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Arsenical Keratoses in Bangladesh—Update and Prevention Strategies
A r s e n i c a l Ke r a t o s e s i n B a n g l a d e s hdU p d a t e a n d P rev e n t i o n Strategies Arlene M. Ruiz de Luzuriaga, MD, MPHa,*, Habibul Ahsan, MD, MMedScb, Christopher R. Shea, MDa KEYWORDS Arsenicosis Bangladesh Skin cancer Keratoses
the WHO guideline to be as much as 35 million to 57 million.7,8 Chronic arsenicosis is defined by the WHO as a “chronic health condition arising from prolonged ingestion of arsenic above a safe dose for at least 6 months, usually manifested by characteristic skin lesions of melanosis and keratosis, occurring alone or in combination, with or without involvement of internal organs.”9 The latency for the appearance of clinical signs and symptoms of chronic exposure can range from 6 to 10 months or even 20 years or more.10,11 Extracutaneous manifestations include neurologic changes, hypertension and cardiovascular disease, pulmonary disease, peripheral vascular disease, diabetes, adverse pregnancy outcomes, and internal malignancy.12,13 Arsenic is considered a Class I human carcinogen by the International Agency for Research on Cancer because of its increased risk for skin cancer, as well as internal cancers, such as lung and bladder cancer.14 Proposed mechanisms for arsenic carcinogenesis include chromosome abnormalities, oxidative stress, altered growth factors, cell proliferation, promotion and/or progression in carcinogenesis, altered DNA repair, p53 gene suppression, altered DNA methylation patterns, and gene amplification.15,16
The authors have nothing to disclose. a Section of Dermatology, Department of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, Mail Code 5067, L502, Chicago, IL 60637, USA b Departments of Medicine and Human Genetics and Cancer Research Center, University of Chicago, 5841 South Maryland Avenue N102, Chicago, IL 60637, USA * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 45–51 doi:10.1016/j.det.2010.09.003 0733-8635/11/$ e see front matter Ó 2011 Elsevier Inc. All rights reserved.
derm.theclinics.com
Arsenic contamination of drinking water in Bangladesh has been called the “largest mass poisoning of a population in history,”1 a consequence of the widespread installation and use of tube wells intended to provide a safer alternative to surface water sources that could easily be contaminated by microorganisms. It has been estimated that by the 1990s, 95% of the rural population of Bangladesh was drinking water from tube wells.2 The current World Health Organization (WHO) guideline designates 0.01 mg/L as the maximum permissible amount of arsenic in drinking water. The National Arsenic Mitigation Information Center reported in 2008 that of 4.8 million tube wells evaluated by field testing kits in Bangladesh, almost 30% had arsenic levels exceeding 0.05 mg/L.3 This inorganic arsenic contamination is of natural origin, with arsenic thought to be released to the groundwater from the surrounding sediment.4,5 A recent survey by Chakraborti and colleagues6 estimated that in Bangladesh, 36 million people are at risk of drinking arsenic-contaminated water at arsenic levels more than 0.01 mg/L, with 22 million at risk of drinking water with arsenic levels more than 0.05 mg/L. Previous estimates put the population at risk for arsenic exposure at levels beyond
46
Ruiz de Luzuriaga et al At very high concentrations of exposure, systemic symptoms, most commonly gastrointestinal symptoms as well as peripheral neuropathy, may precede skin lesions.17 Recently evaluated data from the Health Effects of Arsenic Longitudinal Study (HEALS) show that the risk of all-cause mortality and chronic disease mortality increased with increasing arsenic exposure, particularly long-term exposure.18
CUTANEOUS DISEASE The first case of arsenicosis was identified in a patient in Bangladesh as early as 1984,19 and a recent study found patients with skin lesions in 31 of 33 surveyed districts in Bangladesh.6 Arsenic-related skin lesions are considered the earliest manifestation of nonmalignant disease related to chronic arsenic exposure.20 The risk for nonmalignant and malignant skin disease seems to increase with increasing dose.20,21 One study noted that subjects exposed to an arsenic concentration of 0.05 mg/L had a 59% higher risk of skin lesions compared with unexposed subjects.22 Skin changes can be found with chronic exposure to nonlethal doses of arsenic, ranging from 0.005 to 0.09 mg/kg/d.9
Nonmalignant and Premalignant Disease Of the skin findings occurring in arsenicosis, pigmentary changes are considered to be the earliest dermatologic findings. These alterations can be diffuse or patchy and are often localized to the palms and soles. Characteristic patterns include a freckled raindrop pattern, leucomelanosis (guttate hypopigmentation in a background of hyperpigmentation), and mucosal pigmentation. Conjunctival congestion and nonpitting edema have also been demonstrated.10 The presence of arsenical keratoses has been suggested to be a sensitive marker for early detection of arsenicosis and is the most common manifestation preceding the development of arsenic-related skin cancer.23,24 Typical lesions are hyperkeratotic, punctate, firm papules measuring 2 to 10 mm in diameter and are often located at sites subject to friction or trauma (Fig. 1). Common locations are the palms and soles, although they may also be present on the dorsal surface of the extremities25,26; other locations include the trunk, genitalia, and eyelids. Arsenical keratoses also may present as scaly, erythematous, or hyperpigmented plaques. Thickened leathery plaques may have associated hyperhidrosis. The extent of disease is graded on a scale of mild, moderate, and severe. In mild disease, lesions are usually less than 2 mm in
Fig. 1. Arsenical keratoses involving the palms.
diameter and are most easily found by palpation. Involved skin may be indurated, with a gritlike character. Moderate disease is characterized by raised lesions ranging from 2 to 5 mm in diameter, with punctate or wartlike features. Findings in severe disease include lesions more than 5 mm in diameter, which may coalesce into plaques with subsequent cracking and fissuring of the skin.9,26 In contrast to arsenic-related internal malignancies with long latent periods to manifestation, premalignant arsenical keratoses may appear after only a brief time of arsenic exposure.10 An erythematous halo around the keratoses or a thickening may indicate progression to in situ squamous cell carcinoma (SCC).27 In addition, bleeding and a sudden increase in cracking, fissuring, or size are suggestive of malignant transformation.28 The presence of arsenical keratosis may also mandate further screening for internal malignancy.29 Patients with large, thickened lesions may experience discomfort, particularly because of secondary fissuring and cracking, and they are at increased risk for subsequent infection.3 Social stigmatization can occur as the cutaneous manifestations of arsenicosis are sometimes incorrectly thought to indicate a contagious disease, leading to marital discord, employment difficulties, and social isolation.28,30,31 Other cutaneous diseases that should be included in the differential diagnosis for the skin findings in arsenicosis are listed in Table 1.
Malignant Disease Cutaneous malignancies resulting from arsenic exposure include in situ and invasive SCC (Fig. 2), basal cell carcinoma (BCC), and less often, Merkel cell carcinoma.32e35 These malignancies usually develop 10 to 20 years after the initial manifestation of arsenicosis, often as large
Arsenical Keratoses in Bangladesh
Table 1 Differential diagnosis of cutaneous findings in arsenicosis Primary Skin Finding
Differential Diagnosis
Diffuse melanosis
Ashy dermatosis, actinic dermatosis, melasma, drug-induced hyperpigmentation, acanthosis nigricans, chronic liver disorders, porphyria cutanea tarda, Wilson disease Pityriasis versicolor, solar or simple lentigines, lichen planus, drug-induced hyperpigmentation, xeroderma pigmentosum, Peutz-Jeghers syndrome, post-kala-azar dermal leishmaniasis Idiopathic guttate hypomelanosis, pityriasis versicolor, pityriasis lichenoides chronica, leprosy, post-kala-azar dermal leishmaniasis Palmoplantar psoriasis, atopic dermatitis, frictional/occupational keratosis, tinea pedum, pitted keratolysis, genetic keratodermas and ichthyoses, discoid lupus erythematosus, pityriasis rubra pilaris Frictional/occupational keratosis, verruca vulgaris, corn/callus, seborrheic keratosis, epidermodysplasia verruciformis
Guttate (spotted) melanosis Leucomelanosis Diffuse keratosis
Nodular/Spotted keratosis
Data from Caussy D, editor. A field guide for detection, management, and surveillance of arsenicosis cases. New Delhi (India): World Health Organization, Regional Office of South-East Asia; 2005. p. 1e38; and Saha KC. Diagnosis of arsenicosis. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003;38:255e72.
keratotic nodules.19 In contrast to the typical sunexposed distribution of most nonmelanomatous skin cancers, those resulting from arsenic exposure tend to occur in nonexposed sites.33 In
Fig. 2. (A, B) SCC affecting the hands.
addition, the malignancies may be multiple and can arise both in areas of existing keratoses and in uninvolved skin. Invasive SCC that develops within keratoses in patients with a history of
47
48
Ruiz de Luzuriaga et al arsenic exposure may be aggressive with a heightened metastatic risk.17 BCCs arising in the setting of arsenic exposure tend to be multiple and may resemble in situ SCC clinically.17
Risk Factors Several studies have indicated that men are more susceptible to the arsenic-related skin effects than women, a finding that may be explained by metabolism.23,36e38 A population-based study in Bangladesh showed a strong association between more efficient methylation of arsenic and decreased risk of developing skin lesions in women as compared with men.38 Additional risk factors for skin lesions include tobacco use, sun exposure, increasing age, folate deficiency, hyperhomocysteinemia, and low urinary creatinine excretion.32,36,39e43 Genetic variability affecting the metabolic capacity of arsenic also contributes to risk for skin lesions.44e46
Laboratory Findings Arsenic exposure can be established by testing environmental sources, such as the water being consumed, and by monitoring the patient. Biologic monitoring as a measure of arsenic exposure most commonly includes measuring arsenic concentration in urine, hair, nail, and serum. Urine is the primary route of elimination of most arsenic species. Spot urine samples are taken commonly, being easy and painless to collect.47 Previous data have suggested that the level of arsenic in urine does not vary significantly over time and can be used as a long-term biomarker of arsenic exposure provided that the exposure is current and ongoing.21,24 Urine samples taken more than 24 to 48 hours after the last exposure can underestimate peak exposure because most of the arsenic would have been excreted. In addition, the subject should not have consumed any seafood for 4 days before urine collection.48 Hair and nail samples can be useful to estimate the average amount and rate of arsenic exposure within the previous 9 months.49 However, these samples can be influenced by external contamination by environmental arsenic exposure.50 According to the WHO 2005 field guide for the detection of arsenicosis, a urine sample with arsenic concentration greater than 50 mg/L confirms recent exposure. Dry hair with a concentration greater than 1 mg/kg or nail with a concentration greater than 1.5 mg/kg may indicate of exposure to unsafe doses of arsenic within the previous 11 months.9 Serum concentrations are not so commonly used to screen for chronic exposure because arsenic is rapidly cleared from
the blood; serum testing is most useful to assess recent high-concentration exposures.48 Histologically, premalignant and malignant, cutaneous, arsenic-related tumors are generally indistinguishable from their counterparts due to ultraviolet radiation. Together with clinical and social history, the absence of significant dermal solar elastosis may be a helpful clue to identify the cause. Arsenical keratoses typically demonstrate compact parakeratosis overlying an acanthotic epidermis with mild keratinocytic dysplasia. There may also be some basal keratinocyte vacuolization and a chronic inflammatory dermal infiltrate.10,51 As in non-arsenicerelated SCC in situ, full-thickness intraepidermal atypia with parakeratotic hyperkeratosis, without invasion of the dermis, characterizes arsenic-related SCC in situ. When BCC is caused by arsenic, it is usually of the superficial pattern; however, nodular, reticulated, and pigmented patterns of BCC may all be associated with chronic arsenic exposure.27,52 Arsenic-related BCCs may demonstrate vacuolated cells, dyskeratosis, multinucleated giant cells, and increased numbers of atypical nuclei and mitotic figures.17,52
Management and Prevention Management and prevention of the cutaneous sequelae of chronic arsenic exposure is multifaceted. Symptomatic treatment of arsenical keratoses with or without pigmentary changes includes the use of topical 5% to 10% salicylic acid and 10% to 20% urea ointment.9 Treatment of arsenic-related cutaneous neoplasms includes surgical excision, cryosurgery, electrodesiccation and curettage, oral retinoid therapy, and topical chemotherapy.53e56 Imiquimod 5% cream used once daily for 6 weeks has been found effective against arsenical keratoses, SCCs, and BCCs.54,55 Dietary modifications and vitamin supplementation to influence the methylation and subsequent detoxification of arsenic have been found to reduce the deleterious effects of arsenic on the skin. These measures include supplementation with vitamin E, selenium,57 folic acid,41 riboflavin, and pyridoxine, with the effects of the B vitamins possibly being additive.22 The levels at which such nutrients need to be consumed to have a beneficial effect are greater than the current recommended daily amounts.22 Studies have also confirmed that a lower body mass index is associated with a higher prevalence of skin lesions, supporting that overall malnutrition may increase the risk for arsenic-related skin disease.39,58 Chelation therapy with agents such as dimercaptosuccinic acid, dimercaptopropane succinate,
Arsenical Keratoses in Bangladesh and D-penicillamine has variable benefits for patients with chronic arsenicosis.28 Cessation of consuming contaminated water is of utmost importance. Arsenic mitigation efforts are underway to address this pressing issue. Interventions that have been implemented include person-to-person reporting of well test results, well labeling, village and individual health education, and installation of more deeply situated wells; in Bangladesh, at least 350-m deep aquifers have been found to be safe from arsenic contamination.6 In one study, urinary arsenic levels decreased by 46% in people who switched to a well identified as safe.59 Other proposals to decrease consumption of arsenic-contaminated water include rainwater harvesting, filtration and removal of arsenic from current water supplies via individual devices or treatment plants, and treatment of surface water with pressure filtration and disinfection.9 Arsenical keratoses and their sequelae are significant contributors to morbidity resulting from chronic exposure to arsenic in drinking water in Bangladesh and they may also serve as indicators for further systemic evaluation for disease. It is to be hoped that a combination of mitigation proposals and programs with surveillance by the medical community for latent sequelae and public health education and counseling will mitigate the deadly impact of chronic arsenic exposure in this population and guide future efforts worldwide.
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REFERENCES 1. Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic in Bangladesh: a public health emergency. Bull World Health Organ 2000; 78(9):1093e103. 2. Caldwell BK, Caldwell JC, Mitra SN, et al. Searching for an optimum solution to the Bangladesh arsenic crisis. Soc Sci Med 2003;56(10):2089e96. 3. UNICEF. Arsenic mitigation in Bangladesh. Available at: http://www.unicef.org/bangladesh/Arsenic.pdf. Accessed July 31, 2010. 4. British Geological Survey. Arsenic contamination of groundwater: Bangladesh phase 1. Available at: http://www.bgs.ac.uk/arsenic/bphase1/b_intro.htm. Accessed July 31, 2010. 5. Ng JC, Wang J, Shraim A. A global health problem caused by arsenic from natural sources. Chemosphere 2003;52(9):1353e9. 6. Chakraborti D, Rahman MM, Das B, et al. Status of groundwater arsenic contamination in Bangladesh: a 14-year study report. Water Res 2010. [Epub ahead of print]. 7. Ahsan H, Perrin M, Rahman A, et al. Associations between drinking water and urinary arsenic levels
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and skin lesions in Bangladesh. J Occup Environ Med 2000;42(12):1195e201. Smith MM, Hore T, Chakraborty P, et al. A dugwell program to provide arsenic-safe water in West Bengal, India: preliminary results. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003;38(1):289e99. Caussy D, editor. A field guide for detection, management, and surveillance of arsenicosis cases. New Delhi (India): World Health Organization, Regional Office of South-East Asia; 2005. p. 1e38. Saha KC. Diagnosis of arsenicosis. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003; 38(1):255e72. Haque R, Mazumder DN, Samanta S, et al. Arsenic in drinking water and skin lesions: dose-response data from West Bengal, India. Epidemiology 2003; 14(2):174e82. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res 2008; 68(20):8278e85. von Ehrenstein OS, Guha Mazumder DN, HiraSmith M, et al. Pregnancy outcomes, infant mortality, and arsenic in drinking water in West Bengal, India. Am J Epidemiol 2006;163(7):662e9. An evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data: IARC Monographs Volumes 1 to 20. Report of an IARC Working Group. Cancer Res 1980;40(1):1e12. Kitchin KT. Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol 2001;172(3):249e61. Germolec DR, Spalding J, Yu HS, et al. Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am J Pathol 1998;153(6): 1775e85. Schwartz RA. Arsenic and the skin. Int J Dermatol 1997;36(4):241e50. Argos M, Kalra T, Rathouz PJ, et al. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 2010;376(9737): 252e8. Saha KC. Cutaneous malignancy in arsenicosis. Br J Dermatol 2001;145(1):185. Yoshida T, Yamauchi H, Fan Sun G. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol 2004;198(3):243e52. Chen Y, Parvez F, Gamble M, et al. Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of recent findings from the Health Effects of Arsenic
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Longitudinal Study (HEALS) in Bangladesh. Toxicol Appl Pharmacol 2009;239(2):184e92. Zablotska LB, Chen Y, Graziano JH, et al. Protective effects of B vitamins and antioxidants on the risk of arsenic-related skin lesions in Bangladesh. Environ Health Perspect 2008;116(8):1056e62. Kadono T, Inaoka T, Murayama N, et al. Skin manifestations of arsenicosis in two villages in Bangladesh. Int J Dermatol 2002;41(12):841e6. Tseng WP, Chu HM, How SW, et al. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 1968;40(3): 453e63. Sengupta MK, Mukherjee A, Hossain MA, et al. Groundwater arsenic contamination in the GangaPadma-Meghna-Brahmaputra plain of India and Bangladesh. Arch Environ Health 2003;58(11): 701e2. Sengupta SR, Das NK, Datta PK. Pathogenesis, clinical features and pathology of chronic arsenicosis. Indian J Dermatol Venereol Leprol 2008;74(6): 559e70. Schwartz RA. Premalignant keratinocytic neoplasms. J Am Acad Dermatol 1996;35(2 Pt 1): 223e42. Das NK, Sengupta SR. Arsenicosis: diagnosis and treatment. Indian J Dermatol Venereol Leprol 2008; 74(6):571e81. Cuzick J, Sasieni P, Evans S. Ingested arsenic, keratoses, and bladder cancer. Am J Epidemiol 1992; 136(4):417e21. Ahmad SA, Sayed MH, Khan MH, et al. Sociocultural aspects of arsenicosis in Bangladesh: community perspective. J Environ Sci Health A Tox Hazard Subst Environ Eng 2007;42(12):1945e58. Hassan MM, Atkins PJ, Dunn CE. Social implications of arsenic poisoning in Bangladesh. Soc Sci Med 2005;61(10):2201e11. Elmariah SB, Anolik R, Walters RF, et al. Invasive squamous-cell carcinoma and arsenical keratoses. Dermatol Online J 2008;14(10):24. Boonchai W, Green A, Ng J, et al. Basal cell carcinoma in chronic arsenicism occurring in Queensland, Australia, after ingestion of an asthma medication. J Am Acad Dermatol 2000;43(4):664e9. Wong SS, Tan KC, Goh CL. Cutaneous manifestations of chronic arsenicism: review of seventeen cases. J Am Acad Dermatol 1998;38(2 Pt 1): 179e85. Lien HC, Tsai TF, Lee YY, et al. Merkel cell carcinoma and chronic arsenicism. J Am Acad Dermatol 1999; 41(4):641e3. Rahman M, Vahter M, Sohel N, et al. Arsenic exposure and age and sex-specific risk for skin lesions: a population-based case-referent study in Bangladesh. Environ Health Perspect 2006; 114(12):1847e52.
37. Vahter M, Concha G. Role of metabolism in arsenic toxicity. Pharmacol Toxicol 2001;89(1):1e5. 38. Lindberg AL, Rahman M, Persson LA, et al. The risk of arsenic induced skin lesions in Bangladeshi men and women is affected by arsenic metabolism and the age at first exposure. Toxicol Appl Pharmacol 2008;230(1):9e16. 39. Ahsan H, Chen Y, Parvez F, et al. Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study. Am J Epidemiol 2006;163(12):1138e48. 40. Chen Y, Graziano JH, Parvez F, et al. Modification of risk of arsenic-induced skin lesions by sunlight exposure, smoking, and occupational exposures in Bangladesh. Epidemiology 2006;17(4):459e67. 41. Gamble MV, Liu X, Ahsan H, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect 2005;113(12):1683e8. 42. Lindberg AL, Sohel N, Rahman M, et al. Impact of smoking and chewing tobacco on arsenic-induced skin lesions. Environ Health Perspect 2010;118(4): 533e8. 43. Pilsner JR, Liu X, Ahsan H, et al. Folate deficiency, hyperhomocysteinemia, low urinary creatinine, and hypomethylation of leukocyte DNA are risk factors for arsenic-induced skin lesions. Environ Health Perspect 2009;117(2):254e60. 44. Argos M, Kibriya MG, Parvez F, et al. Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev 2006;15(7):1367e75. 45. De Chaudhuri S, Ghosh P, Sarma N, et al. Genetic variants associated with arsenic susceptibility: study of purine nucleoside phosphorylase, arsenic (13) methyltransferase, and glutathione S-transferase omega genes. Environ Health Perspect 2008; 116(4):501e5. 46. Hernandez A, Marcos R. Genetic variations associated with interindividual sensitivity in the response to arsenic exposure. Pharmacogenomics 2008; 9(8):1113e32. 47. Calderon RL, Hudgens E, Le XC, et al. Excretion of arsenic in urine as a function of exposure to arsenic in drinking water. Environ Health Perspect 1999; 107(8):663e7. 48. Orloff K, Mistry K, Metcalf S. Biomonitoring for environmental exposures to arsenic. J Toxicol Environ Health B Crit Rev 2009;12(7):509e24. 49. Kile ML, Houseman EA, Breton CV, et al. Association between total ingested arsenic and toenail arsenic concentrations. J Environ Sci Health A Tox Hazard Subst Environ Eng 2007;42(12):1827e34. 50. Karagas MR. Arsenic-related mortality in Bangladesh. Lancet 2010;376(9737):213e4.
Arsenical Keratoses in Bangladesh 51. Yeh S. Skin cancer in chronic arsenicism. Hum Pathol 1973;4(4):469e85. 52. Yeh S, How SW, Lin CS. Arsenical cancer of skin. Histologic study with special reference to Bowen’s disease. Cancer 1968;21(2):312e39. 53. Watson K, Creamer D. Arsenic-induced keratoses and Bowen’s disease. Clin Exp Dermatol 2004; 29(1):46e8. 54. Lonergan CL, McNamara EK, Cordoro KM, et al. Imiquimod cream 5% for the treatment of arsenic-induced cutaneous neoplasms. Cutis 2010; 85(4):199e202. 55. Boonchai W. Treatment of precancerous and cancerous lesions of chronic arsenicism with 5% imiquimod cream. Arch Dermatol 2006;142(4): 531e2.
56. Yerebakan O, Ermis O, Yilmaz E, et al. Treatment of arsenical keratosis and Bowen’s disease with acitretin. Int J Dermatol 2002;41(2):84e7. 57. Verret WJ, Chen Y, Ahmed A, et al. A randomized, double-blind placebo-controlled trial evaluating the effects of vitamin E and selenium on arsenicinduced skin lesions in Bangladesh. J Occup Environ Med 2005;47(10):1026e35. 58. Guha Mazumder DN, Haque R, Ghosh N, et al. Arsenic levels in drinking water and the prevalence of skin lesions in West Bengal, India. Int J Epidemiol 1998;27(5):871e7. 59. Chen Y, van Geen A, Graziano JH, et al. Reduction in urinary arsenic levels in response to arsenic mitigation efforts in Araihazar, Bangladesh. Environ Health Perspect 2007;115(6):917e23.
51
the WHO guideline to be as much as 35 million to 57 million.7,8 Chronic arsenicosis is defined by the WHO as a “chronic health condition arising from prolonged ingestion of arsenic above a safe dose for at least 6 months, usually manifested by characteristic skin lesions of melanosis and keratosis, occurring alone or in combination, with or without involvement of internal organs.”9 The latency for the appearance of clinical signs and symptoms of chronic exposure can range from 6 to 10 months or even 20 years or more.10,11 Extracutaneous manifestations include neurologic changes, hypertension and cardiovascular disease, pulmonary disease, peripheral vascular disease, diabetes, adverse pregnancy outcomes, and internal malignancy.12,13 Arsenic is considered a Class I human carcinogen by the International Agency for Research on Cancer because of its increased risk for skin cancer, as well as internal cancers, such as lung and bladder cancer.14 Proposed mechanisms for arsenic carcinogenesis include chromosome abnormalities, oxidative stress, altered growth factors, cell proliferation, promotion and/or progression in carcinogenesis, altered DNA repair, p53 gene suppression, altered DNA methylation patterns, and gene amplification.15,16
The authors have nothing to disclose. a Section of Dermatology, Department of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, Mail Code 5067, L502, Chicago, IL 60637, USA b Departments of Medicine and Human Genetics and Cancer Research Center, University of Chicago, 5841 South Maryland Avenue N102, Chicago, IL 60637, USA * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 45–51 doi:10.1016/j.det.2010.09.003 0733-8635/11/$ e see front matter Ó 2011 Elsevier Inc. All rights reserved.
derm.theclinics.com
Arsenic contamination of drinking water in Bangladesh has been called the “largest mass poisoning of a population in history,”1 a consequence of the widespread installation and use of tube wells intended to provide a safer alternative to surface water sources that could easily be contaminated by microorganisms. It has been estimated that by the 1990s, 95% of the rural population of Bangladesh was drinking water from tube wells.2 The current World Health Organization (WHO) guideline designates 0.01 mg/L as the maximum permissible amount of arsenic in drinking water. The National Arsenic Mitigation Information Center reported in 2008 that of 4.8 million tube wells evaluated by field testing kits in Bangladesh, almost 30% had arsenic levels exceeding 0.05 mg/L.3 This inorganic arsenic contamination is of natural origin, with arsenic thought to be released to the groundwater from the surrounding sediment.4,5 A recent survey by Chakraborti and colleagues6 estimated that in Bangladesh, 36 million people are at risk of drinking arsenic-contaminated water at arsenic levels more than 0.01 mg/L, with 22 million at risk of drinking water with arsenic levels more than 0.05 mg/L. Previous estimates put the population at risk for arsenic exposure at levels beyond
46
Ruiz de Luzuriaga et al At very high concentrations of exposure, systemic symptoms, most commonly gastrointestinal symptoms as well as peripheral neuropathy, may precede skin lesions.17 Recently evaluated data from the Health Effects of Arsenic Longitudinal Study (HEALS) show that the risk of all-cause mortality and chronic disease mortality increased with increasing arsenic exposure, particularly long-term exposure.18
CUTANEOUS DISEASE The first case of arsenicosis was identified in a patient in Bangladesh as early as 1984,19 and a recent study found patients with skin lesions in 31 of 33 surveyed districts in Bangladesh.6 Arsenic-related skin lesions are considered the earliest manifestation of nonmalignant disease related to chronic arsenic exposure.20 The risk for nonmalignant and malignant skin disease seems to increase with increasing dose.20,21 One study noted that subjects exposed to an arsenic concentration of 0.05 mg/L had a 59% higher risk of skin lesions compared with unexposed subjects.22 Skin changes can be found with chronic exposure to nonlethal doses of arsenic, ranging from 0.005 to 0.09 mg/kg/d.9
Nonmalignant and Premalignant Disease Of the skin findings occurring in arsenicosis, pigmentary changes are considered to be the earliest dermatologic findings. These alterations can be diffuse or patchy and are often localized to the palms and soles. Characteristic patterns include a freckled raindrop pattern, leucomelanosis (guttate hypopigmentation in a background of hyperpigmentation), and mucosal pigmentation. Conjunctival congestion and nonpitting edema have also been demonstrated.10 The presence of arsenical keratoses has been suggested to be a sensitive marker for early detection of arsenicosis and is the most common manifestation preceding the development of arsenic-related skin cancer.23,24 Typical lesions are hyperkeratotic, punctate, firm papules measuring 2 to 10 mm in diameter and are often located at sites subject to friction or trauma (Fig. 1). Common locations are the palms and soles, although they may also be present on the dorsal surface of the extremities25,26; other locations include the trunk, genitalia, and eyelids. Arsenical keratoses also may present as scaly, erythematous, or hyperpigmented plaques. Thickened leathery plaques may have associated hyperhidrosis. The extent of disease is graded on a scale of mild, moderate, and severe. In mild disease, lesions are usually less than 2 mm in
Fig. 1. Arsenical keratoses involving the palms.
diameter and are most easily found by palpation. Involved skin may be indurated, with a gritlike character. Moderate disease is characterized by raised lesions ranging from 2 to 5 mm in diameter, with punctate or wartlike features. Findings in severe disease include lesions more than 5 mm in diameter, which may coalesce into plaques with subsequent cracking and fissuring of the skin.9,26 In contrast to arsenic-related internal malignancies with long latent periods to manifestation, premalignant arsenical keratoses may appear after only a brief time of arsenic exposure.10 An erythematous halo around the keratoses or a thickening may indicate progression to in situ squamous cell carcinoma (SCC).27 In addition, bleeding and a sudden increase in cracking, fissuring, or size are suggestive of malignant transformation.28 The presence of arsenical keratosis may also mandate further screening for internal malignancy.29 Patients with large, thickened lesions may experience discomfort, particularly because of secondary fissuring and cracking, and they are at increased risk for subsequent infection.3 Social stigmatization can occur as the cutaneous manifestations of arsenicosis are sometimes incorrectly thought to indicate a contagious disease, leading to marital discord, employment difficulties, and social isolation.28,30,31 Other cutaneous diseases that should be included in the differential diagnosis for the skin findings in arsenicosis are listed in Table 1.
Malignant Disease Cutaneous malignancies resulting from arsenic exposure include in situ and invasive SCC (Fig. 2), basal cell carcinoma (BCC), and less often, Merkel cell carcinoma.32e35 These malignancies usually develop 10 to 20 years after the initial manifestation of arsenicosis, often as large
Arsenical Keratoses in Bangladesh
Table 1 Differential diagnosis of cutaneous findings in arsenicosis Primary Skin Finding
Differential Diagnosis
Diffuse melanosis
Ashy dermatosis, actinic dermatosis, melasma, drug-induced hyperpigmentation, acanthosis nigricans, chronic liver disorders, porphyria cutanea tarda, Wilson disease Pityriasis versicolor, solar or simple lentigines, lichen planus, drug-induced hyperpigmentation, xeroderma pigmentosum, Peutz-Jeghers syndrome, post-kala-azar dermal leishmaniasis Idiopathic guttate hypomelanosis, pityriasis versicolor, pityriasis lichenoides chronica, leprosy, post-kala-azar dermal leishmaniasis Palmoplantar psoriasis, atopic dermatitis, frictional/occupational keratosis, tinea pedum, pitted keratolysis, genetic keratodermas and ichthyoses, discoid lupus erythematosus, pityriasis rubra pilaris Frictional/occupational keratosis, verruca vulgaris, corn/callus, seborrheic keratosis, epidermodysplasia verruciformis
Guttate (spotted) melanosis Leucomelanosis Diffuse keratosis
Nodular/Spotted keratosis
Data from Caussy D, editor. A field guide for detection, management, and surveillance of arsenicosis cases. New Delhi (India): World Health Organization, Regional Office of South-East Asia; 2005. p. 1e38; and Saha KC. Diagnosis of arsenicosis. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003;38:255e72.
keratotic nodules.19 In contrast to the typical sunexposed distribution of most nonmelanomatous skin cancers, those resulting from arsenic exposure tend to occur in nonexposed sites.33 In
Fig. 2. (A, B) SCC affecting the hands.
addition, the malignancies may be multiple and can arise both in areas of existing keratoses and in uninvolved skin. Invasive SCC that develops within keratoses in patients with a history of
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Ruiz de Luzuriaga et al arsenic exposure may be aggressive with a heightened metastatic risk.17 BCCs arising in the setting of arsenic exposure tend to be multiple and may resemble in situ SCC clinically.17
Risk Factors Several studies have indicated that men are more susceptible to the arsenic-related skin effects than women, a finding that may be explained by metabolism.23,36e38 A population-based study in Bangladesh showed a strong association between more efficient methylation of arsenic and decreased risk of developing skin lesions in women as compared with men.38 Additional risk factors for skin lesions include tobacco use, sun exposure, increasing age, folate deficiency, hyperhomocysteinemia, and low urinary creatinine excretion.32,36,39e43 Genetic variability affecting the metabolic capacity of arsenic also contributes to risk for skin lesions.44e46
Laboratory Findings Arsenic exposure can be established by testing environmental sources, such as the water being consumed, and by monitoring the patient. Biologic monitoring as a measure of arsenic exposure most commonly includes measuring arsenic concentration in urine, hair, nail, and serum. Urine is the primary route of elimination of most arsenic species. Spot urine samples are taken commonly, being easy and painless to collect.47 Previous data have suggested that the level of arsenic in urine does not vary significantly over time and can be used as a long-term biomarker of arsenic exposure provided that the exposure is current and ongoing.21,24 Urine samples taken more than 24 to 48 hours after the last exposure can underestimate peak exposure because most of the arsenic would have been excreted. In addition, the subject should not have consumed any seafood for 4 days before urine collection.48 Hair and nail samples can be useful to estimate the average amount and rate of arsenic exposure within the previous 9 months.49 However, these samples can be influenced by external contamination by environmental arsenic exposure.50 According to the WHO 2005 field guide for the detection of arsenicosis, a urine sample with arsenic concentration greater than 50 mg/L confirms recent exposure. Dry hair with a concentration greater than 1 mg/kg or nail with a concentration greater than 1.5 mg/kg may indicate of exposure to unsafe doses of arsenic within the previous 11 months.9 Serum concentrations are not so commonly used to screen for chronic exposure because arsenic is rapidly cleared from
the blood; serum testing is most useful to assess recent high-concentration exposures.48 Histologically, premalignant and malignant, cutaneous, arsenic-related tumors are generally indistinguishable from their counterparts due to ultraviolet radiation. Together with clinical and social history, the absence of significant dermal solar elastosis may be a helpful clue to identify the cause. Arsenical keratoses typically demonstrate compact parakeratosis overlying an acanthotic epidermis with mild keratinocytic dysplasia. There may also be some basal keratinocyte vacuolization and a chronic inflammatory dermal infiltrate.10,51 As in non-arsenicerelated SCC in situ, full-thickness intraepidermal atypia with parakeratotic hyperkeratosis, without invasion of the dermis, characterizes arsenic-related SCC in situ. When BCC is caused by arsenic, it is usually of the superficial pattern; however, nodular, reticulated, and pigmented patterns of BCC may all be associated with chronic arsenic exposure.27,52 Arsenic-related BCCs may demonstrate vacuolated cells, dyskeratosis, multinucleated giant cells, and increased numbers of atypical nuclei and mitotic figures.17,52
Management and Prevention Management and prevention of the cutaneous sequelae of chronic arsenic exposure is multifaceted. Symptomatic treatment of arsenical keratoses with or without pigmentary changes includes the use of topical 5% to 10% salicylic acid and 10% to 20% urea ointment.9 Treatment of arsenic-related cutaneous neoplasms includes surgical excision, cryosurgery, electrodesiccation and curettage, oral retinoid therapy, and topical chemotherapy.53e56 Imiquimod 5% cream used once daily for 6 weeks has been found effective against arsenical keratoses, SCCs, and BCCs.54,55 Dietary modifications and vitamin supplementation to influence the methylation and subsequent detoxification of arsenic have been found to reduce the deleterious effects of arsenic on the skin. These measures include supplementation with vitamin E, selenium,57 folic acid,41 riboflavin, and pyridoxine, with the effects of the B vitamins possibly being additive.22 The levels at which such nutrients need to be consumed to have a beneficial effect are greater than the current recommended daily amounts.22 Studies have also confirmed that a lower body mass index is associated with a higher prevalence of skin lesions, supporting that overall malnutrition may increase the risk for arsenic-related skin disease.39,58 Chelation therapy with agents such as dimercaptosuccinic acid, dimercaptopropane succinate,
Arsenical Keratoses in Bangladesh and D-penicillamine has variable benefits for patients with chronic arsenicosis.28 Cessation of consuming contaminated water is of utmost importance. Arsenic mitigation efforts are underway to address this pressing issue. Interventions that have been implemented include person-to-person reporting of well test results, well labeling, village and individual health education, and installation of more deeply situated wells; in Bangladesh, at least 350-m deep aquifers have been found to be safe from arsenic contamination.6 In one study, urinary arsenic levels decreased by 46% in people who switched to a well identified as safe.59 Other proposals to decrease consumption of arsenic-contaminated water include rainwater harvesting, filtration and removal of arsenic from current water supplies via individual devices or treatment plants, and treatment of surface water with pressure filtration and disinfection.9 Arsenical keratoses and their sequelae are significant contributors to morbidity resulting from chronic exposure to arsenic in drinking water in Bangladesh and they may also serve as indicators for further systemic evaluation for disease. It is to be hoped that a combination of mitigation proposals and programs with surveillance by the medical community for latent sequelae and public health education and counseling will mitigate the deadly impact of chronic arsenic exposure in this population and guide future efforts worldwide.
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