Link to 2.2.6.1 Arsenic Teaching Resources
Link to Problems for Discussion

Arsenic


SUBSTANCES INCLUDED IN THIS CATEGORY


  • Acetoarsenite
  • Arsenic acid
  • Arsenic pentoxide
  • Arsenic trioxide
  • Arsenic trisulphide
  • Arsenous sesquioxide
  • Arsine gas
  • Calcium arsenite
  • Arsenic containing herbicides and pesticides
  • Arsenic contaminated Ayurvedic and Traditional Chinese Medicines
  • Copper Chrome Arsenic (CCA) impregnated timber

OVERVIEW


Ingestion of arsenic is relatively common in the setting of homicide and is occasionally used in deliberate self-poisoning. Arsine gas and CCA exposure are not uncommon industrial exposures. Most organs can be involved and the diagnosis may not be obvious.

Arsenic is a classic poison; implicated in the deaths of Tchaikovsky and Napoleon. It has also been used as a therapeutic substance since ancient times. It has been used in traditional Chinese medicines and most recently as a chemotherapeutic agent for the treatment of acute promyelocytic leukaemia. Chronic arsenic poisoning is a major public health crisis and an environmental disaster in Bangladesh and West Bengal, due to the contamination of ground water that affects millions of people. These chronic problems are beyond the scope of this course.

Arsenic exists in many forms: arsine gas, elemental arsenic, inorganic oxides and organic arsenic. Acute arsenic poisoning is rare. The elemental form of arsenic is non-toxic but the oxides are extremely toxic (trivalent As2O-3 more so than the pentavalent As2O-5). There is limited data on the toxic dose but the lethal dose of inorganic arsenic is about 1-3 mg/kg. Acute toxicity manifests initially within an hour of ingestion as severe nausea, vomiting, diarrhea and abdominal pain. In severe poisoning this is followed by multi-organ failure with cardiac toxicity (QT prolongation, arrhythmias and cardiac failure/collapse), renal failure and hepatic failure. If survival beyond the initial phase occurs, bone marrow suppression, peripheral neuropathy and skin lesions may develop. Treatment includes effective decontamination and early initiation of chelation therapy. The best supportive care is unlikely to prevent death in patients with severe multi-organ failure, or early cardiac effects characterised by QT prolongation, arrhythmias and cardiovascular collapse. Organic arsenic poisoning can cause severe effects but is less toxic than inorganic arsenic.

MECHANISM OF TOXIC EFFECTS


Arsenic binds to a range of sulphydryl containing proteins. These include enzymes involved in oxidative metabolism (leading to lactic acidosis, shock and multiorgan failure), haemoglobin synthesis (leading to a siderocytic anaemia) and methionine synthetase (leading to homocysteinaemia, and atherosclerosis). Mechanisms behind many other features of arsenic poisoning are less well understood but presumably involve similar inhibition of metabolic pathways. Arsenic is also a clastogen and known human carcinogen.

KINETICS IN OVERDOSE


Absorption

Arsenic is absorbed via inhalation, ingestion or through skin.

Distribution

Arsenic is distributed into red blood cells rapidly and binds to haemoglobin. Distribution to other tissues occurs over about 24 hours, except for arsine gas, which remains largely confined to the red cells. The majority of arsenic measured in blood is contained within red cells. Thus in people with anaemia, the blood arsenic concentration may underestimate the total body arsenic.

Metabolism - Elimination

Arsenic is excreted renally. Following an acute exposure, there is an initially relatively rapid fall in concentration (half-life about 24 hours), with a terminal elimination half-life in the order of 10 days. With chronic exposure, there is likely to be substantial amounts in tissue stores (e.g. bone), that is slowly eliminated and not available for chelation.

CLINICAL EFFECTS


Clinical effects differ in acute and chronic exposures. Arsine gas has a unique toxicological syndrome.

Acute arsenic poisoning

The onset of symptoms is usually within a few hours. Local gastrointestinal effects include oropharyngeal burns, dysphagia, vomiting, abdominal pain, and bloody diarrhoea. Multiple organ failure with shock, ARDS, acute renal and hepatic failure, and encephalopathy may lead rapidly to death.

Arsine gas poisoning

The above symptoms may be seen but the major manifestation is severe haemolysis leading to haematuria. Abdominal pain, renal failure, and hyperkalaemia are common. Facial skin burning and dyspnoea may also result (perhaps partly from local effects of the gas exposure). Treatment is different from other arsenic poisonings utilizing exchange transfusion and dialysis. Symptom onset may be delayed up to 24 hours in some cases.

Chronic arsenic poisoning

Subacute or chronic exposures lead to a variety of insidious presentations with peripheral sensorimotor neuropathy, dementia, bone marrow depression resembling myelodysplasia, myocarditis, severe peripheral vascular disease ("Blackfoot disease") and lung and skin cancers. Skin changes including alopecia, pigmentation, nail changes and hyperkeratosis may lead to suspicion of arsenic as the underlying cause.

INVESTIGATIONS


The following investigations may be useful

Blood concentrations

Conversion factor
  • microg/L x 13.35 = nmol/L
  • nmol/L x 0.075 = microg/L

Blood or urine arsenic concentrations are not generally used to determine the need for specific treatments but do confirm poisoning. They are most useful for medicolegal purposes in industrial or homicidal poisonings. False positive elevation of urine arsenic occurs following ingestion of nontoxic organic arsenates in seafood.

Haematology

Full blood count and coagulation studies - The full blood count will detect early onset of haemolysis and late onset bone marrow depression.

Biochemistry

Hepatic and renal toxicity is common, as is a lactic acidosis.

ECG

Arrhythmias and QT prolongation may be seen.

Imaging

Abdominal x-ray may identify arsenic (from ingested arsenic salts) contained within the gastrointestinal tract.

DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS


Acute toxicity from trivalent arsenic (arsenite) compounds occurs at lower doses than from pentavalent arsenic (arsenate) compounds. Arsine gas is the most toxic form and the only one that causes significant haemolysis, however it does not generally lead to long term toxic effects (also see treatment).

DETERMINATION OF SEVERITY


This is based largely on the clinical state and arsenic concentrations are not used to determine severity or need for treatment.

TREATMENT


Acute arsenic exposure

Arsenic is not adsorbed by charcoal. Patients with confirmed ingestion of a potentially toxic dose of arsenic salt within 1-2 hours, should have gastric lavage and polyethylene glycol lavage solution. The presence of arsenic may be detected with abdominal X-ray. Chelation may be useful for acute arsenic exposures and should be based on the ingestion of a potentially toxic dose (> 0.5 to 1 mg/kg) and the presence of significant clinical effects, as the arsenic concentration is not likely to be available at the time when treatment should be commenced. Given the significant long-term sequelae, the threshold for treating acute arsenic ingestion with chelation should be low. Other treatment is primarily supportive and may include intensive cardiovascular and respiratory support.

Arsine gas exposure

Administer 100% oxygen. If evidence of significant haemolysis or haematuria, exchange transfusion should be instituted early. The urine should be alkalinised (pH>7) and high urine flow rates may reduce the risk of haemoglobin precipitation and secondary renal failure. Haemodialysis is indicated for treatment of renal failure or severe hyperkalaemia (it will not significantly enhance the elimination of arsenic). Chelation therapy is ineffective in treating haemolysis

Chronic arsenic exposure

The usefulness of chelation therapy in long term chronic exposures is probably very limited. A small randomised trial found no evidence of benefit from DMSA in this setting (Guha et al, 1998). Removal from the source of exposure, surveillance for arsenic related cancers, and nonspecific cardiovascular preventative strategies should be the mainstay of treatment.

Antidotes

Antidotes for arsenic are chelating agents. Chelation therapy is not useful if the source of arsenic has not been removed. Succimer (where available) is the chelating agent of choice for patients without life-threatening arsenic poisoning, due to its relatively low toxicity. Where urgent parenteral therapy is required, British Anti-Lewisite (BAL) is usually preferred (although DMPS may be available in some places). Iron and zinc supplementation can be given between courses of chelation therapy but not during courses.

Succimer (DMSA)
Succimer is an oral analogue of BAL that chelates arsenic (and other metals including lead, zinc and mercury). The arsenic-succimer complex is renally eliminated. It is given orally in a dose of 10 mg/kg (to a maximum dose of 500 mg) three times daily for five days and then twice daily for a further 14 days. Dosing can also be done on a body surface area basis at 350 mg/m2. The adverse effect profile is substantially better than BAL, but includes gastrointestinal disturbances, and occasional bone marrow suppression and drug induced hepatitis as well as the development of trace element deficiency (e.g. zinc).

Dimercaptopropane-1-sulfonate (DMPS)
DMPS is another analogue of BAL that is available in both oral and IV formulations. It chelates arsenic (and other metals including lead, zinc and mercury). The arsenic-DMPS complex is renally eliminated. Doses recommended are 5 mg/kg q6 - q8h. While experience and clinical trials supporting its use are very limited, the limited availability of BAL may leave this as the only parenteral chelating agent available for some indications. DMPS manufacturer contact information.

British Anti-Lewisite (BAL)
BAL (British Anti-Lewisite, dimercaprol) is administered in a dose of 4 mg/kg by deep intramuscular injection every 4 hours for 5-7 days. The BAL-arsenic complex is excreted primarily via biliary excretion. It is not known whether laxatives improve elimination but constipation should be avoided. It is the only chelating agent that can be used in patients with renal failure. BAL frequently causes adverse effects including severe local pain, acute hypertension and tachycardia, vomiting, paraesthesiae, various oral and ocular symptoms, coma, convulsions, and shock.

D-Penicillamine
This is an oral chelating agent that binds to iron, lead, arsenic, antimony, zinc, mercury, and copper. It is less effective than the other agents are but there is a great deal of experience with it being used over months to years for other conditions (e.g. Wilson's disease). Its use cannot be recommended except where other therapies are unavailable or contraindicated. The D-penicillamine-arsenic complex is renally excreted. The usual dose is 25 to 35 mg/kg/day in divided doses with titration over a few weeks to this dose. It must be given on an empty stomach with no food ingested within the next 1 to 2 hours. Cross allergy between penicillin and d-penicillamine may occur and d-penicillamine should be used with extreme caution (if at all) in patients allergic to penicillin.

Adverse effects are common. Hypersensitivity reactions, including maculopapular or erythematous rashes, urticaria, fever, eosinophilia, arthralgia or lymphadenopathy occur early in therapy. Other adverse reactions that have been reported include glomerulonephritis, hepatic dysfunction, alopecia, bone marrow suppression, nausea, vomiting and diarrhoea, thrombophlebitis, pancreatitis, cheilosis, glossitis, gingivostomatitis, taste disturbance, bruising, poor wound healing, neuropathy, and a variety of auto-immune diseases including drug induced SLE, Goodpasture's syndrome, polymyositis, pemphigus, myasthenia gravis. Iron deficiency may develop and supplemental iron therapy may be required. Patients should be monitored closely during therapy (including regular urinalysis, blood counts, and liver function tests) for such adverse effects, which may occasionally lead to permanent organ damage or death.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


Central neurotoxic effects such as dementia are unlikely to improve substantially despite removal of arsenic. Arsenic is genotoxic, mutagenic and classified as a confirmed human carcinogen. Cardiovascular disease (atherosclerosis) is a common feature of long term exposure (Blackfoot disease).

REFERENCES


Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, Zuniga-Charles M, Xu Z, Hurlbut KM, Junco-Munoz P, Dart RC, Aposhian MM.
Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23-38.
Chen CJ, Chiou HY, Chiang MH, Lin LJ, Tai TY. Dose-response relationship between ischemic heart disease mortality and long-term arsenic exposure. Arteriosclerosis, Thrombosis - Vascular Biology 1996;16:504-510.
Graeme KA, Pollack CV, Jr. Heavy metal toxicity, Part I: arsenic and mercury. Journal of Emergency Medicine 1998;16:45-56.
Guha Mazumder DN, Ghoshal UC, Saha J, Santra A, De BK, Chatterjee A, Dutta S, Angle CR, Centeno JA. Randomized placebo-controlled trial of 2,3-dimercaptosuccinic acid in therapy of chronic arsenicosis due to drinking arsenic-contaminated subsoil water. J Toxicol Clin Toxicol 1998;36:683-690.
Mazumder DN, Das GJ, Santra A, Pal A, Ghose A, Sarkar S. Chronic arsenic toxicity in west Bengal--the worst calamity in the world. Journal of the Indian Medical Association 1998;96:4-7.
International Chemical Safety Card Arsenic
NIEHS - 9th Report on Carcinogens -Arsenic (arseniccmpds.pdf)
ATSDR-CSEM Arsenic toxicity