Acute and chronic arsenic toxicity.

Arsenic toxicity is a global health problem affecting many millions of people. Contamination is caused by arsenic from natural geological sources leaching into aquifers, contaminating drinking water and may also occur from mining and other industrial processes. Arsenic is present as a contaminant in many traditional remedies. Arsenic trioxide is now used to treat acute promyelocytic leukaemia. Absorption occurs predominantly from ingestion from the small intestine, though minimal absorption occurs from skin contact and inhalation. Arsenic exerts its toxicity by inactivating up to 200 enzymes, especially those involved in cellular energy pathways and DNA synthesis and repair. Acute arsenic poisoning is associated initially with nausea, vomiting, abdominal pain, and severe diarrhoea. Encephalopathy and peripheral neuropathy are reported. Chronic arsenic toxicity results in multisystem disease. Arsenic is a well documented human carcinogen affecting numerous organs. There are no evidence based treatment regimens to treat chronic arsenic poisoning but antioxidants have been advocated, though benefit is not proven. The focus of management is to reduce arsenic ingestion from drinking water and there is increasing emphasis on using alternative supplies of water.

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Arsenic is one of the most toxic metals derived from the natural environment. The major cause of human arsenic toxicity is from contamination of drinking water from natural geological sources rather than from mining, smelting, or agricultural sources (pesticides or fertilisers). (1) Many industrialised and less industrialised countries have drinking water contaminated with arsenic. (2 3) The problem is of major concern in the USA--for example, the arsenic content of drinking water from public and private sources in Millard County ranges from 14 parts per billion (ppb) to 166 ppb. (4) The Environment Protection Agency lowered the permissible level of arsenic in drinking water in the USA in 2001 from 50 ppb to 10 ppb. Prolonged ingestion of water contaminated with arsenic may result in the manifestations of toxicity in practically all systems of the body as subsequently discussed. The most serious concern is the potential of arsenic to act as a carcinogen.

The two worst affected areas in the world are Bangladesh and West Bengal, India. In 42 districts in southern Bangladesh and in nine adjacent districts in West Bengal, 79.9 million and 42.7 million people respectively are exposed to groundwater arsenic concentrations that are above the World Health Organisation maximum permissible limit of 50 [mu]g/1. (5) In both these areas, the source of arsenic is geological in origin, contaminating aquifers which provide water for over one million tube wells. (6-8) In West Bengal the arsenic concentration in some tube wells is as high as 3400 [mu]g/1. (9)

The mechanism of arsenic accumulation in the Bengal Delta Plain is thought to have occurred during the late Quaternary age (Holocene age) with arsenic-containing alluvial sediments deposited by the Ganges, Brahmaputra, Meghna, and other smaller rivers that flow across the Bengal Delta Plain into the Bay of Bengal. (8) In the Bengal Delta Plain, the arsenic is adsorbed as arsenic oxyanions onto oxyhydroxides of iron, aluminium, and manganese and then mobilised in the alluvial aquifers where, due to the reducing environment, the oxyhydroxides are dissolved by biogeochemical processes, releasing the arsenic into the groundwater. (8)

Over the centuries, arsenic has been used for a variety of purposes. Arsenic was a constituent in cosmetics, and used more extensively than at present in agriculture to protect crops from pests. Arsenic as copper acetoarsenite was a pigment in paints, the best known being "Paris green". Before electricity was used for illumination, hydrogen liberated from coal fires and from gas for lighting combined with arsenic in the Paris green used in wallpaper to form arsine, a toxic gas. A fungus Scopulariopsis breviculis present in damp wallpaper also metabolised the arsenic in Paris green to arsine.

In industry, arsenic is used to manufacture paints, fungicides, insecticides, pesticides, herbicides, wood preservatives, and cotton desiccants. As it is an essential trace element for some animals, arsenic is an additive in animal feed. Gallium arsenide or aluminium gallium arsenide crystals are components of semiconductors, light emitting diodes, lasers, and a variety of transistors.

Arsenic is a popular murder weapon. Many arsenic compounds resemble white sugar and this apparent innocuousness is enhanced by being tasteless and odourless and was publicised by Frank Capra's film Arsenic and Old Lace, in which two elderly ladies use arsenic in elderberry wine to murder their male suitors.

HISTORICAL THERAPEUTIC USES OF ARSENIC

Arsenic was used as a healing agent after Greek physicians such as Hippocrates and Galen popularised its use. Arsenic compounds became available as solutions, tablets, pastes, and in injectable forms. Fowler's solution, a 1% arsenic trioxide preparation, was widely used during the 19th century. As recently as 1958, the British Pharmaceutical and Therapeutic Products handbook edited by Martindale, listed the indications for Fowler's solution as: leukaemia, skin conditions (psoriasis, dermatitis herpetiformis, and eczema), stomatitis and gingivitis in infants, and Vincent's angina. Fowler's solution was also prescribed as a health tonic. Chronic arsenic intoxication from the long term use of Fowler's solution caused haemangiosarcoma, (10) angiosarcoma of the liver, (11 12) and nasopharyngeal carcinoma. (13) Arsenic was the primary treatment for syphilis until World War II. Arsphenamine (neoarsphenamine), a light yellow compound containing 30% arsenic was used intravenously to treat syphilis, yaws, and some protozoan infections.

CURRENT THERAPEUTIC USES OF ARSENIC

Arsenic trioxide (A[s.sub.2][O.sub.3]) is now widely used to induce remission in patients with acute promyelocytic leukaemia, based on its mechanism as an inducer of apoptosis (programmed cell death). (14-18) Arsenic induces apoptosis by releasing an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space from where it translocates to the cell nucleus. (19) AIF then effects apoptosis, resulting in altered nuclear biochemistry, chromatin condensation, DNA fragmentation, and cell death. AIF has been isolated and cloned and is a flavoprotein with a molecular weight of 57 000. (20)

Arsenic continues to be an essential constituent of many non-western traditional medicine products. Some Chinese traditional medications contain realgar (arsenic sulphide) and are available as pills, tablets, and other preparations. They are used for psoriasis, syphilis, asthma, rheumatism, haemorrhoids, cough and pruritus, and are also prescribed as a health tonic, an analgesic, anti-inflammatory agent, and as a treatment for some malignant tumours. (21-23) …