Toxicology of arsenic compounds

Toxicology of arsenic compounds

Arsenic compounds are generally toxic, especially inorganic ones. Some organic arsenic compounds used as chemical weapons are also highly toxic, but naturally occurring organic arsenic compounds in seafood are less so.

Trivalent arsenic compounds, such as arsenic trioxide (As2O3), arsenic trifluoride (AsF3), arsenic trichloride (AsCl3), and arsine (AsH3), are more toxic than pentavalent compounds because they are more soluble.

Elemental arsenic is not very toxic, but it easily converts to toxic compounds in the body. Pure arsenic(III) sulfide (As2S3) is relatively low in toxicity, but crude arsenic sulfide is often contaminated with arsenic trioxide.

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Despite their toxicity, some pentavalent organic arsenic compounds are used as medicines. These benzene arsenic derivatives have stable carbon-arsenic bonds and are not usually converted into inorganic arsenic compounds. Even arsenic trioxide, which is highly toxic, is used to treat promyelocytic leukemia.

Arsenic can cause acute, subchronic, or chronic poisoning. Acute poisoning is rare compared to subchronic or chronic poisoning.

1. Absorption of Arsenic Compounds

Arsenic compounds are absorbed mainly by ingestion and inhalation, with some absorption possible through the skin.

Arsenic compounds are inhaled as particles, which are deposited in the lungs. The particles are then dissolved and absorbed into the bloodstream. About 30% to 85% of inhaled arsenic is absorbed.

The amount of arsenic absorbed from the gastrointestinal tract depends on the solubility of the arsenic compound and whether food is present. Trivalent and pentavalent inorganic and organic arsenic compounds are readily absorbed, with absorption rates ranging from 45% to 90%. Poorly soluble compounds are absorbed at much lower rates.

Absorption through the skin is generally less than 10%. Lipophilic organic compounds are absorbed more easily than inorganic compounds.

2. Distribution of Arsenic Compounds

After absorption, inorganic arsenic compounds circulate throughout the body in the bloodstream. They prefer to accumulate in the liver, kidneys, lungs, intestines, spleen, bone marrow, skin, and, to a lesser extent, the brain, heart, and uterus.

In these tissues, inorganic arsenic compounds bind to the SH groups of proteins. They also become incorporated into hair and nails, which can be used to detect past exposure to arsenic. Inorganic arsenic can also replace phosphorus in bones, where it can persist for a long time.

Inorganic arsenic compounds do not easily cross the blood-brain barrier, but they can cross the placenta.

3. Metabolism of Arsenic Compounds

Inorganic arsenic compounds are metabolized in two ways:

  1. They can be converted between pentavalent and trivalent states by reduction or oxidation.
  2. They can be methylated, which is more common with trivalent compounds. This produces dimethylarsinic acid, monomethylarsonic acid, and trimethylarsine.

Organic arsenic compounds are metabolized less than inorganic arsenic compounds and are excreted more quickly. Trivalent arsenic compounds can bind to proteins, especially those with two adjacent mercapto groups. This forms stable cyclic structures. It is thought that the first step in cell damage is the inhibition of essential enzymes.

The high affinity of oxoarsenic moieties for the vicinal mercapto groups in compounds like BAL and 2,3-dimercapto-1-propanesulfonic acid is used in arsenic poisoning therapy to increase excretion.

4. Excretion of Arsenic Compounds

Arsenic is excreted mainly in urine (up to 75%), with smaller amounts in feces and hair and skin. Excretion occurs in multiple phases, with half-lives ranging from several days to one month. The main metabolite excreted is dimethylarsinic acid.

After a single dose, arsenic levels in the liver and kidneys start to decrease after 24 hours. In people without arsenic exposure, urine arsenic levels range from zero to 0.22 mg/L, while after industrial exposure, they range from 0.04 to 0.9 mg/L. Small amounts of arsenic may also be exhaled as trimethylarsine.

5. Acute Toxicity of Arsenic Compounds

Arsenic poisoning is mainly caused by swallowing or inhaling inorganic trivalent compounds, such as arsenic trioxide. The smallest fatal dose of arsenic trioxide reported after ingestion is 70 to 180 milligrams.

Symptoms can appear within minutes or hours and include vomiting, diarrhea, damage to the intestines, muscle cramps, facial swelling, heart problems, dehydration, and then shock.

Acute poisoning symptoms are mainly caused by paralysis of the capillaries, followed by changes in local tissues and widening of blood vessels throughout the body. This leads to major problems with circulation and metabolism.

Inhaling irritating arsenic compounds, such as arsenic trichloride or chemical weapons that contain arsenic, causes coughing, shortness of breath, chest pain, severe damage to the respiratory tract, headache, weakness, nausea, vomiting, and diarrhea with cramps.

Dust from these compounds in the air often irritates the skin and mucous membranes, causing conditions such as bronchitis, conjunctivitis, laryngitis, and dermatitis. Arsenic trichloride can also be absorbed through the skin, which can be fatal.

6. Chronic Toxicity of Arsenic Compounds

Chronic arsenic poisoning can occur from eating food or drinking water contaminated with arsenic, or from long-term exposure to arsenic dust in certain jobs, such as working with arsenic-containing ores, making insecticides, or growing grapes.

Chronic arsenic poisoning develops slowly and causes a variety of vague symptoms, such as nausea, weakness, loss of appetite, weight loss, diarrhea or constipation, gastritis, and bronchitis.

Other symptoms include thickened palms and soles (palmar and plantar hyperkeratosis), white streaks on the fingernails, heart problems, myocardial ischemia, hypertension, liver problems, blood problems, and blood vessel problems that can lead to gangrene in the lower extremities (blackfoot disease). Many of these symptoms can last for years even after exposure to arsenic has stopped.

Skin problems are common, especially in people who work with insecticides or smelt copper ore. Common skin symptoms include thickened skin (hyperkeratosis), warts, dark patches (melanosis), contact dermatitis, eczema-like features, and blood vessel problems.

Hyperkeratosis causes the skin to thicken, dry, and crack. Arsenical melanosis can appear on the chest, abdomen, eyelids, scrotum, and back. Other notable symptoms are depigmentation (loss of color) of pigmented areas and white lines on the fingernails (Mees lines).

The mucous membranes can also be affected, causing conjunctivitis with swelling and pain, keratoconjunctivitis (from exposure to the insecticide calcium arsenate), irritation of the pharynx and bronchial passages, and irritation of the nose leading to acute and chronic rhinitis.

Perforation of the nasal septum (due to arsenic compounds) is common among copper smelter workers.

Peripheral neuritis is another concern. Symptoms include pain, difficulty walking, burning and tenderness in the affected limbs, and later, severe weakness in the legs, feet, and arms. Motor paralysis, muscle pain, and atrophy may also occur.

In contrast to lead-induced peripheral neuritis, arsenic-induced neuritis is painful and nerve damage is evident through neuronal degeneration. In severe chronic intoxication, additional symptoms may include headaches, aphasia, drowsiness, disorientation, changes in personality, alterations in taste and smell, and, very rarely, blindness.

Central nervous system (CNS) effects, such as encephalopathy, resulting from arsenicals are comparatively rare and characterized by symptoms like headache, fever, seizures, delirium, and coma. These disturbances likely arise from brain tissue necrosis due to capillary damage.

Liver damage, particularly cirrhosis, has been observed in individuals, such as vintagers using arsenical herbicides and those consuming arsenic-contaminated homemade wine over the long term.

These liver issues, often complicated by chronic hepatitis, ascites, and hepatomegaly, are likely a consequence of arsenic ingestion rather than skin contact or inhalation of arsenic compounds. Liver damage among industrial workers is reported less frequently.

In cases of chronic arsenical poisoning, circulatory system symptoms may manifest as abnormal electrocardiogram findings indicating toxic effects on the heart muscle, peripheral vascular disturbances, extremity gangrene, atrophic acrodermatitis, endoangitis, and the aforementioned “blackfoot disease.”

Gastrointestinal disturbances are less common among workers with prolonged skin exposure to arsenicals. However, in cases of chronic arsenic ingestion, individuals may experience digestive issues such as nausea, vomiting, and loss of appetite.

Hematological changes associated with arsenic compounds result from bone marrow damage. These changes are less common in cases of chronic poisoning due to industrial airborne exposure. Symptoms include moderate hyper- and hypochromic anemia, aplastic anemia, leucopenia, and thrombocytopenia, often observed after prolonged ingestion of inorganic arsenicals.

7. Cancer Risk of Arsenic Compounds

Workers in smelters or insecticide factories who are exposed to arsenic trioxide have a much higher risk of lung cancer than people who are not exposed.

A large study of male textile workers in England and Wales found that they had more oral and pharyngeal cancer, which the researchers think was caused by the use of arsenic disinfectants on sheep.

Skin cancer, with multiple lesions all over the body, has been reported in areas like Cordoba, Argentina, Antofagasta, Chile, and Taiwan, where people drank contaminated water.

Long-term exposure to arsenic by ingestion, inhalation, or skin contact has been linked to many different types of cancer. Arsenic compounds are likely to cause angiosarcoma of the liver in people who drink contaminated water, wine, or medicines. However, this link has not been proven for sure, because there have not been enough cases.

Arsenic is thought to be a cocarcinogen because it can stop DNA-repair enzymes from working without actually mutating DNA. It can take 35 to 40 years for cancer to develop after first exposure to arsenic compounds.

Many epidemiological studies have been done on the possible carcinogenic effects of arsenic compounds. Based on these studies, national and international organizations, including the German MAK Commission, WHO, IARC, ACGIH, and the U.S. EPA, have classified arsenic and its compounds (except arsine) as known human carcinogens when inhaled or ingested.

The German MAK List lists the following compounds as known human carcinogens: arsenic, arsenic trioxide, arsenous acid and its salts, such as sodium arsenite, arsenic pentoxide, arsenic acid and its salts, such as lead arsenate and calcium arsenate. Arsenic is also recognized as a major carcinogenic substance in the ambient atmosphere.

8. Mutagenicity of Arsenic Compounds

Scientists have tested the mutagenic effects of inorganic and organic arsenicals on different organisms, including bacteria, flies, and mammalian cells.

They found that arsenicals can damage DNA, cause chromosome aberrations, and increase the number of sister chromatid exchanges. Arsenicals can also induce gene mutations and form micronuclei.

9. Reproductive Toxicity of Arsenic Compounds

Inorganic arsenicals can harm developing embryos and fetuses in mice and hamsters, whether they are inhaled, eaten, or injected. Arsenite is about ten times more toxic than arsenate.

High doses of pentavalent arsenic can cause birth defects in hamsters and rats, such as cleft palates, urogenital abnormalities, and ear malformations.

Hamster fetuses exposed to disodium arsenate can have birth defects such as exencephaly, cleft palate and lip, microanophthalmia, genitourinary abnormalities, ear deformities, and renal agenesis.

In one case, a 17-year-old girl ingested arsenic during the third trimester of pregnancy. Her baby weighed only 1100 grams and died 11 hours after birth. The baby’s liver, kidney, and brain had high levels of arsenic.

Studies of workers and people living near smelters have found that their babies often have low birth weight, more miscarriages, and more birth defects.

10. Toxicology of Arsine and Organic Arsenic Compounds

Arsine, AsH3, is a compound that often causes acute poisoning in industrial workers. It has several distinctive symptoms, including general malaise, nausea, vomiting, abdominal cramps, coppery skin pigmentation, and reddish conjunctiva.

Acute arsine poisoning is marked by rapid hemolytic anemia, which leads to hemoglobinuria, decreased hemoglobin levels, jaundice, and shock, oliguria, and anuria due to the blockage of renal tubules by red blood cell membrane residues.

Other symptoms include fever, lung edema, delirium, and coma. Death, which can occur within a few days, is usually caused by myocardial failure. Arsine poisoning always causes a T-wave elevation on the electrocardiogram.

The time of symptom onset varies depending on the amount of inhaled arsine and the severity of intoxication, ranging from a few minutes to 24 hours.

Chronic arsine poisoning has a delayed onset of the same symptoms as acute poisoning. In some cases, peripheral neuritis, extremely low hemoglobin levels, and basophilic stippling of red blood cells have been reported.

Organic arsenic compounds of the type RAsCl2, R2AsCl, and R2AsCN were developed and partially used as chemical weapons during World War I. Examples of these compounds include dichloro-2-chlorovinylarsine, lewisite (2-chloroethenyl)arsonous dichloride, chlorodiphenylarsine, and cyanodiphenylarsine.

These compounds are generally very toxic and affect the skin, eyes, respiratory tract, gastrointestinal tract, and central nervous system, causing symptoms similar to those described earlier.

11. Toxicological Data and Exposure Limits of Arsenic Compounds

Toxicological data of commonly used arsenic compounds are summarized in the following table:

Toxicological data of arsenic and some arsenic compounds
Compound Toxicology Dose Species Route
Arsenic LDLo 20 mg/kg rat intramusc.
Arsenic acid, hemihydrate LD50 6 mg/kg rabbit i.v.
Arsenic pentoxide LD50 55 mg/kg mouse oral
Arsenic trichloride LDLo 100 mg/m3, 1 h cat inhal.
Arsenic trifluoride LDLo 2000 mg/m3, 10 min mouse inhal.
Arsenic trioxide LD50 45 mg/kg mouse oral
Arsenic trioxide LD50 20 mg/kg rat oral
Arsenic trioxide LDLo 4 mg/kg (as As) rabbit i.v.
Arsine TCLo 3 mL/m3 human inhal.
Arsine LCLo 25 mL/m3, 30 min human inhal.
Arsine TCLo 93 mL/m3 human inhal.
Calcium arsenate LDLo 50 mg/kg rabbit oral
Disodium arsenate LDLo 30 mg/kg rat i.p.
Disodium arsenate heptahydrate TDLo 43 mg/kg mouse i.p.
Lead arsenate LD50 100 mg/kg rat oral
Lead arsenate LDLo 75 mg/kg rabbit oral
Sodium metaarsenite TDLo 40 mg/kg mouse oral
  • Arsine: The former MAK value (maximum allowable concentration at the workplace) for arsine (AsH3) of 0.2 mg/m3 (0.05 ppm) has been withdrawn due to the lack of meaningful toxicological data.
  • Other arsenicals: MAK values for various arsenicals, including oxides and arsenic acids, and their salts have not been established because these compounds have been proven to cause malignant tumors in humans.
  • Carcinogenicity: The IARC (International Agency for Research on Cancer) has classified arsenic and its compounds as carcinogenic to humans (Group I). The skin and lungs are proven target organs, while the liver, hematopoietic system, gastrointestinal tract, and kidney are suspected target organs.
  • TRK values in Germany: The TRK (technical reference concentration) values for all compounds, with the exception of arsine, is 0.1 mg/m3 (as As).
  • Unit risk value: The unit risk value, representing the additional relative carcinogenic risk caused by arsenic (based on lifelong exposure to 1 mg As/m3), has been established as 0.004 by the LAI (Life-Environment-Workplace).
  • Drinking water limits: The threshold limit value for arsenic in drinking water in Germany and the EU is 10 mg/L.
  • ACGIH TLV-TWA: In the USA, the ACGIH TLV-TWA (Threshold Limit Value-Time-Weighted Average) for arsenic and its compounds is 0.01 mg/m3.
  • WHO PTWI: The provisional tolerable weekly intake (PTWI) value established by the WHO (Joint FAO/WHO Expert Committee on Food Additives) is 15 mg per kilogram per week, based on noncarcinogenic effects.
  • US EPA RfD: The reference dose (RfD) set by the U.S. EPA for inorganic arsenic is 0.3 mg/kg/day, also based on noncarcinogenic effects.

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