Environmental Pathology and Health Effects of Arsenic Poisoning: An Introduction and Overview

 

Jose A. Centeno1, Florabel G. Mullick1, Leonor Martinez1, Herman Gibb2, David Longfellow3 and Claudia Thompson4

1Department of Environmental and Toxicologic Pathology, International Tissue and Tumor Repository on Chronic Arseniasis, Division of Biophysical Toxicology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000; 2National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, D.C. 3Chemical and Physical Carcinogenesis Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; 4National Institute of Environmental Health Sciences, Research Triangle Park, NC.

I. Abstract:

Arsenic is a ubiquitous element in the earth’s crust. It is transported in the environment mainly by water, although other natural and anthropogenic sources of exposure to arsenic including burning of arsenic-rich coal, mining and smelter activities which are of increasing concern. While a wealth of epidemiologic studies have confirmed the carcinogenicity of inhaled and ingested arsenic, the pathological characteristics of arsenic-induced cancers have never been examined extensively. Moreover, recent studies appear also to suggest that the health effects of arsenic are systemic and may involve multiple organs.1-3 In nearly all cases where internal cancers are attributed to arsenic exposure, there has been cutaneous evidence of arsenic adverse effects in the form of arsenical keratosis, hyperpigmentation, and multiple cutaneous malignancies.4 The aim of this short communication is to provide an overview of arsenic health effects, and to discuss with examples, our recent studies on the environmental pathology of arsenic poisoning including a histopathological description of arsenic-induced lesions. The data were derived from the International Tissue and Tumor Repository on Chronic Arsenosis.5,*

II. Arsenic Poisoning: Adverse Health Effects

Skin. Epidemiological and clinical studies reported in the medical literature have confirmed the role of arsenic in the induction of cancers of the skin. Arsenic-induced skin lesions may include keratosis, squamous cell carcinoma and basal cell carcinoma. Arsenical keratosis in its fully developed form is a well established clinical syndrome, characterized by several specific pathological features, including hyperkeratosis, parakeratosis, arsenical pigmentation, and squamous cell carcinoma in situ (indistinguishable from Bowen's disease). Within the spectrum of keratotic lesion, arsenical keratosis may be differentiated from the more commonly diagnosed actinic keratosis by the absence of epidermal atrophy and basophilic degeneration of the upper dermis. All arsenical skin changes, including keratoses, tend to occur in non-exposed sites with an absence of dermal solar elastosis noted histologically. The lesions are normally most pronounced on the feet and hands, although they can occur on the trunk and other areas of the extremities.

Squamous cell carcinoma in situ is the most common form of skin cancer induced by arsenic, which may develop from two to 20 years after exposure. Bowen's Disease is an intraepidermal squamous cell carcinoma, referred to as squamous cell carcinoma in situ. It is considered a precancerous dermatosis, in the same group as leukoplakia, senile keratosis, and xeroderma pigmentosum. Histologically, Bowen's Disease presents as intraepithelial atypism, with marked variation in cell and nuclear size and shape. Multinucleated giant cells, and numerous mitotic figures are observed throughout all levels of the epidermis.

Arsenic-induced skin lesions assume protean forms. Besides keratotic lesions and skin cancers, pigmentation disorders represent another characteristic manifestation of arsenic exposure. The pigmentation may present as hyper- or hypopigmentation. Hyperpigmentation is reported to be one of the most common skin changes seen in people chronically exposed to arsenic. It most often occurs in the trunk, but may be more accentuated in areas that are more heavily pigmented such as the groin and areola. Histologic examination reveals increased melanin pigment in melanocytes in the basal cell of the epidermis extending up to the granular cell layer. Signs of arsenic pigmentation may herald the later development of skin cancer. In one study of patients showing signs of arsenical pigmentation, nearly 90% developed skin cancer. Hypopigmentation occurs as well and may show a characteristic "rain drop" pattern.

Internal Lesions. In addition to skin lesions, including skin cancer, epidemiological studies have provided suggestive evidence linking arsenic exposure to various internal cancers, including angiosarcoma of the liver (see Figure 1), lung cancer, and bladder cancer. In the majority of cases in which the internal cancer is ascribed to arsenic exposure, some dermatological hallmark of arsenic poisoning is identified.1 Gastrointestinal manifestations have also been reported due to chronic arsenic exposure and includes noncirrhotic portal hypertension (NCPH),6 hepatic or splenic enlargement, hepatocellular carcinoma (see Figure 2),5 and liver angiosarcoma.7 NCPH is a rare, but relatively specific effect that may occur after years of arsenic ingestion at concentrations of 0.01 mg/kg/d. Recent case reports indicate a possible relationship between arsenic exposure and the occurrence of hepatocellular carcinoma; however, epidemiologic studies have not as yet confirmed this association. The increased incidence of hepatocellular carcinoma in arsenic-exposed endemic areas of Taiwan may have an arsenic etiology in addition to a viral causation. The association between arsenic exposure and angiosarcomas of the liver has also been reported. However, most of the published literature has consisted of case reports rather than population-based epidemiological studies.

Figures 1 and 2 present microscopic views of an angiosarcoma and hepatocellular carcinoma, respectively (Reference 5. Centeno JA, et al. Arsenic-Induced Lesions, 2000).

Non-Cancer Effects of Chronic Arsenic Poisoning. In addition to internal cancers, recent published studies have suggested an association between arsenic exposure and an increased risk for a variety of non-cancer effects. These include peripheral vascular disease, cardiovascular disease, diabetes, neurological effects, chronic lung diseases (shortness of breath and chest signs), diminished hearing, and cerebrovascular disease.1-3, 8-10 It is quite apparent that the hazardous effects of arsenic are multi-organ related with extensive system pathology.

Reproductive effects of arsenic in humans has not been extensively investigated. Evidence from both animal and human studies suggests reproductive toxicity from arsenic, but data in humans is still sparse, and the results from laboratory experiments in animals are not conclusive. The evidence from a few human studies suggests that arsenic exposure may increase the incidence of pre-clampsia in pregnant women, decrease birth weight of newborn infants and increase in the risk of malformations and stillbirths, as well as that of spontaneous abortions.11,12 Although recent laboratory studies suggest an increase in malformations and stillbirths in animals,13,14 the effects of arsenic from drinking water in human reproduction have not been adequately studied. In order to assess the potential effects of arsenic in human reproduction, a properly designed epidemiological study in a large enough population is necessary.

In conclusion, the evidence for a casual relationship between cancers of the skin and arsenic exposure is strong and indisputable. Arsenic-induced skin cancers are predictable from exposure biomarkers of the skin, including hyperkeratosis, and hyper- or hypopigmentation. Cancers of the internal organs do not have such distinct exposure biomarkers and thus their association with a particular etiologic agent cannot be established with the same degree of confidence. Nevertheless, chronic arsenic exposure represents a significant risk factor for future development of liver cancer.

*Part of this work has been published in "Arsenic-Induced Lesions" (April 2000), Armed Forces Institute of Pathology, ISBN:1-881041-68-9.

 

References:

1. Tsai S-M, Wang T-N, Ko Y-C. Mortality for certain diseases in areas with high levels of

arsenic in drinking water. Arch Environ Health 1999;54:186-193.

2. Lai MS, Hsueh YM, Chen CJ, et al. Ingested inorganic arsenic and prevalence of diabetes

Mellitus. Am J Epidemiol 1994;139:484-492.

3. Chen CJ, Chiou HY, Chiang MH, et al. Dose-response relationship between ischemic heart

disease mortality and long-term arsenic exposure. Arterioscler Thromb Vasc Biol 1996;

16:504-510.

4. Maloney M. Arsenic in dermatology. Dermatol Surg 1996; 22:301-304.

5. Centeno JA, Martinez L, Ladich ER, Page NP, Mullick FG, Ishak KG, et al. Arsenic-Induced

Lesions. Armed Forces Institute of Pathology, Washington D.C. (April 2000), pp 1-46. ISBN: 1-881041-68-9.

6. Nevens F, Fevery J, van Stenbergen W, et al. Arsenic and non-cirrhotic portal hypertension:

A report of eight cases. J Hepatol 1990;11:80-85.

7. Neshiwat LF, Friedland ML, Schorr-Lesnick B, Felman S, Glucksman WJ, Russo RD.

Hepatic Angiosarcoma. Am J Med 1992;93:219-222.

8. Chen CJ, Hsueh YM, Lai MS, et al. Increased prevalence of hypertension and long-term

arsenic exposure. Hyppertension 1995; 25:53-60.

9. Wu MM, Kuo TL, Hwang YH, et al. Dose-response relation between arsenic concentration in

well water and mortality from cancers and vascular diseases. Am J Epidemiol

1989;130:1123-1132.

10. Guha Mazumder DN, De BK, Santra A, Dasgupta J, et al. Chronic arsenic toxicity:

epidemiology, natural history, and treatment. In Arsenic Exposure and Health Effects (ed. By

Chappell WR, Abernathy CO, Calderon RL) 1999 Elsevier Science B.V. pp 335-347.

11. Stein Z, et al. Spontaneous abortions as a screening device: the effect of fetal survival on

the incidence of birth defects. Am J. Epidemiol 1975;102:275.

12. Nordstrom S. et al. Occupational and environmental risks in an around a smelter in northern

Sweden: III. Frequencies of spontaneous abortion. Hereditas 1978;88:51.

13. Leonard A, Lauwerys RR. Carcinogenicity, teratogenicity, and mutagenicity of arsenic.

Mutation Research 1980;75:49.

14. Hodd RD, et al. Effects in the mouse and rot of prenatal to arsenic. Environ Health Perspec

1977;19:219.

 

 

Figure 1. Angiosarcoma of the liver in 15-year-old arsenic exposed patient.

The sinusoidal spaces are lined by malignant endothelial cells5.

 

 

 

Figure 2. Hepatocellular carcinoma. The nuclei are irregular,

hyperchromatic, and occasionally multi-nucleated5.