Introduction
Background
Arsenic is a natural element found in many types of rocks. Inorganic arsenicals are known to be chemical carcinogens. Arsenical compounds are used in industrial, agricultural, and medicinal substances. Arsenic is also found to be an environmental contaminant in drinking water (well water) and an occupational hazard for miners and glass workers.
Hutchinson reported skin cancer in patients who had taken arsenical medications as early as 1888. 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 eMedicine articles on arsenic include Arsenic, Toxicity, Arsenic (critical care focus), and Toxicity, Arsenic (emergency medicine focus).
Pathophysiology
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,1 and it may also affect gene expression by increasing or decreasing DNA methylation. 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,2 induce overexpression of growth factors,3 and enhance proliferation of human keratinocytes. These in vitro findings may have revealed part of the pathogenesis of arsenical keratoses. The oncogenesis of arsenic-induced cancers still awaits elucidation.
Frequency
United States
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.
International
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 Taiwan, Mexico, South America, India, and Bangladesh.
According to a large epidemiologic study conducted by Yeh et al4 and Tseng et al5 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 Fierz6 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 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.7
Mortality/Morbidity
Arsenical keratoses may persist indefinitely, and some may develop into invasive squamous cell carcinoma. Metastatic arsenic squamous cell carcinoma and arsenic-induced visceral malignancies may result in mortality.
Race
Several large studies were focused in the regional endemic area. No global epidemiologic study exists, and no direct comparison has been found among races.
Sex
In a study8 in Bangladesh, 430 out of 1481 research subjects older than age 30 years from 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.
Age
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, though a latency period does occur.
- Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. In the study by Fierz,6 the minimal latency period from exposure to 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 in 10 years, squamous cell carcinoma in 20 years, and lung cancer after 30 years of apparent arsenic exposure.9
- In Taiwanese studies, the youngest patients reported to have skin hyperpigmentation, arsenical keratoses, and skin cancer were aged 3, 4, and 24 years, respectively.
Clinical
History
- Arsenical keratoses, skin hyperpigmentation, and several types of skin cancers including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma are characteristic skin lesions of long-term arsenic exposure.
- A long latency period (years to decades) occurs before the development of these cutaneous lesions.
- Chronic arsenicism is usually asymptomatic, and the skin lesions are usually the first sign to present clinically.
Physical
- Arsenical keratoses are usually multiple and typically occur at sites of friction and trauma, especially on the palms and the soles. These lesions are most frequently seen on the thenar and lateral borders of the palms, the base and lateral aspect of the digits, the soles, heels, and toes of the feet.
- Keratoses may also develop on the dorsum of the hands, the arms, and the legs.
- Keratoses usually present as small, punctate, nontender, horny, hard, yellowish, often symmetric, cornlike papules.
- The diameter of the papule ranges from 0.2-1 cm.
- Lesions may coalesce to form large verrucous plaques.
- Another type of arsenical keratosis that presents as scaly erythematous or pigmented patches on unexposed body areas is seen in most patients with arsenical cancers.
- Mees lines on the fingernails are seen in acute and chronic arsenicalism.
Causes
A dose-response relationship exists between the amount of arsenic exposure and the frequency of various skin lesions. Three main categories of sources from which patients might have been exposed to arsenic include medicinal, drinking water (environmental), and occupational hazards.
- Medicinal arsenic
- Inorganic arsenic has been used in medicine for at least 2,500 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.10,11
- Drinking water
- 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,12 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 showed a high prevalence of skin cancer. Both conditions were dose related to high arsenic levels in artesian well water that local residents consumed daily.
- In a Taiwanese study, Morales et al13 reported the lifetime risk of death is 1 in 100 from consuming 50 mcg/L of arsenic in drinking water.
- Occupational hazards
- 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.
More on Arsenical Keratosis |
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| References |
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Further Reading
Keywords
long-term arsenic exposure, chronic arsenic exposure, arsenic-induced skin cancers
