By Dr. AK Bajaj (Allahabad) and Dr. Abir Saraswat (Lucknow)
The colour of skin is invested with a lot of psychosocial significance in all societies. Any visible abnormality in skin colour can potentially produce significant deterioration in the quality of life. Some of the most distressed patients seen by any Asian dermatologist are those who have depigmented skin lesions. Especially in South East Asia, these patients face tremendous embarrassment and even social isolation resulting in inability to find a partner in marriage, suitable employment, etc. The authors have known patients even committing suicide due to the inability to cope with psychological burden of living with visible depigmented skin lesions. The commonest disorder causing these unsightly lesions is vitiligo, which is an idiopathic, partly genetically determined disease. However, in some cases there are identifiable and therefore preventable factors that cause depigmented skin lesions.
Chemical leucoderma occurs due to direct skin exposure to some substances that are selectively toxic to melanocytes. This exposure can occur either in the workplace or even in day-to-day life with common objects that come in contact with the skin. However, chemical leucoderma is relatively uncommon whereas the chemicals implicated in it are widely used and commonly present in the environment. From this, it is evident that some individuals have inherently “fragile” melanocytes that are more susceptible to injury upon exposure to these chemicals. It has been shown both in vitro and in vivo that certain aliphatic and aromatic derivatives of phenols and catechols are directly toxic to melanocytes, more so in genetically susceptible individuals. Other chemicals that have been implicated to cause chemical leucoderma are p-phenylenediamine, certain azo dyes, sulfhydryls, mercurials, arsenic and several drugs of chemically related classes.
Most Asian populations have black hair and consequently use hair dyes containing high concentrations of p-phenylenediamine.(PPD), which has been reported to cause contact leucoderma in some cases. Another popular cosmetic in South Asia is henna, which is used both as a semi-permanent hair dye and for producing traditional decorative tattoos on the skin. Recently, there have been several reports from all over the world, specifically Asia, of henna being adulterated by PPD and causing chemical leucoderma.
In India, we have seen that several traditional materials of cosmetic use in women are laced with these chemicals in their modern avatars. Bindi, a coloured dot worn on the centre of the forehead by Hindu women; alta, a traditional red dye used to colour the feet and hands of women; sindoor or vermilion powder applied to the hair parting and sacred threads worn as religious amulets, all contain chemicals with depigmenting potential. Our hot and humid weather allows easy penetration of these chemicals through the compromised stratum corneum. Because of these factors there have been increasing reports of chemical leucoderma in Indian patients in recent literature. Indian dermatologists have recognized these cases and we have investigated some of these agents to identify specific chemicals that have the potential to produce chemical leucoderma and the mechanisms underlying these reactions.
Bindi Leucoderma
This entity is peculiar to Hindu women form the Indian subcontinent who apply a small coloured dot called bindi to the centre of the forehead to enhance their appearance or as a mark of married status. Traditionally, mineral or vegetable based dyes were used to make the bindi. However, these would be washed off by sweat or water and the messy powder or liquid dyes had to be carried on the wearer’s person so that they could be re-applied. A modern solution to this problem was devised by producing plastic bindis in various shapes, sizes and colours that were backed by an adhesive making them easy to stick, remove and re-apply. In the early 1980s, one of us (AKB) started seeing women with depigmented spots exactly conforming to the site of wearing the sticker bindi. In many cases, this was preceded by dermatitis at the site. In a study of 100 such patients seen over a 1-year period, it was observed that most of these women were in the habit of wearing bindi continuously, day and night. A dermatitis preceded the onset of depigmentation in almost three-quarters of these women. Five of the 15 women who were patch tested with the adhesive material showed positive reaction and three out of those developed depigmentation at the test site after 15 to 60 days. Upon testing by infrared spectrophotometry and chromatography, free p- tertiary butylphenol (PTBP) in very high concentration (up to 80%) was found in various samples of the adhesive. Low concentrations of PTBP on patch testing did not produce any positive reactions, ruling out sensitization in these patients.
PTBP is a known melanocytotoxic agent and depigmentation in workers exposed to it during its manufacture has been reported from many countries, including Japan. Amongst bindi users, it affects a small fraction, suggesting that individual susceptibility may play an important role. The lag period between use and depigmentation is highly variable, ranging from a few months to a few years. Other common sources of exposure to PTBP are deodorants, spray perfumes, detergents and household cleansers, all of which have been reported to cause chemical leucoderma in Indian patients.
The treatment of bindi leucoderma hinges upon the early recognition of the condition (which is usually easy) and cessation of use of sticker bindis (which can be difficult). Orthodox Hindu women are strongly conditioned to wear a bindi at all times, especially in public. Faced with chemical leucoderma, they often resort to wearing bigger and bigger bindis in an attempt to hide the white patch. Counselling is therefore a very crucial part of treatment. While early stoppage of exposure can lead to slow spontaneous repigmentation, active treatment of bindi depigmentation is typically more difficult than vitiligo, since PTBP can permanently destroy the melanocytes .. However, topical corticosteroids and/or phototherapy are usually beneficial, with resistant cases requiring melanocyte transfer surgery.
Synthetic leather/rubber items causing leucoderma
A peculiar pattern of chemical leucoderma affecting the left breast has been reported in Indian women, who wear clothes that typically do not have any pockets, forcing them to carry their wallets tucked into their blouses. Most women are right-handed, therefore the wallet rests against the left breast. These wallets are made of synthetic leather and we have demonstrated that this contains monobenzyl ether of hydroquinone (MBH). We have also reported a patient with localized depigmentation of the external auditory meatus who was using a hearing aid earpiece containing MBH. All patients seen by us have had negative patch test results to MBH suggesting direct melanocyte toxicity or inhibition of melanogenesis. Almost all cases occur when the offending item is in tight apposition against the skin, and is kept there for prolonged periods leading to leaching of the melanotoxic chemical.Even mobile cover has been observed to produce leucoderma on the left breast and front of the ear.
We have also reported MBH induced chemical leucoderma in 19 patients who wore bathroom rubber slippers and rain shoes and developed chemical leucoderma at the exposed sites. Five of them had associated vitiligo at other sites and 6 had developed a dermatitis preceding the appearance of depigmentation. However, when patch tested to MBH, PTBP and PTBP formaldehyde resin, all were negative, indicating that the dermatitis may have been irritant in nature. Peculiar features of footwear depigmentation in India are that most of the patients wear shoes without socks and are exposed to high humidity, leading to ideal conditions for any chemicals to leach into the skin. Other common items from which synthetic leather/rubber related leucoderma has been reported are condoms, watch straps and rubber gloves.
.MBH, also known as “Agerite Alba” is a rubber antioxidant and is well known to cause chemical leucoderma at sites of direct exposure, as well as distant sites on the body of predisposed individuals. The depigmentation often starts as a cluster of guttate, confetti-like round macules that later coalesce to form large patches clinically indistinguishable from vitiligo. Usually, the depigmented patches conform closely to the shape of the offending article. An irritant dermatitis may precede its appearance in some cases. Although the earliest reports of chemical leucoderma to MBH from the US reported a high incidence of allergic sensitization, this has not been seen in Indian patients. Leucoderma can be reproduced at the patch test site with 20% MBH after a variable period, but not consistently.
Other related compounds such as monomethyl ether of hydroquinone, pyrocatechol and hydroquinone have also been reported to cause chemical leucoderma, but these are much rarer culprits than MBH. Commercial bleaching creams containing 2 to 5% hydroquinone have rarely been reported to cause chemical leucoderma as have photographic developing solutions containing 0.06 to 7% hydroquinone. Mercaptobenzthiazole (MBT), a rubber accelerator, has been reported as the cause in a patient who developed depigmentation on the penis after using latex condoms. This patient was also allergic to MBT and condom latex.
Reports of depigmentation to MBH and related chemicals from India are usually to household objects, whereas Western reports are usually from an industrial setting. This is also true of other chemicals producing leucoderma. The poorly regulated nature of the small and medium scale manufacturing industry in India can probably account for this difference. For example, Taylor et al have reported that the US rubber industry has stopped using MBH in processing for several years now, whereas Indian made rubber items still contain MBH. Similarly, the very high concentrations of free PTBP found in some Indian sticker bindis are not found in western society outside of factories producing the chemical itself. Another cause of paucity of Indian reports of occupational depigmentation is probably the under-developed nature of occupational medicine in general and occupational dermatology in particular.
Treatment is on similar lines as bindi leucoderma, except that exquisite photosensitivity has been seen in many patients with footwear dermatitis by one of the authors (AKB).
Hair dye induced Depigmentation
In India, hair dyes are used in most cases to cover grey hair and impart it a jet black or very dark brown colour. The cheapest and most commonly used ones are the misleadingly labeled “black henna” dyes that contain extremely high concentrations of p-phenylenediamine (PPD). We have seen many patients, one of whom was reported in the literature, who developed depigmentation over the scalp, forehead and the neck after a variable period of using PPD containing hair dyes. Most cases have been preceded by dermatitis which leads to the appearance of depigmented lesions. In the one patient that we patch tested, it was strongly positive to PPD and depigmentation also appeared at the patch test sites after a few weeks. The hair dye in this case contained 16% PPD. Whilst western countries have strict limits to the amount of PPD permitted in hair dyes, the Indian hair dye market is dominated by small poorly regulated brands and our labeling laws do not make it mandatory for manufacturers to declare ingredients and concentrations in their brands. Treatment of hair dye-induced chemical leucoderma is done along the usual lines, with discontinuation of the offending agent being paramount. The response to treatment of depigmentation on the head and neck is usually better than other sites due to the high follicle density.
Alta, Vermilion and Amulet String Leucoderma
This entity is almost entirely confined to India and presumably its neighbours, where alta, vermilion and coloured threads are worn for socio –religious reasons. The depigmentation in these cases is caused by azo dyes, that are also present in several items of everyday use, including coloured clothes. Other items that have been reported to cause azo dye-related depigmentation are lipsticks, lipliners, eyeliners and faux fur from soft toys7. The bulk of investigation on this entity has focused on alta related cases. This scarlet red solution is commonly applied by women to their feet on festive occasions and has rarely been associated with sharply localized depigmentation corresponding to the sites of application. We investigated the composition of a popular brand of alta and found that it contains mainly two dyes, namely Crocein Scarlet MOO and Rhodamine B (an inert dye) as well as Solvent yellow 3, possibly a contaminant. Crocein Scarlet Moo and Solvent yellow 3 are azo dyes. These dyes easily undergo oxidation in the air, which is further catalyzed by sunlight. This produces several complex compounds, which may contribute to the melanocytotoxicity of these dyes. There is significant structural homology between PPD and azo dyes, and cross-reactions are well known. Crocein Scarlet MOO and Solvent Yellow 3 have been shown to be capable of causing depigmentation.
Vermilion or kumkum is a red powder that is applied to the hair parting on the scalp, forehead or neck and is both a socio-religious symbol as well as a mark of married status. Vermilion was traditionally prepared by alkalizing pure turmeric powder, but commercially available vermilion powder is a cocktail of various azo dyes, coal tar dyes, fragrance, vegetable oils and parabens. Contact dermatitis to this powder, especially of the pigmented variety is well known, but recently, a case of chemical leucoderma caused by vermilion has been reported from South India. Presumably, the culprits there too are azo dyes.
Miscellaneous Chemical Leucodermas
Recently, toothpaste-induced chemical leucoderma has also been reported in some patients from India, although it is not clear whether these patients were patch tested. In the past, perioral depigmentation from cinnamic aldehyde- containing toothpaste with depigmentation at the patch test sites has been reported from the west. Since the oral mucosa and lips are common sites for occurrence of vitiligo, these patients need to be carefully examined for distant lesions before diagnosing chemical leucoderma.
Recently, ophthalmologists from Pondicherry reported a patient who presented with an allergic reaction to olopatadine eye drops that was rapidly followed by periocular depigmentation. Several other eye preparations have also been reported to cause similar leucoderma, viz. physostigmine, diisopropyl fluorophosphates, thiotepa and guanonitrofuracin.
Due to our lax product safety laws, a lot of potentially melanocytotoxic chemicals come in contact with our skin everyday. Chemical leucoderma is therefore an important preventable cause of localized skin depigmentation in Indians. It presents in several identifiable patterns and the causative agent can be identified and instructions for its avoidance given in most cases. Further study into contact leucoderma is urgently needed to understand whether we are missing many more cases and mis-classifying them as idiopathic vitiligo. Also, research into the mechanisms of production of depigmentation can give us valuable insights into the pathogenesis of vitiligo, which is showing increasing incidence in recent years. It is important for every dermatologist to acquaint him/herself with chemical leucoderma and give appropriate preventive advice to our patients.
Chemical leucoderma occurs due to direct skin exposure to some substances that are selectively toxic to melanocytes. This exposure can occur either in the workplace or even in day-to-day life with common objects that come in contact with the skin. However, chemical leucoderma is relatively uncommon whereas the chemicals implicated in it are widely used and commonly present in the environment. From this, it is evident that some individuals have inherently “fragile” melanocytes that are more susceptible to injury upon exposure to these chemicals. It has been shown both in vitro and in vivo that certain aliphatic and aromatic derivatives of phenols and catechols are directly toxic to melanocytes, more so in genetically susceptible individuals. Other chemicals that have been implicated to cause chemical leucoderma are p-phenylenediamine, certain azo dyes, sulfhydryls, mercurials, arsenic and several drugs of chemically related classes.
Most Asian populations have black hair and consequently use hair dyes containing high concentrations of p-phenylenediamine.(PPD), which has been reported to cause contact leucoderma in some cases. Another popular cosmetic in South Asia is henna, which is used both as a semi-permanent hair dye and for producing traditional decorative tattoos on the skin. Recently, there have been several reports from all over the world, specifically Asia, of henna being adulterated by PPD and causing chemical leucoderma.
In India, we have seen that several traditional materials of cosmetic use in women are laced with these chemicals in their modern avatars. Bindi, a coloured dot worn on the centre of the forehead by Hindu women; alta, a traditional red dye used to colour the feet and hands of women; sindoor or vermilion powder applied to the hair parting and sacred threads worn as religious amulets, all contain chemicals with depigmenting potential. Our hot and humid weather allows easy penetration of these chemicals through the compromised stratum corneum. Because of these factors there have been increasing reports of chemical leucoderma in Indian patients in recent literature. Indian dermatologists have recognized these cases and we have investigated some of these agents to identify specific chemicals that have the potential to produce chemical leucoderma and the mechanisms underlying these reactions.
Bindi Leucoderma
This entity is peculiar to Hindu women form the Indian subcontinent who apply a small coloured dot called bindi to the centre of the forehead to enhance their appearance or as a mark of married status. Traditionally, mineral or vegetable based dyes were used to make the bindi. However, these would be washed off by sweat or water and the messy powder or liquid dyes had to be carried on the wearer’s person so that they could be re-applied. A modern solution to this problem was devised by producing plastic bindis in various shapes, sizes and colours that were backed by an adhesive making them easy to stick, remove and re-apply. In the early 1980s, one of us (AKB) started seeing women with depigmented spots exactly conforming to the site of wearing the sticker bindi. In many cases, this was preceded by dermatitis at the site. In a study of 100 such patients seen over a 1-year period, it was observed that most of these women were in the habit of wearing bindi continuously, day and night. A dermatitis preceded the onset of depigmentation in almost three-quarters of these women. Five of the 15 women who were patch tested with the adhesive material showed positive reaction and three out of those developed depigmentation at the test site after 15 to 60 days. Upon testing by infrared spectrophotometry and chromatography, free p- tertiary butylphenol (PTBP) in very high concentration (up to 80%) was found in various samples of the adhesive. Low concentrations of PTBP on patch testing did not produce any positive reactions, ruling out sensitization in these patients.
PTBP is a known melanocytotoxic agent and depigmentation in workers exposed to it during its manufacture has been reported from many countries, including Japan. Amongst bindi users, it affects a small fraction, suggesting that individual susceptibility may play an important role. The lag period between use and depigmentation is highly variable, ranging from a few months to a few years. Other common sources of exposure to PTBP are deodorants, spray perfumes, detergents and household cleansers, all of which have been reported to cause chemical leucoderma in Indian patients.
The treatment of bindi leucoderma hinges upon the early recognition of the condition (which is usually easy) and cessation of use of sticker bindis (which can be difficult). Orthodox Hindu women are strongly conditioned to wear a bindi at all times, especially in public. Faced with chemical leucoderma, they often resort to wearing bigger and bigger bindis in an attempt to hide the white patch. Counselling is therefore a very crucial part of treatment. While early stoppage of exposure can lead to slow spontaneous repigmentation, active treatment of bindi depigmentation is typically more difficult than vitiligo, since PTBP can permanently destroy the melanocytes .. However, topical corticosteroids and/or phototherapy are usually beneficial, with resistant cases requiring melanocyte transfer surgery.
Synthetic leather/rubber items causing leucoderma
A peculiar pattern of chemical leucoderma affecting the left breast has been reported in Indian women, who wear clothes that typically do not have any pockets, forcing them to carry their wallets tucked into their blouses. Most women are right-handed, therefore the wallet rests against the left breast. These wallets are made of synthetic leather and we have demonstrated that this contains monobenzyl ether of hydroquinone (MBH). We have also reported a patient with localized depigmentation of the external auditory meatus who was using a hearing aid earpiece containing MBH. All patients seen by us have had negative patch test results to MBH suggesting direct melanocyte toxicity or inhibition of melanogenesis. Almost all cases occur when the offending item is in tight apposition against the skin, and is kept there for prolonged periods leading to leaching of the melanotoxic chemical.Even mobile cover has been observed to produce leucoderma on the left breast and front of the ear.
We have also reported MBH induced chemical leucoderma in 19 patients who wore bathroom rubber slippers and rain shoes and developed chemical leucoderma at the exposed sites. Five of them had associated vitiligo at other sites and 6 had developed a dermatitis preceding the appearance of depigmentation. However, when patch tested to MBH, PTBP and PTBP formaldehyde resin, all were negative, indicating that the dermatitis may have been irritant in nature. Peculiar features of footwear depigmentation in India are that most of the patients wear shoes without socks and are exposed to high humidity, leading to ideal conditions for any chemicals to leach into the skin. Other common items from which synthetic leather/rubber related leucoderma has been reported are condoms, watch straps and rubber gloves.
.MBH, also known as “Agerite Alba” is a rubber antioxidant and is well known to cause chemical leucoderma at sites of direct exposure, as well as distant sites on the body of predisposed individuals. The depigmentation often starts as a cluster of guttate, confetti-like round macules that later coalesce to form large patches clinically indistinguishable from vitiligo. Usually, the depigmented patches conform closely to the shape of the offending article. An irritant dermatitis may precede its appearance in some cases. Although the earliest reports of chemical leucoderma to MBH from the US reported a high incidence of allergic sensitization, this has not been seen in Indian patients. Leucoderma can be reproduced at the patch test site with 20% MBH after a variable period, but not consistently.
Other related compounds such as monomethyl ether of hydroquinone, pyrocatechol and hydroquinone have also been reported to cause chemical leucoderma, but these are much rarer culprits than MBH. Commercial bleaching creams containing 2 to 5% hydroquinone have rarely been reported to cause chemical leucoderma as have photographic developing solutions containing 0.06 to 7% hydroquinone. Mercaptobenzthiazole (MBT), a rubber accelerator, has been reported as the cause in a patient who developed depigmentation on the penis after using latex condoms. This patient was also allergic to MBT and condom latex.
Reports of depigmentation to MBH and related chemicals from India are usually to household objects, whereas Western reports are usually from an industrial setting. This is also true of other chemicals producing leucoderma. The poorly regulated nature of the small and medium scale manufacturing industry in India can probably account for this difference. For example, Taylor et al have reported that the US rubber industry has stopped using MBH in processing for several years now, whereas Indian made rubber items still contain MBH. Similarly, the very high concentrations of free PTBP found in some Indian sticker bindis are not found in western society outside of factories producing the chemical itself. Another cause of paucity of Indian reports of occupational depigmentation is probably the under-developed nature of occupational medicine in general and occupational dermatology in particular.
Treatment is on similar lines as bindi leucoderma, except that exquisite photosensitivity has been seen in many patients with footwear dermatitis by one of the authors (AKB).
Hair dye induced Depigmentation
In India, hair dyes are used in most cases to cover grey hair and impart it a jet black or very dark brown colour. The cheapest and most commonly used ones are the misleadingly labeled “black henna” dyes that contain extremely high concentrations of p-phenylenediamine (PPD). We have seen many patients, one of whom was reported in the literature, who developed depigmentation over the scalp, forehead and the neck after a variable period of using PPD containing hair dyes. Most cases have been preceded by dermatitis which leads to the appearance of depigmented lesions. In the one patient that we patch tested, it was strongly positive to PPD and depigmentation also appeared at the patch test sites after a few weeks. The hair dye in this case contained 16% PPD. Whilst western countries have strict limits to the amount of PPD permitted in hair dyes, the Indian hair dye market is dominated by small poorly regulated brands and our labeling laws do not make it mandatory for manufacturers to declare ingredients and concentrations in their brands. Treatment of hair dye-induced chemical leucoderma is done along the usual lines, with discontinuation of the offending agent being paramount. The response to treatment of depigmentation on the head and neck is usually better than other sites due to the high follicle density.
Alta, Vermilion and Amulet String Leucoderma
This entity is almost entirely confined to India and presumably its neighbours, where alta, vermilion and coloured threads are worn for socio –religious reasons. The depigmentation in these cases is caused by azo dyes, that are also present in several items of everyday use, including coloured clothes. Other items that have been reported to cause azo dye-related depigmentation are lipsticks, lipliners, eyeliners and faux fur from soft toys7. The bulk of investigation on this entity has focused on alta related cases. This scarlet red solution is commonly applied by women to their feet on festive occasions and has rarely been associated with sharply localized depigmentation corresponding to the sites of application. We investigated the composition of a popular brand of alta and found that it contains mainly two dyes, namely Crocein Scarlet MOO and Rhodamine B (an inert dye) as well as Solvent yellow 3, possibly a contaminant. Crocein Scarlet Moo and Solvent yellow 3 are azo dyes. These dyes easily undergo oxidation in the air, which is further catalyzed by sunlight. This produces several complex compounds, which may contribute to the melanocytotoxicity of these dyes. There is significant structural homology between PPD and azo dyes, and cross-reactions are well known. Crocein Scarlet MOO and Solvent Yellow 3 have been shown to be capable of causing depigmentation.
Vermilion or kumkum is a red powder that is applied to the hair parting on the scalp, forehead or neck and is both a socio-religious symbol as well as a mark of married status. Vermilion was traditionally prepared by alkalizing pure turmeric powder, but commercially available vermilion powder is a cocktail of various azo dyes, coal tar dyes, fragrance, vegetable oils and parabens. Contact dermatitis to this powder, especially of the pigmented variety is well known, but recently, a case of chemical leucoderma caused by vermilion has been reported from South India. Presumably, the culprits there too are azo dyes.
Miscellaneous Chemical Leucodermas
Recently, toothpaste-induced chemical leucoderma has also been reported in some patients from India, although it is not clear whether these patients were patch tested. In the past, perioral depigmentation from cinnamic aldehyde- containing toothpaste with depigmentation at the patch test sites has been reported from the west. Since the oral mucosa and lips are common sites for occurrence of vitiligo, these patients need to be carefully examined for distant lesions before diagnosing chemical leucoderma.
Recently, ophthalmologists from Pondicherry reported a patient who presented with an allergic reaction to olopatadine eye drops that was rapidly followed by periocular depigmentation. Several other eye preparations have also been reported to cause similar leucoderma, viz. physostigmine, diisopropyl fluorophosphates, thiotepa and guanonitrofuracin.
Due to our lax product safety laws, a lot of potentially melanocytotoxic chemicals come in contact with our skin everyday. Chemical leucoderma is therefore an important preventable cause of localized skin depigmentation in Indians. It presents in several identifiable patterns and the causative agent can be identified and instructions for its avoidance given in most cases. Further study into contact leucoderma is urgently needed to understand whether we are missing many more cases and mis-classifying them as idiopathic vitiligo. Also, research into the mechanisms of production of depigmentation can give us valuable insights into the pathogenesis of vitiligo, which is showing increasing incidence in recent years. It is important for every dermatologist to acquaint him/herself with chemical leucoderma and give appropriate preventive advice to our patients.
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