The word arsenic (As) is derived from the Greek word arsenikon, which itself is derived from the Persian word Zarnikh, meaning yellow orpiment, a brightly colored compound of arsenic and sulfur.
Although it is a metalloid with characteristics of both metals and nonmetals, arsenic is commonly characterized as a heavy metal.
Arsenic compounds have been known for at least 5000 years. Although As compounds were mined and used by the early Chinese, Greek and Egyptian civilizations, it is believed that As itself was first identified by Albertus Magnus, a German alchemist, in 1250. The first precise directions for the preparation of metallic arsenic, however, are found in the writings of Paracelsus, a physician-alchemist in the late Middle Ages who is often called the father of modern toxicology.
In Europe from the time of the Roman Empire through the Middle Ages and the Renaissance, arsenic was the king of poisons. The odorless and tasteless properties of inorganic arsenic compounds such as arsenic trioxide (white arsenic) made them an ideal poison. Hence, arsenic has been used as a means for settling old scores, an instrument for personal advancement, to execute criminals, and by those who found life to be an intolerable burden.
In 1940, it became known to Allied intelligence that the Germans had developed an organic blistering war gas containing As, which was known by the code name Lewisite. On contact with the skin, the gas reacted with sulfur on keratin, a skin protein, to produce huge blisters that were worsened by the release of caustic hydrochloric acid, also produced by the chemical reaction.
The British response to this threat was an intensive research program that culminated in the discovery of a simple sulfur-containing organic molecule which was highly effective in inactivating Lewisite on the skin, since it attracted arsenic away from biologically more important sites. This effective antidote became known by the acronym of BAL, for British Anti-Lewisite. Later it was given the generic name, dimercaprol.
After the war, interest in dimercaprol continued, and in view of its low toxicity, it was tested against As that had been taken internally. It was found to bind arsenic tenaciously and to hasten its excretion in the urine. It thus became the first rationally developed chelating agent – a chemical trap that sequesters and disables toxins. It is also used in treating people with mercury and gold poisoning.
In both 2007 and 2011, arsenic topped the Agency for Toxic Substances and Disease Registry (ATSDR) Priority List of Hazardous Substances, which ranks hazardous substances based on their frequency, toxicity, and potential for human exposure from hazardous waste sites.
Environmental contamination of As – particularly in drinking water – is a major cause for concern in many parts of the world. Reports of large-scale As contamination in the Gangetic Delta region in Bangladesh and India have drawn significant attention. In this part of the world alone, more than 38 million people are at risk of developing arsenic-related health hazards. The World Health Organization recommends maximum permissible value for As in drinking water to be 10 ppb. However, many countries like Argentina (200 ppb), Mexico (400 ppb), and the Indo-Bangladesh region (800 ppb) have extremely high As concentrations in their drinking water.
Arsenic is a naturally occurring element but is most often found in the minerals arsenopyrite (FeAsS), realgar (AsS) and orpiment (As2S3). Inorganic As compounds are more toxic than organic compounds, but organic As compounds are converted to inorganic compounds when absorbed in biological systems.
The following are all potential As sources: air pollution, antibiotics given to commercial livestock, certain marine plants, chemical processing industry (reagents, catalysts), electroplating, galvanizing and etching processes, coal-fired power plants, tap water, drying agents for cotton, contaminated shellfish (mussels, oysters), or other seafood, defoliants, some fungicides, insecticides – especially those used to treat lumber, meats (from commercially raised poultry and cattle), metal ore smelting, fireworks (intense white and blue colors), leather tanning and taxidermy, textile printing, lead and copper alloys (cable sheaths, solders, shot), specialty glass (opal glass, IR transmitting, decolorizing).
Arsenic is no longer produced in the United States; all the As used in the United States is imported. Arsenic is found in the preservative chromated copper arsenate (CCA) used to preserve wood. 90% of all As consumed in the U.S. is used in the production of CCA. The CCA treated wood is referred to as “pressure-treated”. There is considerable concern over this type of arsenic introduced into the environment. In the past, As was primarily used as a pesticide on cotton fields and in orchards. Inorganic As compounds can no longer be used in agriculture in the US. However, organic arsenicals, namely cacodylic acid, disodium methylarsenate (DSMA), and monosodium methylarsenate (MSMA) are still used as pesticides, principally on cotton. Small quantities of As metal are added to other metals forming metal mixtures or alloys with improved properties. The greatest use of As in alloys is in lead-acid batteries used in automobiles. Another important use of As compounds is in semiconductors and light-emitting diodes.
In the 19th century, women applied As powder to whiten their faces as well as to their hair and scalp to destroy vermin. It was also thought that As consumption by women gave “beauty and freshness” to the skin, an appearance of “pour rajeunisante”.
In 1786, Thomas Fowler, a British physician, published a study on the effectiveness of his solution of 1% potassium arsenite which he called “Liquor mineralis”, for “agues, remittent fevers, and periodical headaches”. In 1809, “Liquor mineralis”, known by that time as “Fowler’s solution”, was accepted into the London Pharmacopeia and became widely used as an alternative to quinine for “agues” (malaria) and was used for “sleeping sickness” (trypanosomiasis). By the 1880s, Fowler’s solution was used for a variety of other ailments including asthma, eczema, psoriasis, anemia, hypertension, gastric ulcers, heartburn, rheumatism, and tuberculosis, and arsenic paste was used to treat cancers of the skin and breast. Taking Fowler’s solution as a treatment for various chronic disorders was popular with Victorian prostitutes to give them rosy cheeks, an effect due to damage to the capillaries of the skin.
Other As preparations at that time included Donovan’s solution (arsenic triiodide and mercuric iodide) and de Valagin’s solution (arsenic trichloride), both used to treat similar disorders. In 1878, Fowler’s solution was discovered to lower the white cell count in chronic myelogenous leukemia and was used as the main treatment for leukemia until the advent of radiation and chemotherapy in the 20th century. Fowler’s solution remained a treatment for many conditions well into the 20th century, and is listed along with As-trioxide and sodium arsenate in the 1914 edition of the American Medical Association’s Handbook of Useful Drugs as treatment for skin cancer, chronic inflammatory skin disorders, malaria, syphilis and protozoal diseases.
In 1918, the US Army Chemical Warfare Service developed As-based Lewisite and Adamsite to counter the Central Powers’ effective use of gas agents against the Allies in the trenches of Western Europe. Lewisite is C2H2AsCl3, dichloro(2-chlorovinyl)arsine, also called “L” and “M-1” agent. Lewisite is primarily a vesicant (or blistering agent) but is also a potent respiratory and eye irritant and a systemic poison when absorbed. Upon contact with skin and mucous membranes, it immediately causes large, painful, fluid-filled blisters. When inhaled, it causes severe respiratory tract inflammation and necrosis resulting in acute pneumonitis.
During and after the Second World War, many countries stockpiled chemical weapons, particularly the United States and the former Soviet Union. Both the U.S. and the Russian Federation have since destroyed most of their chemical munitions, and as of January 2012, seven of nine U.S. chemical weapons destruction sites had been closed or were under closure. However, as time goes on, remaining munitions continue to deteriorate with an increasing risk of explosion or leakage – they also pose a potentially serious bioterrorism threat. Remaining stockpiles of Lewisite and Adamsite are still of international concern and are still listed by the CDC as potential bioterrorism agents.
In 2000, the US FDA approved As-trioxide for the treatment of acute promyelocytic leukemia (APL). In 2001, researchers from the University of Arkansas for Medical Sciences demonstrated the “efficacy” of As-trioxide in the treatment of end-stage high-risk multiple myeloma. Currently, As-trioxide is still approved to treat relapsed or refractory APL and research is continuing to determine its efficacy in other hematological cancers.
Arsenic is the 20th most abundant element in the Earth’s crust and is a component of more than 245 minerals. Arsenic and its compounds are mobile in the environment. Weathering of rocks converts As-sulfides to As-trioxide, which enters the As cycle as dust or by dissolution in rain, rivers, or groundwater. Wastes generated by the mining of gold and other base metals often contain elevated concentrations of As and there are many examples of environmental arsenic enrichment near mining operations. Arsenic toxicity has become an especially serious problem in Mexico, China, and Southeast Asia, where As is used in the rapidly growing semiconductor industry.
Arsenic belongs to the same group of the periodic table as antimony, nitrogen, phosphorus and bismuth, and is often described as a metalloid element. In most situations, however, its chemical behavior can be considered that of a non-metal.
Arsenic exerts its toxicity by inactivating up to 200 enzymes, especially those involved in cellular energy pathways and DNA synthesis and repair. Trivalent As is the primary toxic moiety and binds avidly to enzymes and proteins with thiol (-SH) groups. Lipoic acid is an important enzyme cofactor that has two thiol groups. Arsenic binds and depletes lipoic acid in cells, interfering with the production of chemical energy (adenosine triphosphate – ATP). Multiple enzymes use lipoic acid as cofactors and are blocked as arsenic interferes with function particularly pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. In addition, arsenic can be methylated, although this process may increase arsenic toxicity rather than contributing toward detoxification.
Acute poisoning has a mortality rate of 50-75% and death usually occurs within 48 hours. A lethal dose will vary with compound, but 0.2-0.3 g of arsenic trioxide (As2O3) is usually fatal in an adult. Of even more concern, however, is epidemiological evidence that long-term exposure to lower doses of As causes cancers of the lung, skin, bladder, and liver. Due to its apparent carcinogenicity and high concentrations in certain pollution sites, the U.S. Environmental Protection Agency puts As at the top of its list of hazardous chemicals. The Department of Health and Human Services, the International Agency for Research on Cancer, the EPA and the National Toxicology Program have all classified inorganic arsenic as a known human carcinogen.
Scientists have found it very difficult, however, to study how As might cause cancer. For unknown reasons, arsenic does not cause cancer in laboratory animals. Cell-culture studies have shown that As can break chromosomes, stop cell division, and inhibit DNA repair, among other effects. However, cell mutation assays have generally come up negative. These results led to unconfirmed hypotheses that arsenic causes cancer by inducing DNA hypomethylation and abnormal gene expression.
Arsenic can produce all three types of toxicity at difference dosages: acute, sub-acute, and chronic. One sign of acute exposure is edema of the eyelids; moreover, gastrointestinal irritation and both central and peripheral neuropathies frequently occur. During chronic intoxication “garlic breath”, skin sensitivity, and dermatitis frequently occur. All types of arsenic exposure can cause kidney and liver damage, and in the most severe exposure there is erythrocyte hemolysis.
The long-term retention of arsenic is most apparent in hair and skin, squamous epithelium of the upper gastrointestinal tract (oral cavity, esophagus, and the esophageal part of the stomach mucosa), the epididymis, thyroid (see Blackfoot disease below), lens and skeleton. The accumulation in hair, skin and the upper gastrointestinal tract may be ascribed to a binding to keratin, the content of which is high in squamous epithelia.
Blackfoot disease is an endemic peripheral vascular disorder that is confined to a limited land area on the southwest coast of Taiwan. It has long been related to the consumption of high levels of As found in the artesian well water. Arsenic-contaminated substances have been extracted from the well water and have been reported as a primary source of environmentally induced goiters.
Inorganic As has been recognized as a human poison since ancient times, and large oral doses (above 60,000 ppb in food or water) can cause death. If you swallow lower levels of inorganic As (ranging from about 300 to 30,000 ppb in food or water), you may experience irritation of your stomach and intestines, with symptoms such as stomachache, nausea, vomiting, and diarrhea. Other effects might include decreased production of red and white blood cells which may cause fatigue, abnormal heart rhythm, blood-vessel damage resulting in bruising, and impaired nerve function causing a “pins and needles” sensation in the
hands and feet.
Perhaps the single most characteristic effect of long-term oral exposure to inorganic As is a pattern of skin changes. These include a darkening of the skin and the appearance of small “corns” or “warts” on the palms, soles, and torso. A small number of the corns may ultimately develop into skin cancer. Swallowing As has also been reported to increase the risk of cancer in the liver, bladder, kidneys, prostate, and lungs. If inhaled at high levels of inorganic As, you are likely to experience a sore throat and irritated lungs. The exposure level that produces these effects is uncertain, but it is probably above 100 micrograms of As per cubic meter (g/m3) for a brief exposure. Longer exposure at lower concentrations can lead to skin effects, and also to circulatory and peripheral nervous disorders. There are some data suggesting that inhalation of inorganic As may also interfere with normal fetal development, although this is not certain. An important concern is the ability of inhaled inorganic As to increase the risk of lung cancer. This has been seen mostly in workers exposed to As at smelters, mines, and chemical factories, but also in residents living near smelters and arsenic chemical factories. People who live near waste sites with As may have an increased risk of lung cancer as well.
There are limited evidence-based treatment regimens to treat chronic arsenic poisoning, but the nutrients selenium, zinc, lipoic acid and vitamin C appear to be antagonistic for arsenic uptake and retention. The focus of management is to reduce As ingestion from drinking water and there is increasing emphasis on using alternative supplies of water. Certain sulfur-containing amino acids and sulfur compounds (Dimercaprol, DMSA, DMPS), as well as EDTA have been clinically shown to be an effective IV chelating agent for arsenic. Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes.
It is rather surprising that since the late 1940s, Dimercaprol (BAL) has remained the drug of choice in the United States for the treatment of As poisoning. It has many disadvantages, e.g. high toxicity, low therapeutic index, unpleasant side effects, limited water solubility, instability in solution, and the need to administer by im injection. Side effects, including nausea, vomiting, and headache, have been experienced by 50% of patients receiving BAL. By 1958, however, publications were beginning to appear in the Soviet literature indicating the superiority of DMPS as an antidote for As poisoning. By 1965, the effectiveness of DMSA for this purpose was reported in the Chinese and Soviet literature.
The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high-water solubility. While these advantages make it likely that DMPS and DMSA will replace Dimercaprol for the treatment of chronic arsenic poisoning, acute intoxication – especially with lipophilic organoarsenicals – may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. Be advised: although DMSA is efficacious against arsenic toxicity, the US FDA has only approved DMSA for lead chelation in children.
Blood Testing: Commercial blood tests are available for many metals (universally toxic metals, such as lead and mercury, as well as essential metals that are toxic above certain thresholds, such as iron or copper). Blood levels of cadmium and lead are usually indicative of recent exposures and may not reflect whole body burdens. For example, in the case of lead, blood levels are only indicative of exposure over the previous 90 days. In the case of arsenic, which is cleared rapidly from the blood, blood tests may only be reliable during early stages of intoxication (< 7-10 days after exposure).
Urine: Arsenic toxicity may be determined by urine analysis. Comparison of urine As levels pre- and post-provocation (DMPS, DMSA, D-penicillamine) permit differentiation between recent uptake and body stores. Generally, post-challenge or post-provocation urine tests, which involve the measurement of urine metal concentrations following administration of a chelator, may reveal sources of stored toxic metals. However, since there are no broadly accepted reference ranges for urine metals determined by this technique, these tests are likely of limited diagnostic value and are not completely validated. Reference ranges for individual tests depend on the laboratory performing the analysis.
Hair, in general, provides a rough estimate of exposure to As absorbed from food and water. However, hair can be contaminated externally with As from air, water, dust, shampoos and soap. When in doubt, As burden can be confirmed by urine elements analysis.
Acute arsenic poisoning is a medical emergency. For acute exposure, seek immediate medical attention and call Poison Control Services. As with all detoxification protocols, the type, dose and duration of detoxification agents should always be individually assessed and administered by a licensed medical practitioner.