquinone.
      and wheat products.
      • Deisinger P.J.
      • Hill T.S.
      • English J.C.
      Human exposure to naturally occurring hydroquinone.
      Still, no reports of malignancy associated with hydroquinone have been confirmed, and regulatory groups have determined that evidence is insufficient to classify hydroquinone as a carcinogen.
      • Nordlund J.J.
      • Grimes P.E.
      • Ortonne J.P.
      The safety of hydroquinone.
      In fact, several large studies have shown that individuals with occupational exposure to hydroquinone have similar
      • Friedlander B.R.
      • Hearne F.T.
      • Newman B.J.
      Mortality, cancer incidence, and sickness—absence in photographic processors: an epidemiologic study.
      or decreased
      • Pifer J.W.
      • Hearne F.T.
      • Friedlander B.R.
      • et al.
      Mortality study of men employed at a large chemical plant, 1972 through 1982.
      • Pifer J.W.
      • Hearne F.T.
      • Swanson F.A.
      • et al.
      Mortality study of employees engaged in the manufacture and use of hydroquinone.
      all-cause mortality and cancer rates compared with controls. Although excessive oral ingestion of photographic developer containing hydroquinone has been associated with suicide,
      • Saito T.
      • Takeichi S.
      Experimental studies on the toxicity of lithographic developer solution.
      studies investigating intentional ingestion of hydroquinone in large quantities have reported no significant abnormalities.
      • DeCaprio A.P.
      The toxicology of hydroquinone—relevance to occupational and environmental exposure.

       Africa

      Use of skin lightening products is popular in Africa,
      • Mahe A.
      • Ly F.
      • Badiane C.
      • et al.
      Irrational use of skin-bleaching products can delay the diagnosis of leprosy.
      with an estimated prevalence of 25% to 96%.
      • Wone I.
      • Tal-Dia A.
      • Diallo O.F.
      • et al.
      Prevalence of the use of skin bleaching cosmetics in two areas in Dakar (Senegal).
      • Ly F.
      • Soko A.S.
      • Dione D.A.
      • et al.
      Aesthetic problems associated with the cosmetic use of bleaching products.
      In Sub-Saharan Africa, a desire to have lighter skin has been reported as a major motivating factor for using these products, as white skin is still associated with social privileges in certain communities.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      Several prospective studies conducted in Dakar, Sénégal showed that skin lightening is most prevalent among dark-skinned, illiterate, working, married women between 30 to 44 years of age.
      • Wone I.
      • Tal-Dia A.
      • Diallo O.F.
      • et al.
      Prevalence of the use of skin bleaching cosmetics in two areas in Dakar (Senegal).
      TCs and hydroquinone are the most frequently used lighteners, with joint hyperpigmentation, striae, and skin atrophy being the most commonly reported complications.
      • Wone I.
      • Tal-Dia A.
      • Diallo O.F.
      • et al.
      Prevalence of the use of skin bleaching cosmetics in two areas in Dakar (Senegal).
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      In a dermatologic clinic in Lagos, Nigeria, 92% of women and 5% of men reported using skin lighteners, and most were not aware that skin pigment served a protective function.
      • Ajose F.O.
      Consequences of skin bleaching in Nigerian men and women.
      A study conducted at a maternity clinic in Dakar, Sénégal by Mahe and colleagues
      • Mahe A.
      • Perret J.L.
      • Ly F.
      • et al.
      The cosmetic use of skin-lightening products during pregnancy in Dakar, Senegal: a common and potentially hazardous practice.
      showed that 68.7% of pregnant women used skin lighteners, specifically hydroquinone and highly potent TCs, throughout their gestational period, some even reporting initiating or increasing use as a result of their pregnancy. Regarding pregnancy outcomes, no significant difference was noted between skin lighteners and controls, but users of highly potent TCs had lower plasma cortisol levels, smaller placentas, and a higher rate of low birthweight infants.
      • Mahe A.
      • Perret J.L.
      • Ly F.
      • et al.
      The cosmetic use of skin-lightening products during pregnancy in Dakar, Senegal: a common and potentially hazardous practice.
      Application of these agents is of particular concern in Africa, where products are readily available without prescription and are used for prolonged periods. Percutaneous absorption is also enhanced in tropical climates because of the occlusive effect of heat and humidity.
      Exogenous ochronosis from hydroquinone use is most commonly observed in Africans (>750 of the nearly 800 reported cases),
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      but has also been described in Americans,
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      • Lawrence N.
      • Bligard C.A.
      • Reed R.
      • et al.
      Exogenous ochronosis in the United States.
      Mexicans,
      • Howard K.L.
      • Furner B.B.
      Exogenous ochronosis in a Mexican-American woman.
      Brazilians,
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      Spaniards,
      • Huerta B.M.
      • Sanchez V.M.
      Exogenous ochronosis.
      Asians,
      • Tan S.K.
      • Sim C.S.
      • Goh C.L.
      Hydroquinone-induced exogenous ochronosis in Chinese—two case reports and a review.
      and Arabs.
      • Alikhan A.
      • Daly M.
      • Wu J.
      • et al.
      Cost-effectiveness of a hydroquinone/tretinoin/fluocinolone acetonide cream combination in treating melasma in the United States.
      The high prevalence in Africa may be confounded by several factors, such as the widespread use of antimalarials in the area, which is also known to cause exogenous ochronosis; the lack of biopsies performed; and the reliance on clinical diagnosis.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      Resorcinol is also often used simultaneously with hydroquinone to hasten lightening, and the synergistic effect of these agents may contribute to the increased incidence of exogenous ochronosis in Africa.
      • Burke P.
      • Maibach H.
      Exogenous ochronosis: an overview.
      Furthermore, in South Africa, most OTC hydroquinone products are in the form of a penetrating enhancing vehicle (ie, hydroalcoholic lotion), which enhances cutaneous absorption.
      • Bucks D.A.
      • McMaster J.R.
      • Guy R.H.
      • et al.
      Percutaneous absorption of hydroquinone in humans: effect of 1-dodecylazacycloheptan-2-one (azone) and the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (Escalol 507).
      After the study by Findlay and colleagues,
      • Findlay G.H.
      • Morrison J.G.
      • Simson I.W.
      Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
      in 1980 the upper limit of hydroquinone in OTC skin lightening products in South Africa was reduced from 8% to 2%,
      • Hardwick N.
      • Van Gelder L.W.
      • Van der Merwe C.A.
      • et al.
      Exogenous ochronosis: an epidemiological study.
      although no proper studies showed this concentration to be safe.
      • Mire A.
      Skin-bleaching: poison, beauty, power, and the politics of the colour line.

       India

      Studies assessing the prevalence of skin lightening in India could not be found, although this practice accounts for approximately 61% (1000 crore rupees, $250 million) of the Indian dermatologic market.
      • Verma S.B.
      Obsession with light skin-shedding some light on use of skin lightening products in India.
      The desire for lighter skin in India likely originated from the structure of Hinduism’s social hierarchy, in which those belonging to higher castes typically had fairer complexions.

      Radio NPR. In India, Skin-whitening creams reflect old biases. 2009. Available at: http://www.npr.org/templates/story/story.php?storyId=120340646. Accessed August 20, 2010.

      Furthermore, throughout its history, India has been invaded by lighter-skinned nations, such as Great Britain, and therefore fairness, strength, and supremacy have become interconnected.

      Radio NPR. In India, Skin-whitening creams reflect old biases. 2009. Available at: http://www.npr.org/templates/story/story.php?storyId=120340646. Accessed August 20, 2010.

      Today, lighter skin is associated with superior status and beauty, as evidenced by newspaper matrimonial advertisements, in which fairness is considered a favorable factor for engagement.
      • Verma S.B.
      Obsession with light skin-shedding some light on use of skin lightening products in India.

      Radio NPR. In India, Skin-whitening creams reflect old biases. 2009. Available at: http://www.npr.org/templates/story/story.php?storyId=120340646. Accessed August 20, 2010.

      Paradoxically, in a country fixated on attaining a fair complexion, depigmentation disorders, such as vitiligo, are socially stigmatized and hinder one’s possibility for marriage.
      • Verma S.B.
      Obsession with light skin-shedding some light on use of skin lightening products in India.
      Although Indian women have used bleaching agents for decades, the skin lightening industry also has began targeting men recently.

      Radio NPR. In India, Skin-whitening creams reflect old biases. 2009. Available at: http://www.npr.org/templates/story/story.php?storyId=120340646. Accessed August 20, 2010.

      Various television, newspaper, and Internet advertisements are attempting to convey the message that lighter skin makes men more attractive and successful. For example, to promote its male-directed line of skin lighteners, Vaseline recently released a Facebook skin-whitening application, “Vaseline Men: Be Prepared,” inviting users to, “Transform your face on Facebook with Vaseline men,” adding that their product “not only whitens your skin but is also designed to reduce five types of dark spots on your face.”

       North America

      No formal studies have assessed the prevalence of skin lightening in North America. According to the US Food and Drug Administration (FDA) Over-The-Counter Miscellaneous Panel, 2% hydroquinone has long been considered a safe concentration.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      However, on August 29, 2006, the FDA proposed banning all OTC hydroquinone skin lightening agents that were not approved through the New Drug Application process.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      • Toombs E.L.
      Hydroquinone—what is its future?.
      This motion was stimulated by the increasing incidence of hydroquinone-induced exogenous ochronosis and other adverse drug reactions (most of which are reported in Africa), and several drug manufacturers’ disregard of the FDA’s request for hydroquinone safety studies.
      • Dadzie O.E.
      • Petit A.
      Skin bleaching: highlighting the misuse of cutaneous depigmenting agents.
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      The purpose of the proposal was to “establish that OTC skin bleaching drug products are not generally recognized as safe and effective (GRASE),” according to the Kefauver Harris Amendment, which was passed in 1962 to ensure that drugs demonstrated efficacy in addition to safety, a requirement included in the original Food, Drug and Cosmetics Act of 1938.
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      • Toombs E.L.
      Hydroquinone—what is its future?.
      In March 2010, the FDA
      • FDA
      Hydroquinone studies under the national toxicology program (NTP).
      announced that the National Toxicology Program would be conducting further studies on hydroquinone’s potential for reproductive toxicity and dermal carcinogenicity in mice and rats.
      Classically believed to only occur with use of high-concentration (≥3.5%) hydroquinone products used for prolonged periods (≥1 year),
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      • Findlay G.H.
      Ochronosis following skin bleaching with hydroquinone.
      exogenous ochronosis has also been reported with use of lower concentrations (≤3%)
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      • Connor T.
      • Braunstein B.
      Hyperpigmentation following the use of bleaching creams. Localized exogenous ochronosis.
      • Lawrence N.
      • Bligard C.A.
      • Reed R.
      • et al.
      Exogenous ochronosis in the United States.
      • Charlin R.
      • Barcaui C.B.
      • Kac B.K.
      • et al.
      Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy.
      • Howard K.L.
      • Furner B.B.
      Exogenous ochronosis in a Mexican-American woman.
      • Huerta B.M.
      • Sanchez V.M.
      Exogenous ochronosis.
      • Bongiorno M.R.
      • Arico M.
      Exogenous ochronosis and striae atrophicae following the use of bleaching creams.
      and acute use (≤1 year).
      • Cullison D.
      • Abele D.C.
      • O’Quinn J.L.
      Localized exogenous ochronosis.
      • Hoshaw R.A.
      • Zimmerman K.G.
      • Menter A.
      Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
      • Connor T.
      • Braunstein B.
      Hyperpigmentation following the use of bleaching creams. Localized exogenous ochronosis.
      • Lawrence N.
      • Bligard C.A.
      • Reed R.
      • et al.
      Exogenous ochronosis in the United States.
      • Howard K.L.
      • Furner B.B.
      Exogenous ochronosis in a Mexican-American woman.
      Of the 22 cases of exogenous ochronosis reported in the United States, 21 were associated with low-concentration hydroquinone (1%–2%), generally used for prolonged periods (≥1 year).
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      Thus, the average number of exogenous ochronosis cases reported in the United States is approximately one per year, or 1 in 10 million tubes sold, leading some to disagree with the FDA, believing that hydroquinone’s benefits outweigh its risks.
      • Levitt J.
      The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register.
      In 1973, mercury-containing cosmetics were banned in the United States because of safety concerns but, despite this apparent prohibition, unregulated mercurials are still readily attainable without a prescription. In 1996, mercury poisoning associated with a skin lightening product, Creme de Belleza—Manning, which was produced in Mexico and illegally imported into the United States, was reported in more than 400 Mexican-American women in Arizona, California, New Mexico, and Texas.
      • Centers for Disease Control and Prevention (CDC)
      Update: mercury poisoning associated with beauty cream—Arizona, California, New Mexico, and Texas, 1996.
      • Centers for Disease Control and Prevention (CDC)
      Mercury poisoning associated with beauty cream—Texas, New Mexico, and California, 1995–1996.
      Recently, toxicity associated with mercury-containing soap has been reported,
      • Harada M.
      • Nakachi S.
      • Tasaka K.
      • et al.
      Wide use of skin-lightening soap may cause mercury poisoning in Kenya.
      and an investigation of 50 skin lightening creams, most purchased OTC in Chicago stores and some online, detected unlawful amounts of mercury in 6 products.
      • Gabler E.
      • Roe S.
      Some skin whitening creams contain toxic mercury, testing finds.

      Alternatives to traditional skin lightening compounds

      The gold standard dermatologic agent for skin lightening has classically been hydroquinone, until regulatory agencies in Africa, Asia, Europe, and the United States questioned its safety profile. This scrutiny encouraged research into alternative agents to reduce skin pigmentation, such as aleosin, arbutin, azelaic acid, ascorbic acid, kojic acid, licorice extract, mequinol, N-acetyl glucosamine, soy proteins, and retinoids
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      (Table 2). The three primary prescription alternatives to hydroquinone are mequinol (4-hydroxyanisole), often in combination with 0.01% tretinoin and vitamin C (ascorbic acid)
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      ; azelaic acid,
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      • Fitton A.
      • Goa K.L.
      Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders.
      which is derived from Pityrosporum ovale cultures; and retinoids, in the form of adapalene, tazarotene, and tretinoin.
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      • Kimbrough-Green C.K.
      • Griffiths C.E.
      • Finkel L.J.
      • et al.
      Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial.
      The most effective OTC alternatives to hydroquinone are arbutin,
      • Hori I.
      • Nihei K.
      • Kubo I.
      Structural criteria for depigmenting mechanism of arbutin.
      extracted from the leaves of the bear-berry plant; its synthetic and more efficacious form, deoxyarbutin
      • Boissy R.E.
      • Visscher M.
      • DeLong M.A.
      DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency.
      ; and kojic acid,
      • Lim J.T.
      Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid.
      which is obtained from Aspergillus and Penicillium cultures. Other less-effective, but safer OTC alternative agents include licorice extract (liquiritin)
      • Amer M.
      • Metwalli M.
      Topical liquiritin improves melasma.
      ; soybean extract (soybean trypsin inhibitor [STI])
      • Paine C.
      • Sharlow E.
      • Liebel F.
      • et al.
      An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.
      ; N-acetyl glucosamine
      • Bissett D.L.
      • Miyamoto K.
      • Sun P.
      • et al.
      Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin.
      ; aleosin,
      • Choi S.
      • Lee S.K.
      • Kim J.E.
      • et al.
      Aloesin inhibits hyperpigmentation induced by UV radiation.
      derived from the aloe vera plant and often combined with arbutin or deoxyarbutin to enhance effectiveness
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      ; and ascorbic acid,
      • Espinal-Perez L.E.
      • Moncada B.
      • Castanedo-Cazares J.P.
      A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma.
      which is typically ineffective unless used in combination with licorice extract, retinoids, or STI.
      • Draelos Z.D.
      Skin lightening preparations and the hydroquinone controversy.
      Given the questionable toxicity of currently popular skin lighteners on the market, further investigations into effective alternative agents with enhanced safety profiles are necessary.
      Table 2Alternative skin lightening agents
      Skin LightenersMechanism of Action
      AleosinTyrosinase inhibition
      ArbutinTyrosinase inhibition
      Azelaic acidTyrosinase inhibition
      Ascorbic acidMelanogenesis inhibition
      Kojic acidTyrosinase inhibition
      Licorice extractMelanogenesis inhibition
      MequinolTyrosinase inhibition
      N-acetyl glucosamineTyrosinase glycosylation inhibition
      RetinoidsMelanogenesis inhibition
      Soy extractMelanosome transfer inhibition
      Due to potential for various cutaneous and systemic complications associated with monotherapeutic skin lightening agents, combination compounds have been manufactured to reduce toxicity and improve effectiveness. In 2002, a triple-combination cream composed of 4% hydroquinone, 0.01% fluocinolone acetonide (class VI low-potency TC), and 0.05% tretinoin or retinoic acid (Tri-Luma) was FDA-approved for the treatment of melasma. Once-daily application of this triple-combination therapy (TCT) was shown to be more effective for treating melasma than monotherapies (4% hydroquinone applied twice daily)
      • Chan R.
      • Park K.C.
      • Lee M.H.
      • et al.
      A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.
      • Cestari T.
      • Adjadj L.
      • Hux M.
      • et al.
      Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.
      and dual therapies (hydroquinone + retinoic acid; hydroquinone + fluocinolone acetonide; or fluocinolone acetonide + retinoic acid).
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      Compared with hydroquinone alone, TCT was associated with superior patient satisfaction,
      • Chan R.
      • Park K.C.
      • Lee M.H.
      • et al.
      A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.
      enhanced self-perception,
      • Rendon M.I.
      Utilizing combination therapy to optimize melasma outcomes.
      overall quality of life improvement,
      • Cestari T.F.
      • Hexsel D.
      • Viegas M.L.
      • et al.
      Validation of a melasma quality of life questionnaire for Brazilian Portuguese language: the MelasQoL-BP study and improvement of QoL of melasma patients after triple combination therapy.
      and improved cost-effectiveness,
      • Alikhan A.
      • Daly M.
      • Wu J.
      • et al.
      Cost-effectiveness of a hydroquinone/tretinoin/fluocinolone acetonide cream combination in treating melasma in the United States.
      • Cestari T.
      • Adjadj L.
      • Hux M.
      • et al.
      Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.
      as well as a comparable safety profile.
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      • Chan R.
      • Park K.C.
      • Lee M.H.
      • et al.
      A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.
      • Cestari T.
      • Adjadj L.
      • Hux M.
      • et al.
      Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.
      • Cestari T.F.
      • Hexsel D.
      • Viegas M.L.
      • et al.
      Validation of a melasma quality of life questionnaire for Brazilian Portuguese language: the MelasQoL-BP study and improvement of QoL of melasma patients after triple combination therapy.
      Furthermore, TC-induced skin atrophy has been minimal in patients using combination creams, possibly because of tretinoin, which seems to act as a protective factor by promoting dermal collagen synthesis and epidermal growth without lessening the anti-inflammatory effect.
      • Kligman L.H.
      • Schwartz E.
      • Lesnik R.H.
      • et al.
      Topical tretinoin prevents corticosteroid-induced atrophy without lessening the anti-inflammatory effect.
      Incidence of adverse events have varied among studies, with similar
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      • Cestari T.
      • Adjadj L.
      • Hux M.
      • et al.
      Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.
      and worse
      • Chan R.
      • Park K.C.
      • Lee M.H.
      • et al.
      A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.
      safety profiles reported with TCT, although all complications have been mild, with no reports of severe side effects. The most commonly reported adverse effects associated with TCT are erythema, burning, and desquamation, with few reports of minor atrophy and no reports of exogenous ochronosis.
      • Taylor A.
      • Pawaskar M.
      • Taylor S.L.
      • et al.
      Prevalence of pigmentary disorders and their impact on quality of life: a prospective cohort study.
      • Chan R.
      • Park K.C.
      • Lee M.H.
      • et al.
      A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.
      • Cestari T.
      • Adjadj L.
      • Hux M.
      • et al.
      Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.
      • Torok H.
      • Taylor S.
      • Baumann L.
      • et al.
      A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads.
      Two cases of skin atrophy related to TCT use have been reported, although reactions were mild and did not lead to treatment discontinuation.
      • Torok H.
      • Taylor S.
      • Baumann L.
      • et al.
      A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads.
      Therefore, TCT seems to be effective and exhibits a safe profile with low potential for adverse events.

      Summary

      Given the widespread use of topical skin lightening compounds, practicing dermatologists must be aware of their current clinical indications and potential adverse effects. Dermatologists should also be able to differentiate melasma from hydroquinone-induced exogenous ochronosis, because these conditions are often confused. Prescriptions for skin lightening products should be precise in terms of concentration, amount to apply, and duration of treatment. Furthermore, patients should be provided with information regarding potential adverse effects, such as exogenous ochronosis or skin atrophy, and potentiation of these toxicities if multiple lightening agents are used simultaneously. If any of the aforementioned severe effects occur, the offending agent should be discontinued and, if treatment is still necessary, an alternative prescribed, such as mequinol or azelaic acid. Further studies investigating the prevalence of skin lightener use, motivating factors, and complications are warranted in the United States, India, and other countries where skin bleaching is practiced.

      Acknowledgments

      The authors kindly acknowledge Dr Scott Norton for the generous contribution of his photographs.

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