Arsenic poisoning

Overview
Arsenic poisoning kills by allosteric inhibition of essential metabolic enzymes, leading to death from multi-system organ failure.

Arsenic is tasteless and odorless and was used medicinally in centuries past for syphilis, psoriasis, lichen planus, anorexia, parasitism, and epilepsy. Though it has most notoriously been used for poisoning, it is not a particularly efficient toxin, leading to a slow and painful death.

Neron poisoned Briticannicus to secure the Roman throne in 55 A.D., and it has been quite popular ever since. Marie Madeleine in the 17th century and Catherine Deshayes in the 19th century became quite famous for the many people they poisoned with it. Reports of Napolean’s death by arsenic poisoning are probably not true, though he may have been given arsenic for treatment of anorexia associated with the gastric cancer he died from. Arsenic’s popularity faded with the development of a sensitive assay in 1836. Arsenic is found in some soils and is released into the air from volcanoes. Humans may be exposed in the smelting industry (arsenic is a byproduct of ores containing copper, iron, lead, gold, zinc, cobalt and nickel), from arsenic-contaminated fossil fuels, and from the use of inorganic arsenic compounds in wood preservatives, pesticides (including ant killers), herbicides, fungicides, feed additives, war gases and paints, and in some folk remedies. It is the most common heavy metal toxin.

Pathophysiology & Etiology
Normal intake of arsenic in humans is 0.05-1 mg/d, mostly from organic arsenic in seafood. It is absorbed easily through the mucous membranes, and is transported bound to both red cells and proteins, but minimal amounts pass the blood-brain barrier. Arsenic is subsequently redistributed to the liver, spleen, kidneys, lungs, and GI tract, and then is rapidly cleared. Arsenic leaves a residue in keratin-rich tissues like skin, hair and nails, bound to sulfhydryl groups. Most of the arsenic is cleared through the kidney. It is both filtered and actively transported by proximal tubule cells. Arsenic is reduced to arsenite, the most toxic form, which binds to sulfhydryl groups, including those of important enzymes, including those of the Kreb’s cycle and oxidative phosphorylation. Toxic doses are usually 120-200 mg in adults, 2 mg/kg in children. There is heterogeneity depending on the dose, form and host – deaths have been reported with as little as 20 mg, and recovery after as much as 10 grams.

Symptoms
Arsenic poisoning is easy if the appropriate tests are ordered. Many patients are admitted multiple times before the diagnosis is established.

Acute

 * Acute ingestion damages capillaries and small vessels, increasing permeability, leading to hypoxia, transudation of fluid, inflammation, necrosis, and hypovolemia.
 * Cutaneous
 * Patchy hair loss
 * Cardiac
 * Acute or delayed cardiomyopathy
 * EKG changes
 * QRS broadening
 * QT prolongation
 * ST-segment depression
 * T wave flattening
 * Ventricular fibrillation
 * Multifocal ventricular tachycardia
 * Pulmonary
 * Garlicky odor to breath
 * Pulmonary edema
 * Gastrointestinal
 * Metallic taste, dry mouth
 * Abdominal pain
 * Nausea and Vomiting
 * Dysphagia
 * Diarrhea – rice water or bloody
 * Hepatic fatty infiltration, and even acute hepatic failure
 * Renal
 * Acute tubular necrosis
 * Tubulointerstitial nephritis
 * Glomerular damage
 * Neurologic
 * Hyperpyrexia
 * Tremor
 * Personality change
 * Headache
 * Vertigo
 * Delirium
 * Coma
 * Seizures
 * Extremities
 * Acrocyanosis

Chronic

 * Onset is 2-8 weeks
 * Skin
 * Flushing
 * Hyperkeratosis – sometimes of the palms and soles
 * Hyperpigmentation / melanosis / depigmentation
 * Exfoliative dermatitis / desquamation
 * Facial edema
 * Increased risk of skin cancer, including Bowen’s disease
 * Patchy alopecia
 * Nails: Mees’ lines – transverse white bands across the nails
 * Present 2-3 weeks after acute intoxication, but may also be present with chronic ingestion
 * Occur as a consequence of disturbed nail matrix keratinization
 * Similar findings may also be present after thallium, lead, pilocarpine, sulfonamide and cancer chemotherapy ingestion
 * Not to be confused with Beau’s lines, growth arrest lines, in associated with acute stress, such as myocardial infarction (MI), Hodgkin’s lymphoma, pellagra, renal failure, systemic lupus erythematosus (SLE), ulcerative colitis, acute transplant rejection, etc.
 * Neurologic
 * Sensory and motor polyneuritis with numbness and tingling in a stocking glove distribution, distal weakness, and quadriplegia – mimicking (and often misdiagnosed as) Guillain-Barre Syndrome.
 * Encephalopathy
 * Tremor
 * Ophthalmology
 * Conjunctivitis
 * Respiratory
 * Mucosal inflammation
 * Probable increased risk of lung cancer
 * Cardiac
 * Cardiomyopathy
 * Gastrointestinal
 * Nausea, vomiting
 * Anorexia
 * Weight loss
 * Diarrhea
 * Hepatomegaly, cirrhosis
 * Jaundice
 * Possible increased risk of colon cancer, angiosarcoma of the liver
 * Genitourinary
 * Probable increased risk of bladder cancer
 * Teratogen
 * Extremities
 * Blackfoot disease – gangrenous extremity disease
 * Hematologic
 * Leukopenia
 * Thrombocytopenia
 * Bone marrow hypoplasia and dysplastic erythropoesis: megaloblastic anemia, anisopoikolcytosis, basophilic stipling; nuclear lobulation, irregular pyknotic nuclei, multiple Howell-Jolly bodies
 * Hemolysis

Symptoms include violent stomach pains in the region of the bowels; tenderness and pressure; retching; vomiting; sense of dryness and tightness in the throat; thirst; hoarseness and difficulty of speech; the matter vomited, greenish or yellowish, sometimes streaked with blood; diarrhea; tenesmus; sometimes excoriation of the anus; urinary organs occasionally affected with violent burning pains and suppression; convulsions and cramps; clammy sweats; lividity of the extremities; countenance collapsed; eyes red and sparkling; delirium; death. Some of these symptoms may be absent where the poisoning results from inhalation, as of arseniuretted hydrogen.

Symptoms of arsenic poisoning start with mild headaches and can progress to lightheadedness and usually, if untreated, will result in death.

Arsenic poisoning can lead to a variety of problems, from skin cancer to keratoses of the feet.

Electrolyte and Biomarker Studies
Arsenic is rapidly cleared by most organs. Excess levels are as follows:
 * Serum levels > 7 ug/dl (0.9 umol/L)
 * Urine – 24 hour collection (48 hours after last seafood ingestion) > 50 ug/d (0.67 umol/d)

Hair and Nails
One way to test for arsenic poisoning is by checking hair follicles. If arsenic is in the bloodstream, it will enter hair and remain there for many years.
 * Hair and nails may show arsenic for months after exposure.
 * Hair normal 0.5-5 mg/kg
 * Nail normal 4-10 mg/kg

Chest X Ray
In patients with acute arsenic poisoning, the plain film may show the radioopaque substance.

Treatment
It is extremely important to seek medical advice immediately if arsenic poisoning is suspected.

Chemical and synthetic methods are now used to treat arsenic poisoning. Dimercaprol and Succimer are chelating agents which sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning. The most important side-effect is hypertension. Dimercaprol is considerably more toxic than succimer.

Acute Pharmacotherapies

 * Gastric lavage plus charcoal
 * IV hydration
 * BAL (2,3-dimercaprol) 3-5 mg/kg IM
 * Oral may be substituted
 * Adjust for renal failure
 * May redistribute to brain and testes
 * Q4h x 2 days
 * Q6h x day 3
 * Q12 h x 10 days
 * DMPS (2,3-dimercaptopropanesulphonate) and DMSA (meso-2,3-dimercaptosuccinic acid) may be other effective agents
 * Hemodialysis – most commonly used in patients with renal failure

Chronic Pharmacotherapies

 * Agent withdrawal
 * Recovery of peripheral neuropathy can take months and may not be complete

Potency
The LD50 for pure arsenic is 763 mg/kg (by ingestion) and 13 mg/kg (by intraperitoneal injection). For a 70 kg (~155 lb) human, this works out to about 53 grams (less than 2 ounces). However, compounds containing arsenic can be significantly more toxic.

Nearly all reported arsenic poisonings were not caused by pure arsenic, but by arsenic-oxygen compounds ( hereby especially arsenic trioxide, which is approximaeltly 500 times more toxic than pure arsenic was the most common agent) and arsenic hydrogen.

Unintentional poisoning
In addition to its use as a poison, arsenic was used medicinally for centuries and was used extensively to treat syphilis before penicillin was introduced. Arsenic was replaced as a therapeutic agent by sulfa drugs and then by antibiotics. Arsenic was also an ingredient in many tonics (or "patent medicines"). In addition, during the Victorian era, some women used a mixture of vinegar, chalk, and arsenic applied topically to whiten their skin. The use of arsenic was intended to prevent aging and creasing of the skin, but some arsenic was inevitably absorbed into the blood stream.

Some pigments, most notably the popular Emerald Green (known also under several other names), were based on arsenic compounds. Overexposure to these pigments was a frequent cause of accidental poisoning of artists and craftsmen.

Arsenicosis - chronic arsenic poisoning from drinking water
Chronic arsenic poisoning results from drinking water with high levels of arsenic over a long period of time. This may occur due to arsenic contamination of groundwater.

Effects include changes in skin color, formation of hard patches on the skin, skin cancer, lung cancer, cancer of the kidney and bladder, and can lead to gangrene. The World Health Organization recommends a limit of 0.01 mg/L (10ppb) of arsenic in drinking water. This recommendation was established based on the limit of detection of available testing equipment at the time of publication of the WHO water quality guidelines. More recent findings show that consumption of water with levels as low as 0.00017mg/L (0.17ppm) over long periods of time can lead to arsenicosis.

Non-carcinogenic chronic effects include liver injury&mdash;jaundice and cirrhosis;&mdash;peripheral vascular disease involving blueness of the extremities; Raynaud's syndrome; blackfoot disease (a type of gangrene); anemia, resulting from impaired heme biosynthesis; and hyperkeratosis of the skin.

There are also multiple lines of evidence for the carcinogenic effects of arsenic.

Arsenic has been known to cause many problems in Third World countries where groundwater supplies have been contaminated by arsenic derived from geologically recent fluvial deposits containing arseno-pyrites. This is a particular problem in Bangladesh where tube wells installed since the 1970s have intercepted ground waters flowing in the fluvial deposits. Concentrations in these wells can exceed 1 part per thousand whereas the WHO maximum level is 10 parts per billion. See Arsenic contamination of groundwater.

Roger Smith, Professor of Pharmacology and Toxicology Emeritus, Dartmouth Medical School, , has confirmed that natural arsenic contamination of drinking water has also been a problem in wells in New Hampshire. Chronic low-level arsenic poisoning, or arsenicosis, as is seen in Bangladesh, can potentially cause cancer.

Intentional poisoning
In the 700s, an Arab alchemist named Jabir became the first to prepare arsenic trioxide, a white, tasteless, odorless powder. Jabir's preparation seemed the ideal poison as it left no traceable (at the time) elements in the body.

Arsenic became a favorite murder weapon of the Middle Ages and Renaissance, particularly among ruling classes in Italy, notably the Borgias. Because the symptoms are similar to those of cholera, which was common at the time, arsenic poisoning often went undetected. By the 19th C., it had acquired the nickname "inheritance powder," perhaps because impatient heirs were known or suspected to use it to ensure or accelerate their inheritances. Elizabeth Bathory is also suspected of having used arsenic to poison male lovers so that they could never leave her, probably as a result of her first husband having an affair.

Acknowledgements
The content on this page was first contributed by: and ELLISON L. SMITH, M.D.

List of contributors: