Because it targets ubiquitous enzyme reactions, arsenic affects nearly all organ systems.
Arsenic is strongly associated with lung and skin cancers and may cause other cancers.
Two mechanisms of arsenic toxicity that impair tissue respiration have been described. Arsenic binds with sulfhydryl groups and disrupts sulfhydryl-containing enzymes; As(III) is particularly potent in this regard. As a result of critical enzyme effects, there is inhibition of the pyruvate and succinate oxidation pathways and the tricarboxylic acid cycle, impaired gluconeogenesis, and reduced oxidative phosphorylation. Another mechanism involves substitution of As(V) for phosphorus in many biochemical reactions. Replacing the stable phosphorus anion in phosphate with the less stable As(V) anion leads to rapid hydrolysis of high-energy bonds in compounds such as ATP. That leads to loss of high-energy phosphate bonds and effectively "uncouples" oxydative phosphorylation.
Unlike other arsenicals, arsine gas causes a hemolytic syndrome.
Arsine gas poisoning results in a considerably different syndrome from that caused by other forms of arsenic. After inhalation, arsine rapidly fixes to red cells, producing irreversible cell-membrane damage. At low levels, arsine is a potent hemolysin, causing dose-dependent intravascular hemolysis. At high levels, arsine produces direct multisystem cytotoxicity.
Gastrointestinal effects are seen primarily after arsenic ingestion, and less often after inhalation or dermal absorption.
The gastrointestinal (GI) effects of arsenic generally result from exposure via ingestion; however, GI effects may also occur after heavy exposure by other routes. The fundamental GI lesion appears to be increased permeability of the small blood vessels, leading to fluid loss and hypotension. Extensive inflammation and necrosis of the mucosa and submucosa of the stomach and intestine may occur and progress to perforation of the gut wall. A hemorrhagic gastroenteritis may develop, with bloody diarrhea as a presenting symptom.
Acute arsenic toxicity may be associated with hepatic necrosis and elevated levels of liver enzymes.
Arsenic intoxication may also result in hepatic toxicity, including toxic hepatitis and elevated liver enzyme levels. Autopsies of Japanese children poisoned with arsenic-contaminated milk revealed hepatic hemorrhagic necrosis and fatty degeneration of the liver. Chronic arsenic ingestion may lead to cirrhotic portal hypertension. Case reports have also linked chronic high-level arsenic exposure with hepatic angiosarcoma, a rare form of cancer.
Arsenic is capable of causing acute renal failure, as well as chronic renal insufficiency.
The systemic toxicity occurring in severe acute arsenic poisoning may be accompanied by acute tubular necrosis, and acute renal failure; chronic renal insufficiency from cortical necrosis has also been reported. The actual cause of injury may be hypotensive shock, hemoglobinuric or myoglobinuric tubular injury, or direct effects of arsenic on tubule cells. Glomerular damage can result in proteinuria. The kidney is not a major target organ for chronic toxicity.
Acute arsenic poisoning may cause both diffuse capillary leak and cardiomyopathy, resulting in shock.
The extent of cardiovascular injury may vary with age, arsenic dose, and individual susceptibility. In acute arsenic poisoning-usually suicide attempts-the fundamental lesion, diffuse capillary leak, leads to generalized vasodilation, transudation of plasma, hypotension, and shock. Delayed cardiomyopathy may also develop. Myocardial damage can result in a variety of electrocardiographic findings, including broadening of the QRS complex, prolongation of the QT interval, ST depression, flattening of T waves, and atypical, multifocal ventricular tachycardia.
Long-term ingestion of arsenic in drinking water has resulted in pronounced peripheral vascular changes.
Epidemiological evidence indicates that chronic arsenic exposure is associated with vasospasm and peripheral vascular insufficiency. Gangrene of the extremities, known as Blackfoot disease, has been associated with drinking arsenic-contaminated well water in Taiwan, where the prevalence of the disease increased with increasing age and well-water arsenic concentration (10 to 1,820 ppb). Persons with Blackfoot disease also had a higher incidence of arsenic-induced skin cancers. However, investigators believe other vasoactive substances found in the water may have been contributory.
Raynaud's phenomenon and acrocyanosis resulted from contamination of the city's drinking water supply in Antofagasta, Chile, at arsenic concentrations ranging from 20 to 400 ppb. Autopsies of Antofagasta children who died of arsenic toxicity revealed fibrous thickening of small and medium arteries and myocardial hypertrophy. Similar vascular disorders, as well as abnormal electrocardiographs (ECGs), have been noted in vineyard workers exposed to arsenical pesticides.
Arsenic-exposed patients develop destruction of axonal cylinders, leading to peripheral neuropathy.
Peripheral neuropathy is a common complication of arsenic poisoning. The classic finding is a peripheral neuropathy involving sensory and motor nerves in a symmetrical, stocking-glove distribution. Sensory effects, particularly painful dysesthesia, occur earlier and may predominate in moderate poisoning, whereas ascending weakness and paralysis may predominate in more severe poisoning. Those cases may at first seem indistinguishable from Guillain-Barré syndrome (i.e., acute inflammatory demyelinating polyneuropathy). Cranial nerves are rarely affected, even in severe poisoning. Encephalopathy has been reported after both acute and chronic exposures.
Onset may begin within 24 to 72 hours following acute poisoning, but it more often develops slowly as a result of chronic exposure. The neuropathy is primarily due to destruction of axonal cylinders (axonopathy). Nerve conduction and electromyography studies can document severity and progression. Subclinical neuropathy, defined by the presence of abnormal nerve conduction with no clinical complaints or symptoms, has been described in chronically exposed individuals.
Recovery from neuropathy induced by chronic exposure to arsenic compounds is generally slow, sometimes taking years, and complete recovery may not occur. Follow-up studies of Japanese children who chronically consumed arsenic-contaminated milk revealed an increased incidence of severe hearing loss, mental retardation, epilepsy, and other brain damage. Hearing loss as a sequela of acute or chronic arsenic intoxication has not been confirmed by other case reports or epidemiologic studies.
Pigment changes and palmoplantar hyperkeratosis are characteristic of chronic arsenic exposure.
Benign arsenical keratoses may progress to malignancy.
The types of skin lesions occurring most frequently in arsenic-exposed humans are hyperpigmentation, hyperkeratosis, and skin cancer. Patchy hyperpigmentation, a pathologic hallmark of chronic exposure, may be found anywhere on the body, but occurs particularly on the eyelids, temples, axillae, neck, nipples, and groin. The classic appearance of the dark brown patches with scattered pale spots is sometimes described as "raindrops on a dusty road." In severe cases, the pigmentation extends broadly over the chest, back, and abdomen. Pigment changes have been observed in populations chronically consuming drinking water containing 400 ppb or more arsenic.
Arsenical hyperkeratosis occurs most frequently on the palms and soles. Keratoses usually appear as small corn-like elevations, 0.4 to 1 cm in diameter. In most cases, arsenical keratoses show little cellular atypia and may remain morphologically benign for decades. In other cases, cells develop marked atypia (precancerous) and appear indistinguishable from Bowen disease, which is an in situ squamous cell carcinoma discussed in Carcinogenic Effects.
Inhalation of high concentrations of arsenic compounds produces irritation of the respiratory mucosa.
Smelter workers experiencing prolonged exposures to high concentrations of airborne arsenic at levels rarely found today had inflammatory and erosive lesions of the respiratory mucosa, including nasal septum perforation. Lung cancer has been associated with chronic arsenic exposure in smelter workers and pesticide workers.
Bone marrow depression may result from acute or chronic arsenic intoxication and may initially manifest as pancytopenia.
Both acute and chronic arsenic poisoning may affect the hematopoietic system. A reversible bone marrow depression with pancytopenia may occur. Anemia and leukopenia are common in chronic arsenic toxicity, and are often accompanied by thrombocytopenia and mild eosinophilia. The anemia may be normocytic or macrocytic, and basophilic stippling may be noted on peripheral blood smears.
Increased frequency of spontaneous abortions and congenital malformations has been linked to arsenic exposure.
Arsenic is a reproductive toxicant and a teratogen. It is readily transferred across the placenta, and concentrations in human cord blood are similar to those in maternal blood. A published case report described acute arsenic ingestion during the third trimester of pregnancy leading to delivery of a live infant that died within 12 hours. Autopsy revealed intra-alveolar hemorrhage and high levels of arsenic in the brain, liver, and kidneys.
A study of women working at or living near a copper smelter where ambient arsenic levels were elevated reported increased frequencies of spontaneous abortions and congenital malformations. The frequency of all malformations was twice the expected rate and the frequency of multiple malformations was increased fivefold. However, a number of other chemicals, including
lead, cadmium, and sulfur dioxide were also present, and thus it is difficult to assess the role of arsenic in the etiology of these effects.
The carcinogenicity of arsenic in humans has been established, but no animal model has been developed.
In humans, chronic arsenic ingestion is strongly associated with an increased risk of skin cancer, and may cause cancers of the lung, liver, bladder, kidney, and colon; chronic inhalation of arsenicals has been closely linked with lung cancer. The precise mechanism of arsenic-related carcinogenicity is unknown. Arsenic does not induce genetic mutations in most test systems, but chromosomal damage has been reported in cultured mammalian cells, possibly as a result of arsenic's effects on the enzymes involved in DNA replication and repair. Paradoxically, cancer associated with arsenic exposure has not been produced in experimental animals.
Latency for skin cancer associated with ingestion of arsenic may be 3 to 4 decades, whereas the noncarcinogenic skin effects typically develop several years after exposure.
An increased risk of skin cancer in humans is associated with chronic exposure to inorganic arsenic in medication, contaminated water, and the workplace. Arsenic-induced skin cancer is frequently characterized by lesions over the entire body, mostly in unexposed areas such as the trunk, palms, and soles. More than one type of skin cancer may occur in a patient. Most of the Taiwanese who developed skin cancer in association with ingestion of arsenic-contaminated drinking water had multiple cancer types. The most commonly reported types, in order of decreasing frequency, were intraepidermal carcinomas (Bowen disease), squamous cell carcinomas, basal cell carcinomas, and "combined forms." Seventy-two percent of the Taiwanese with skin cancer also had hyperkeratosis, and 90% had hyperpigmentation.
Some hyperkeratinized lesions can develop into intraepidermal carcinoma, which may ultimately become invasive. The lesions are sharply demarcated round or irregular plaques that tend to enlarge; they may vary in size from 1 millimeter to >10 centimeters. Arsenical basal cell carcinomas most often arise from normal tissue, are almost always multiple, and frequently occur on the trunk. The superficial spreading lesions are red, scaly, atrophic, and are often indistinguishable from Bowen disease by clinical examination. Arsenic-associated squamous cell carcinomas are distinguished from UV-induced squamous cell carcinomas by their tendency to occur on the extremities (especially palms and soles) and trunk rather than on sun-exposed areas such as the head and neck. However, it may be difficult to distinguish other arsenic-induced skin lesions from those induced by other causes.
Epidemiological studies indicate that a dose-response relationship exists between the level of arsenic in drinking water and the prevalence of skin cancers in the exposed population. Excessive mortality rates due to arsenic-induced skin cancer have also been observed in vineyard workers with dermal and inhalation exposure.
In arsenic-exposed workers, there is a systematic gradient in lung cancer mortality rates, depending on duration and intensity of exposure.
An association between lung cancer and occupational exposure to inorganic arsenic has been confirmed in several epidemiologic studies. A higher risk of lung cancer was found among workers exposed predominantly to arsenic trioxide in smelters and to pentavalent arsenical pesticides in other settings. Neither concomitant exposure to sulfur dioxide nor cigarette smoke were determined to be essential co-factors in these studies.
