Arsenic is a natural occurring metalloid, an abundant element found in many types of rocks. Weathering of rocks releases arsenic-containing dust and allows arsenic compounds to enter groundwater. Arsenical compounds are used in industrial, agricultural, and medicinal substances. Arsenic is also an environmental contaminant in drinking water (well water) and the food chain and is an occupational hazard for miners and glass workers. Higher levels of arsenic are notoriously poisonous to multicellular life. Lower levels of inorganic arsenicals are known to be chemical carcinogens.
As early as 1888, Hutchinson reported skin cancer in patients who had taken arsenical medications. Numerous reports have since confirmed that ingested arsenic can cause Bowen disease (squamous cell carcinoma in situ); invasive squamous cell carcinoma; basal cell carcinoma of the skin; and (less frequently) internal cancers of the lung, the kidney, the bladder, and the liver. 
Arsenic also causes pigment changes and (very frequently) hyperkeratotic lesions of the skin called arsenical keratoses. Arsenical keratoses are the most characteristic skin feature of long-term arsenic exposure.
Other Medscape articles related to arsenic include Neurological Manifestations of Arsenic Intoxication and Arsenic Toxicity in Emergency Medicine.
The carcinogenic mechanism of arsenic is not well understood. Arsenic compounds have shown no mutagenicity in standard bacterial and mammalian test systems; however, they can increase the mutagenicity of other DNA-damaging agents. Arsenite impairs nucleotide excision repair,  and it may also affect gene expression by increasing or decreasing DNA methylation. [3, 4] The high affinity of arsenic for sulfhydryl groups makes keratin-rich cells (eg, epidermal keratinocytes) a sensitive target for arsenic-induced toxicity.
Arsenic has been shown to alter epidermal keratinocyte differentiation processes,  affect cell cycle and apoptosis, induce overexpression of growth factors such as transforming growth factor-α and epidermal growth factor receptor, [6, 7] and enhance proliferation of human keratinocytes. These in vitro findings may have revealed part of the pathogenesis of arsenical keratoses. Whether it is arsenic-induced DNA damage or senescence-associated indirect carcinogenesis, the oncogenesis of arsenic-induced cancers still awaits elucidation. [8, 9]
In the endemic region of West Bengal, India, only 10-30% of people exposed long term to arsenic developed characteristic skin lesions. A 2008 study suggests the individual capacity of DNA repair determines the level of chromosomal aberration, which leads to a susceptibility to develop arsenic-induced premalignant hyperkeratoses. 
A dose-response relationship exists between the amount of arsenic exposure and the frequency of various skin lesions. However, several studies have shown skin lesions that have developed in persons who consumed drinking water containing arsenic concentrations of less than 50 μg/L. A detail investigation has found that arsenic exposures of greater than 100 μg/L, even 200 μg/L in drinking water, are the cause of the characteristic skin lesions.  Three main categories of sources from which patients might have been exposed to arsenic include medicinal, drinking water (environmental), and occupational hazards.
Inorganic arsenic has been used in medicine for at least 2500 years, particularly since the 18th century, when it was used to treat a great variety of illnesses (eg, acne, diarrhea, gastric ulcer, asthma, malaria, lupus, psoriasis, neurodermatitis, eczema, rheumatism). During the 19th and early 20th centuries, the most popular preparation in the Western world was called Fowler solution, which contained 1% potassium arsenite.  In Asia, Chinese proprietary herbal medicine has been the mainstay of remedies for thousands of years and is still popular in that area; it is also available in the United States. Some of these traditional Chinese medicines have been reported to contain high levels of arsenic. [13, 14, 15]
Studies from endemic areas have found that arsenic-contaminated water (mainly well water) is the source of exposure. Cases of arsenic-induced toxicity have been reported in some endemic areas of Chile, Taiwan, India,  Bangladesh, and Mexico. An area on the southwest coast of Taiwan has been referred to as the endemic area of Blackfoot disease (a chronic peripheral vascular disease that may progress into gangrenous changes of the lower extremities). The same area also shows a high prevalence of skin cancer. Both conditions are dose related to high arsenic levels in artesian well water that local residents consume daily. In a Taiwanese study, Morales et al  reported the lifetime risk of death related to arsenic toxicity is 1 in 100 from consuming 50 μg/L of arsenic in drinking water.
Legge reported skin manifestations and lung cancer in sheep dip workers exposed to arsenic as early as 1902. Other reports showed arsenic carcinogenesis in smelter workers, pesticide workers, glass manufacturers, and miners. Burning plywood may cause arsenic-containing fumes to be inhaled. High-tech industries use gallium arsenide to produce semiconductor computer chips.
Arsenical keratosis and arsenic-induced skin cancers are very rare in the United States. Only isolated incidences of cutaneous toxicity from environmental or medicinal exposure have been reported. Several epidemiologic studies of communities exposed to drinking water with higher arsenic levels have not shown any excess incidence of skin cancers.
Documented regions with natural groundwater arsenic contamination include Millard County, Utah; Lane County, Oregon; Lassen County, California; Fallon, Nevada; Fairbanks, Alaska; and New Hampshire.  One study suggests persons living in the southwestern United States are at higher risk for being exposed to elevated levels of arsenic in drinking water. 
Arsenic-induced skin lesions have been noticed in some endemic regions, mainly due to long-term exposure to high levels of arsenic in drinking water. Such regions have been reported in Southern Taiwan, Japan, Vietnam, China, New Zealand, Poland, Hungary, Spain, Canada, Mexico, Chile, Argentina, West Bengal (India), Sri Lanka, Bangladesh, and western Iran. [18, 20]
According to large epidemiologic studies conducted by Yeh et al  and Tseng et al  in 1968 in Taiwan, among a high-risk population of 40,421 people, arsenic-induced hyperpigmentation was recognized in 18.4% of patients, arsenical keratosis in 7.1%, and skin cancers in 1.5%. Of the 428 people with skin cancer, 72% also presented with arsenical keratosis and 90% had hyperpigmentation.
A study conducted by Fierz  in Germany of 262 patients who had been taking Fowler solution for 6-26 years revealed that 40% of these patients developed arsenical keratosis and that 8% had skin cancers.
In a large-scale study in an endemic region, 18,000 persons in Bangladesh and 86,000 persons in West Bengal (India) were clinically examined. Of them, 3695 (20.6%, including 6.11% children) in Bangladesh and 8500 (9.8%, including 1.7% children) in West Bengal had arsenical dermatological features. 
An epidemiologic study has been conducted in Kurdistan (western Iran), where the arsenic concentration in drinking water ranges from 42-1500 μg/L. Among 587 villagers examined, 30.7% had skin manifestations of chronic arsenic toxicity. The prevalence rates of Mee lines (transverse bands of leukonychia) on the nails, arsenic keratoses, and pigment disorders among these patients were 86.1%, 77.2%, and 67.8%, respectively. 
Several large studies have focused in regional endemic areas. No global epidemiologic studies have been performed, and no direct predilection has been found among persons of different races.
In a study in Bangladesh, 430 out of 1481 research subjects older than 30 years who lived in villages with arsenic-contaminated wells were found to have arsenic-induced skin lesions, such as keratosis and hyperpigmentation or hypopigmentation.  The prevalence rate is approximately 30%, with a slightly higher prevalence in males than in females. Another study in West Bengal (India) revealed the prevalence of arsenic-induced skin lesions in men was 2- to 3-fold higher than in women. 
Immediately consider possible arsenic exposure if skin cancer is found in a relatively young person. The presence of arsenic skin toxicity can be seen in all age groups, although a latency period does occur.
Symptoms of chronic arsenic toxicity develop insidiously after 6 months to 2 years or more of exposure. In the study by Fierz,  the minimal latency period from exposure to the development of arsenical keratoses was 2.5 years, and the average latency period for skin cancer was 14 years.
A Japanese study reported the appearance of Bowen disease after 10 years, squamous cell carcinoma after 20 years, and lung cancer after 30 years of apparent arsenic exposure. 
In Taiwanese studies, the youngest patients reported to have skin hyperpigmentation, arsenical keratoses, and skin cancer were aged 3, 4, and 24 years, respectively.
Arsenical keratosis is not a fatal disease, but it may persist indefinitely and can become bothersome over time because of pain, bleeding, fissuring, and ulceration. Additionally, some may develop into invasive squamous cell carcinoma. Metastatic arsenic-induced squamous cell carcinoma and arsenic-induced visceral malignancies may result in mortality. [28, 29]
A dose-response relationship exists between arsenic exposure and health effects. Exposure to higher concentrations of arsenic and a longer duration of exposure to arsenic may increase the risk of invasive skin cancers and internal malignancies, which may result in fatality. 
Tapio S, Grosche B. Arsenic in the aetiology of cancer. Mutat Res. 2006 Jun. 612(3):215-46. [Medline].
Hartwig A, Groblinghoff UD, Beyersmann D, Natarajan AT, Filon R, Mullenders LH. Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts. Carcinogenesis. 1997 Feb. 18(2):399-405. [Medline].
Jha AN, Noditi M, Nilsson R, Natarajan AT. Genotoxic effects of sodium arsenite on human cells. Mutat Res. 1992 Dec 16. 284(2):215-21. [Medline].
Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci U S A. 1997 Sep 30. 94(20):10907-12. [Medline].
Kachinskas DJ, Phillips MA, Qin Q, Stokes JD, Rice RH. Arsenate perturbation of human keratinocyte differentiation. Cell Growth Differ. 1994 Nov. 5(11):1235-41. [Medline].
Germolec DR, Yoshida T, Gaido K, et al. Arsenic induces overexpression of growth factors in human keratinocytes. Toxicol Appl Pharmacol. 1996 Nov. 141(1):308-18. [Medline].
Chen Y, Parvez F, Gamble M, Islam T, Ahmed A, Argos M. 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 Longitudinal Study (HEALS) in Bangladesh. Toxicol Appl Pharmacol. 2009 Sep 1. 239(2):184-92. [Medline].
Ghosh P, Banerjee M, Giri AK, Ray K. Toxicogenomics of arsenic: classical ideas and recent advances. Mutat Res. 2008 Sep-Oct. 659(3):293-301. [Medline].
Madhyastha H, Madhyastha R, Nakajima Y, Maruyama M. Deciphering the molecular events during arsenic induced transcription signal cascade activation in cellular milieu. Biometals. 2018 Feb. 31 (1):7-15. [Medline].
Banerjee M, Sarma N, Biswas R, Roy J, Mukherjee A, Giri AK. DNA repair deficiency leads to susceptibility to develop arsenic-induced premalignant skin lesions. Int J Cancer. 2008 Jul 15. 123(2):283-7. [Medline].
Smith AH, Steinmaus CM. Health effects of arsenic and chromium in drinking water: recent human findings. Annu Rev Public Health. 2009 Apr 29. 30:107-22. [Medline].
Merck Pharmaceuticals. Merck’s Manual of the Materia Medica. 1st ed. Whitehouse Station, NJ: 1899.
Tay CH. Cutaneous manifestations of arsenic poisoning due to certain Chinese herbal medicine. Australas J Dermatol. 1974 Dec. 15(3):121-31. [Medline].
Tay CH, Seah CS. Arsenic poisoning from anti-asthmatic herbal preparations. Med J Aust. 1975 Sep 13. 2(11):424-8. [Medline].
Chi YW, Chen SL, Yang MH, et al. [Heavy metals in traditional Chinese medicine: ba-pao-neu-hwang-san]. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1993 May-Jun. 34(3):181-90. [Medline].
Guha Mazumder DN. Chronic arsenic toxicity: clinical features, epidemiology, and treatment: experience in West Bengal. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2003 Jan. 38(1):141-63. [Medline].
Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect. 2000 Jul. 108(7):655-61. [Medline].
Mandal BK, Suzuki KT. Arsenic round the world: a review. Talanta. 2002 Aug 16. 58(1):201-35. [Medline].
Tollestrup K, Frost FJ, Cristiani M, McMillan GP, Calderon RL, Padilla RS. Arsenic-induced skin conditions identified in southwest dermatology practices: an epidemiologic tool?. Environ Geochem Health. 2005 Feb. 27(1):47-53. [Medline].
Barati AH, Maleki A, Alasvand M. Multi-trace elements level in drinking water and the prevalence of multi-chronic arsenical poisoning in residents in the west area of Iran. Sci Total Environ. 2010 Mar 1. 408(7):1523-9. [Medline].
Yeh S, How SW, Lin CS. Arsenical cancer of skin. Histologic study with special reference to Bowen’s disease. Cancer. 1968 Feb. 21(2):312-39. [Medline].
Tseng WP, Chu HM, How SW, Fong JM, Lin CS, Yeh S. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst. 1968 Mar. 40(3):453-63. [Medline].
Fierz U. [Follow-up studies of the side-effects of the treatment of skin diseases with inorganic arsenic]. Dermatologica. 1965. 131(1):41-58. [Medline].
Rahman MM, Chowdhury UK, Mukherjee SC, et al. Chronic arsenic toxicity in Bangladesh and West Bengal, India–a review and commentary. J Toxicol Clin Toxicol. 2001. 39(7):683-700. [Medline].
Tondel M, Rahman M, Magnuson A, Chowdhury IA, Faruquee MH, Ahmad SA. The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh. Environ Health Perspect. 1999 Sep. 107(9):727-9. [Medline].
Haque R, Mazumder DN, Samanta S, et al. Arsenic in drinking water and skin lesions: dose-response data from West Bengal, India. Epidemiology. 2003 Mar. 14(2):174-82. [Medline].
Miki Y, Kawatsu T, Matsuda K, Machino H, Kubo K. Cutaneous and pulmonary cancers associated with Bowen’s disease. J Am Acad Dermatol. 1982 Jan. 6(1):26-31. [Medline].
Ahsan H, Steinmaus C. Invited commentary: use of arsenical skin lesions to predict risk of internal cancer: implications for prevention and future research. Am J Epidemiol. 2013 Feb 1. 177(3):213-6. [Medline]. [Full Text].
Sánchez G, Nova J. Risk factors for squamous cell carcinoma, a study by the National Dermatology Centre of Colombia. Actas Dermosifiliogr. 2013 Oct. 104(8):672-8. [Medline].
Shannon RL, Strayer DS. Arsenic-induced skin toxicity. Hum Toxicol. 1989 Mar. 8(2):99-104. [Medline].
Lien HC, Tsai TF, Lee YY, Hsiao CH. Merkel cell carcinoma and chronic arsenicism. J Am Acad Dermatol. 1999 Oct. 41(4):641-3. [Medline].
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 Aug 1. 198(3):243-52. [Medline].
Islam R, Khan I, Hassan SN, McEvoy M, D’Este C, Attia J, et al. Association between type 2 diabetes and chronic arsenic exposure in drinking water: a cross sectional study in Bangladesh. Environ Health. 2012 Jun 7. 11:38. [Medline].
WashingtonDeceit. Dermatopathology of arsenical keratosis. YouTube. Available at http://www.youtube.com/watch?v=xBreXMMHmLU. Accessed: February 26, 2008.
Son SB, Song HJ, Son SW. Successful treatment of palmoplantar arsenical keratosis with a combination of keratolytics and low-dose acitretin. Clin Exp Dermatol. 2008 Mar. 33(2):202-4. [Medline].
Yerebakan O, Ermis O, Yilmaz E, Basaran E. Treatment of arsenical keratosis and Bowen’s disease with acitretin. Int J Dermatol. 2002 Feb. 41(2):84-7. [Medline].
Boonchai W. Treatment of precancerous and cancerous lesions of chronic arsenicism with 5% imiquimod cream. Arch Dermatol. 2006 Apr. 142(4):531-2. [Medline].
Kjerkegaard UK, Heje JM, Vestergaard C, Stausbøl-Grøn B, Stolle LB. [Arsenical keratosis treated by dermatome shaving.]. Ugeskr Laeger. 2014 May 5. 176(19):[Medline].
Hsueh YM, Cheng GS, Wu MM, Yu HS, Kuo TL, Chen CJ. Multiple risk factors associated with arsenic-induced skin cancer: effects of chronic liver disease and malnutritional status. Br J Cancer. 1995 Jan. 71(1):109-14. [Medline].
Chih-Shan Jason Chen, MD, PhD Attending Physician, Dermatology Service, Memorial Sloan-Kettering Cancer Center; Director, Dermatologic Surgery and Mohs Micrographic Surgery Unit, MSK Skin Cancer Center; Chief, Dermatologic Surgery, Northport Veterans Affairs Medical Center; Associate Professor of Clinical Dermatology, Stony Brook University School of Medicine
Chih-Shan Jason Chen, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery, Association of Professors of Dermatology, Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Daniel Mark Siegel, MD, MS Clinical Professor of Dermatology, Department of Dermatology, State University of New York Downstate Medical Center
Daniel Mark Siegel, MD, MS is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Association for Physician Leadership, American Society for Dermatologic Surgery, American Society for MOHS Surgery, International Society for Dermatologic Surgery
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Steven R Feldman, MD, PhD Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine
Steven R Feldman, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, North Carolina Medical Society, Society for Investigative Dermatology
Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.
Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Arash Taheri, MD Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Nothing to disclose.
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