Understanding Arsenic Toxicity

Arsenic is one of the most toxic metals derived from the natural environment. The primary cause of arsenic toxicity in humans is contamination of drinking water rather than geological and mining or agricultural sources (pesticides or fertilizers). Many countries, more or less industrialized, have drinking water contaminated with arsenic.

The US Environmental Protection Agency decided that, locally, the allowable level of arsenic in drinking water in 2001 was from 50 parts per billion (ppb) to 10 ppb. Prolonged ingestion of water contaminated with arsenic can cause manifestations of toxicity in virtually all body systems. The most serious concern is the potential for arsenic to act as a carcinogen.

The 2 most affected areas in the world are Bangladesh and West Bengal, in India. In 42 districts of southern Bangladesh and 9 adjacent districts of West Bengal, 79.9 million and 42.7 million people respectively are exposed to arsenic concentrations in groundwater exceeding the maximum permissible limit recommended by WHO. 50 μg/l.

In both areas, the source of arsenic is of geological origin and contaminates the aquifers that supply water to more than 1 million tube wells. In West Bengal, the arsenical concentration in some tubewells reaches as much as 3,400 μg/l. The mechanism of arsenic accumulation in the Bengal delta plain is believed to have occurred during the late Quaternary (Holocene) with arsenic-bearing alluvial sediments deposited by the Ganges, Brahmaputra, Meghna and other smaller rivers, flowing through the Bengal Delta plain to the Bay of Bengal.

In the Bengal delta plain, arsenic is absorbed as arsenic oxyanions onto iron, aluminum and manganese oxyhydroxides and then mobilized to alluvial aquifers where, due to environmental reduction, the oxyhydroxides dissolve through biogeochemical processes, releasing the arsenic to groundwater.

Over the centuries, arsenic has been used for various purposes. At one time, arsenic was a cosmetic ingredient and more broadly, in agriculture, to protect crops from pests. It was also used as a pigment in paints, such as copper acetoarsenite, the best known being “Paris green.” Before the use of electric lighting, hydrogen released by burning coal and gases from gas lighting fixtures, combined with arsenic from Paris Green used in wallpaper, led to the formation of arsine, a gas toxic.

The fungus Scopulariopsis breviculis present in the wet wallpaper also metabolized arsenic from Paris Green to arsine. In industry, arsenic is used to make paints, fungicides, insecticides, pesticides, herbicides, wood preservatives, and cotton desiccants. Being an essential trace element for some animals, arsenic is an additive in animal feed.

Gallium arsenide or gallium aluminum 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 which makes it seem harmless, added to which it is tasteless and odorless and was publicized by the Frank Capra film Arsenic and Old Lace, in which 2 old ladies use arsenic in wine on of elderberry to murder her male suitors.

Arsenic has been used as a healing agent after Greek physicians such as Hippocrates and Galen popularized its use. Arsenic compounds were available in the form of solutions, tablets, pastes, and injectables. Fowler’s solution, a 1% arsenic trioxide preparation, was widely used during the 19th century.

In 1958, the British Manual of Pharmaceuticals and Therapeutics listed indications for Fowler’s solution as: leukemia, skin conditions (psoriasis, dermatitis herpetiformis and eczema), stomatitis and gingivitis in infants, and Vincent’s angina. Fowler’s solution was also used as a health tonic. Chronic arsenic poisoning due to prolonged use of Fowler’s solution caused hemangiosarcoma, angiosarcoma of the liver, and nasopharyngeal carcinoma.

Arsenic was the main 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.

Currently, arsenic trioxide (As2O3) is widely used to induce remission in patients with acute promyelocytic leukemia , due to its apoptosis (programmed cell death) inducing action.

Arsenic induces apoptosis by releasing an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space, from where it is transferred to the cell nucleus. FIA then produces apoptosis, resulting in altered nuclear biochemistry, chromatin condensation, DNA fragmentation, and cell death. FIA has been isolated as a flavoprotein, with a molecular weight of 57,000.

Arsenic remains an essential component of many non-Western traditional medicine products. Some traditional Chinese medicines contain realgar (arsenic sulfide) and are available in the form of pills, tablets, and other preparations. They have been used for psoriasis, syphilis, asthma, rheumatism, hemorrhoids, coughs, and itching, and are also prescribed as a health tonic. Likewise, it is used as an analgesic, anti-inflammatory and in some malignant tumors.

In India, herbal medicines containing arsenic are used in some homeopathic preparations and in hematological malignancies. In Korea, it is prescribed in herbal medicine for hemorrhoids. However, more than a intended ingredient, arsenic is often a contaminant, sometimes with mercury and lead.

The California Department of Health Services tested 251 products at retail health stores and detected arsenic in 36 (14%) at concentrations of 20.4 to 114,000 parts per million (ppm) with a mean of 145.53 ppm and median of 180. .5 ppm.

A study conducted in Singapore identified 17 patients over a 5-year period with skin lesions related to chronic arsenic toxicity, while in 14 (82%) patients, the toxicity was due to arsenic contained in Chinese medicines. The other 3 consumed tube well water contaminated with arsenic.

Arsenic occurs in 2 oxidation states: a trivalent form, arsenite (As2O3; As III) and a pentavalent form, arsenate (As2O5; As V). As III is 60 times more toxic than As V. Organic arsenic is not toxic while inorganic arsenic is.

Arsenic toxicity inactivates up to 200 enzymes, particularly those involved in cellular energy pathways and DNA replication and repair. In highly energetic compounds such as ATP it is replaced by phosphate.

Free arsenic also exerts its toxicity by generating reactive oxygen that mediates during its redox cycle and metabolic activation processes causing lipid peroxidation and DNA damage. Especially As III, it binds to thiol or sulfhydryl groups, tissue proteins of the liver, lungs, kidney, spleen, gastrointestinal mucosa and tissues rich in keratin (skin, hair and nails). Many other toxic effects due to arsenic are also being detected.

Exposure to arsenic occurs through inhalation, skin absorption and, mainly, by ingestion of, for example, contaminated drinking water.

Arsenic in foods occurs as relatively non-toxic organic compounds (arsenobentaine and arsenocholine).

Shellfish, fish and algae are the organic products richest in arsenic. These organic compounds cause elevated levels of arsenic in the blood but are rapidly excreted unchanged in the urine. Arsenic intake is greater in solid foods than in liquids, including drinking water.

Organic and inorganic arsenic compounds can enter the plant food chain from agricultural products or soils irrigated with arsenic-contaminated water.

The main site of absorption is the small intestine due to an electrogenic process that involves a proton gradient. The optimal pH for arsenic absorption is 5.0.38 although in the small intestine environment, the pH is approximately 7.0 due to pancreatic secretion of bicarbonate.

Absorbed arsenic undergoes hepatic biomethylation to form monomethylarsonic acid and dimethylarsinic acid, which are less toxic but not completely harmless. About 50% of the ingested dose can be eliminated in the urine in 3 to 5 days. Dimethylarsinic acid is the dominant urinary metabolite (60%–70%) compared to monomethylarsonic acid. A small amount of unchanged inorganic arsenic is also excreted. After acute poisoning, electrothermal atomic absorption spectrometry studies show that the highest concentration of arsenic is found in the kidneys and liver.

With chronic ingestion of arsenic, it accumulates in the liver, kidneys, heart and lungs and, in smaller amounts, in the muscles, nervous system, gastrointestinal tract and spleen. Although most of the arsenic is removed from these sites, there are residues that remain in keratin-rich tissues, nails, hair and skin. After about 2 weeks of ingestion, arsenic is deposited in the hair and nails.

> Acute poisoning

Most cases of acute arsenic poisoning occur from accidental ingestion of insecticides or pesticides and less commonly from attempted suicide. Small amounts (<5 mg) cause vomiting and diarrhea but resolve within 12 hours and treatment is unnecessary. The lethal dose of arsenic in acute poisoning ranges between 100 and 300 mg.

The risk to humans in cases of acute ingestion has been assessed from a lethal dose of inorganic arsenic of approximately 0.6 mg/kg/day. A 23-year-old man who ingested 8 g of arsenic survived for 9 days. One student who consumed 30 g of arsenic called for help after 15 hours and survived 48 hours, but died despite gastric lavage and treatment with British anti-lewisite antidote and hemodialysis. Depending on the amount consumed, death usually occurs within 24 hours to 4 days.

Initially, clinical features are invariably related to the gastrointestinal system, with nausea, vomiting, abdominal cramps, abdominal pain, and profuse watery diarrhea.

Abdominal pain can be severe and mimic an acute abdomen.

Excessive salivation also occurs and may be the presenting complaint in the absence of other gastrointestinal symptoms. Other clinical features include acute psychosis, diffuse skin rash, toxic cardiomyopathy, and seizures. Diarrhea attributed to increased permeability of blood vessels is a dominant feature.

Large, watery stools are described as “choleric diarrhea . ” In cholera, the stool is described as “rice water,” but in the case of acute arsenic poisoning, it is called “bloody rice water” due to the presence of blood in the gastrointestinal tract. The cause of death is massive fluid loss due to secretion from the gastrointestinal tract resulting in severe dehydration, reduction in circulating blood volume and consequent circulatory collapse. The autopsy examination revealed esophagitis, gastritis, and hepatic steatosis.

Reported hematologic abnormalities include   hemoglobinuria, intravascular coagulation, bone marrow depression, severe pancytopenia, normocytic normochromic anemia, and basophilic stippling. Renal failure was reported in 4 of 8 sailors exposed to arsine. Other common features of acute poisoning are respiratory failure and pulmonary edema.

The most common neurological manifestation is peripheral neuropathy, which can last up to 2 years. This neuropathy can cause a rapid and severe increase in weakness, similar to Guillain-Barré syndrome, requiring mechanical ventilation. Another common manifestation is encephalopathy, and if its etiology is uncertain, the possibility of arsenical toxicity must be ruled out. Encephalopathy has occurred after intravenous administration of arsphenamines. Encephalopathy is thought to be due to hemorrhage. Metabolic changes have been reported with acute arsenic poisoning. Acidosis has occurred in only one patient and hypocalcemia in cattle. In acute poisoning, the best indicator of recent ingestion (1 to 2 days) is the urinary arsenic concentration.

> Chronic poisoning

Chronic arsenic poisoning leads to multisystem diseases; the most serious consequence is malignancy.

The clinical characteristics of arsenical poisoning vary between individuals and population groups and geographic areas. It is not clear what factors determine the appearance of a particular clinical manifestation, or which body system it targets. Thus, a wide range of clinical characteristics occur in people exposed to chronic toxicity. The onset is insidious with nonspecific symptoms of abdominal pain, diarrhea, and sore throat.

> Skin

Numerous skin changes occur in long-term exposure and are a common feature. Often, the initial clinical diagnosis is based on the presence of hyperpigmentation and palmar and solar keratosis. Keratosis may appear as uniform thickening or discrete nodules. It is highlighted that both palmar and solar keratosis are an important diagnostic criterion.

Hyperpigmentation presents as diffuse dark brown spots, less discrete diffuse skin darkening, or a characteristic “raindrop” appearance. Skin cancer or Bowen’s disease, associated with arsenic, is a rare manifestation in Asian people and may be due to the high melanin content in the skin and greater exposure to ultraviolet radiation.

Arsenic can cause basal cell carcinoma in a person with skin not pigmented with melanin. The latency period after exposure can last up to 60 years and has been reported in patients treated with Fowler’s solution, in sheep dipping workers, in vineyard workers using arsenical pesticides, and from drinking contaminated wine. Another manifestation due to arsenic deposition in keratins are prominent transverse white lines located on the fingernails and toenails, known as Mee’s lines.

Large population studies from West Bengal show a relationship between arsenic concentration in tube well water, dose per body weight, hyperpigmentation and keratosis, and that people with poor nutritional status were more susceptible. However, the study by Smith et al reported that arsenic-induced skin lesions occur among Atacameños from northern Chile, despite good nutritional status. These subjects from the village of Chiu Chiu were from an area “famous” for its cultivation of carrots and other vegetables, but the arsenic contained in the foods consumed was not measured, to determine if arsenic in the food chain could “nullify” the value nutrition of the foods consumed.

> Gastrointestinal system

Although in cases of acute poisoning, diarrhea is an important and early-onset symptom, in chronic toxicity it occurs in recurrent attacks that may be associated with vomiting. If there are other manifestations such as skin changes and neuropathy, arsenic ingestion should be suspected.

In 248 patients with evidence of chronic arsenical toxicity from West Bengal, who consumed arsenic-contaminated drinking water for 1 to 15 years, hepatomegaly was found in 76.6%, and of the 69 who were biopsied, 63 (91.3% ) showed non-cirrhotic portal fibrosis. In another study, arsenic was considered the etiologic agent in 5 of 42 patients with incomplete septal cirrhosis, an inactive form of macronodular cirrhosis characterized by thin incomplete septa demarcating discrete nodules and an unusually high incidence of variceal bleeding.

> Cardiovascular system

Increased risk of cardiovascular disease is reported in foundry workers due to exposure to arsenic.

In a study conducted in Millard, County, USA, based on a cumulative arsenic exposure matrix, a significant increase in mortality was observed in both sexes due to hypertensive heart disease. In Bangladesh, Rahman et al in 1999 reported an increased incidence of hypertension in a large study of 1,481 subjects exposed to arsenic-containing tube-well water. 74 Taiwanese patients with ischemic heart disease in “hyperendemic arseniasis villages” were studied and a link was found between ischemic heart disease and long-term exposure to arsenic. Arsenic causes direct damage to the myocardium, causing cardiac arrhythmias and cardiomyopathy.

Blackfoot disease is a unique peripheral vascular disease causing gangrene of the foot, unique to a limited area on the southwestern coast of Taiwan and resulting from long-term exposure to elevated levels of arsenic in artesian well water. Peripheral vascular disease is also reported in Chile.

> Neurological system

The neurological system is the main target of the toxic effects of various metals, especially heavy metals such as mercury, lead and arsenic. The neurological effects are many and varied. The most common finding is a peripheral neuropathy that mimics Guillain-Barré syndrome, with similar symptoms and electromyographic signs. Initially, the neuropathy is sensory with “glove and stocking” anesthesia.

The effects of toxicity also include behavioral changes, confusion, and memory loss. Cognitive impairment was reported in 2 workers with 14 to 18 months of exposure; Mental function returned to normal after the source of arsenic was eliminated. A higher prevalence of cerebrovascular diseases, especially cerebral infarction, was observed in a large number of people.

> Genitourinary system

The Millard County study also reported increased mortality from nephritis and prostate cancer . A registry of bladder and kidney tumors in Taiwan reported that high levels of arsenic in drinking well water was associated with the transition to cell carcinomas of the bladder, kidney, ureter and entire urethra, with higher rates of bladder cancer. in men. This suggested to the authors that arsenic carcinogenicity may be cell type specific. In contrast, a study from Finland found an association with the risk of bladder cancer, but not kidney cancer, despite very low concentrations of arsenic in drilled wells.

Regarding the relationship between arsenic ingestion and adverse outcomes during pregnancy and neonatal morbidity and mortality, studies are still lacking. In pregnant Andean women who consumed water with arsenic concentrations of approximately 200 μg/l, arsenic in umbilical cord blood (9 μg/l) was almost as high as in maternal blood (11 μg/l). Placental arsenic in the same group was 34 μg/L compared with 7 μg/L in women not exposed to arsenic. The results of the studies by Concha et al. in the Andes, in Argentina, add another dimension to this problem. The fetus and breastfed infants and children are exposed to maternal arsenic toxicity.

> Respiratory system

Studies from West Bengal draw attention to lung disease, both restrictive and obstructive. Respiratory disease was more common in patients with chronic arsenic toxicity lesions. Similar findings of an association between skin manifestations and lung disease were reported in Chilean children. The possibility of increased arsenic deposition in the lung is supported by necropsy studies in a limited number of patients, although the reason is unknown. An increased incidence of bronchitis was found in a study of patients with blackfoot disease in Taiwan.

Endocrine and hematological systems

Exposure to elevated concentrations of arsenic is associated with an increased risk of diabetes mellitus . Neutropenia occurs in chronic poisoning .

malignant diseases

The relationship between arsenic and malignancy is of significant and growing concern as many millions of people are potential victims. In Bangladesh and India, arsenic is associated with cancers of the skin, lung, liver, kidney and bladder. There is evidence that in other countries, exposure to arsenic causes malignant diseases of the skin, lung, liver, kidney and bladder. Data from Taiwan also document malignant tumors of the bladder, kidney, skin, lung, nasal cavity, bone, liver, larynx, colon and stomach, as well as lymphoma.

The mechanisms, although not completely determined, are possibly an adverse effect on DNA repair and methylation and increased free radical formation and activation of the c-myc proto-oncogene . Under certain circumstances, arsenic can act as a cocarcinogen and tumor promoter or progressor. Elevated levels of arsenic are teratogenic in animals. Structural chromosomal aberrations were studied in a group of people who consumed arsenic from well water in Finland, and stronger associations were found in current users than in the 10 subjects who had stopped using contaminated well water for 2 to 4 months. prior to sampling.

Analysis of blood, urine, and hair samples is used to quantify and monitor arsenic exposure. Levels between 0.1 and 0.5 mg/kg per day in a hair sample indicate chronic poisoning while 1.0 to 3.0 mg/kg indicate acute poisoning.

In animals, deficiency manifests as increased mortality, reduced fertility, increased spontaneous abortion rate, low birth weight in offspring, and damage to red blood cells.

The economic importance of arsenic poisoning includes medical expenses, loss of income, and reduced crop productivity and quality due to soil and water contamination. The current health, economic and nutritional problems would be greatly offset if information on arsenic contamination of the food chain were better known and if we knew which agricultural and livestock products were contaminated. These issues are of great concern, especially in Bangladesh, where 97% of the rural population depends on groundwater for drinking, cooking and irrigation.

The human tragedy due to arsenic toxicity is most acute in the developing world, where in countries like Bangladesh, the lives of millions of people are affected.

To solve the growing problem of arsenic contamination and the impact on health, many issues must be clarified. Information is required to determine whether there is a threshold for the carcinogenic effects of arsenic to manifest, and also to define the dose and duration of exposure. Studies are required to link toxic manifestations with a possible genetic polymorphism, age, sex, nutrition and the protective role of vitamins, minerals and antioxidants. There is marked variation in clinical characteristics among individuals from the same household, as is often the case in Bangladesh, which may be due to “slow” or “fast” methylators of arsenic, similar to patients with inflammatory bowel disease, who are acetylators.” “slow” or “fast”, and therefore respond differently to salicylate treatment.

The supply of drinking water is a priority.

There are various methods of varying complexity to eliminate arsenic from drinking water. The methodology, urgently required, especially in developing countries, should be affordable, sustainable for the population and profitable.

Among the methods available to remove arsenic from water are precipitation or ion exchange processes. Filtration of arsenic from tube well water has generated a range of filters of varying degrees of sophistication and cost, with affordability, efficiency, and maintenance issues associated with their use. It is noted that the process and cost of removing sequestered arsenic after filtration requires careful consideration.

Promising studies report using iron-treated natural materials, such as iron-treated activated carbon, iron-treated gel beads, and iron oxide-coated sand. Of these iron oxide-coated sands, sand was the most effective compound.

Stevens’ technology for arsenic removal is inexpensive and involves mixing a small packet of powder containing iron sulfate and calcium hypochlorite into a large bucket of water, which is then filtered through several centimeters of sand. An attractive and economical option, widely available, is to harvest rainwater and use surface water.

In Bangladesh, the volume of water flowing into the Bay of Bengal is second only to that flowing into the Amazon basin. Bangladesh has an annual rainfall of 1,500 to 2,000 mm but the eastern parts of the country receive 3,500 mm. The option of harnessing this natural wealth of Bangladesh has received insufficient attention. However, the cheapest solution would depend on the community’s goodwill to encourage the use of a neighbor’s well (shared well) that is not contaminated. More than 90% of Bangladesh’s population lives within 200 m of a clean and safe well water source.

There is currently no proven beneficial treatment available to treat chronic arsenic poisoning.

The recommended therapeutic options are vitamins, mineral supplements and antioxidant therapy. The benefits of these treatment measures must be the evidence base to receive support and broader application. At the cellular level, in view of the apoptotic action of arsenic, the effects, especially of antioxidants, are theoretically valuable. However, the cellular benefits of these compounds need to be validated in humans with chronic arsenic poisoning. Currently, in chronic poisoning, therapy is limited to supportive measures.