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Emergency Medicine > TOXICOLOGY
Toxicity, Arsenic
Article Last Updated: Nov 6, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Steven Marcus, MD, Professor, Department of Preventive Medicine and Community Health, Associate Professor, Department of Pediatrics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey; Executive and Medical Director, New Jersey Poison Information and Education System; Consulting Staff, Departments of Pediatrics and Internal Medicine, University Hospital, University of Medicine and Dentistry of New Jersey; Consulting Staff, Department of Pediatrics, Newark Beth Israel Medical Center
Steven Marcus is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Clinical Toxicology, American Academy of Pediatrics, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, and Medical Society of New Jersey
Editors: David C Lee, MD, Research Director, Department of Emergency Medicine, Assistant Professor, North Shore University Hospital and New York University Medical School; John T VanDeVoort, PharmD, ABAT, Director of Pharmacy, Sacred Heart Hospital; Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Author and Editor Disclosure
Synonyms and related keywords:
arsenic toxicity, element 33, poison, As, arsenic poisoning, arsenic exposure, trivalent arsenic, pentavalent inorganic arsenic, arsine, arsine exposure, arsenic gas, arsenic trioxide, heavy metal exposure, heavy metal toxicity
Background
Arsenic, element 33, has a long and nefarious history; its very name has become synonymous with poison. In the 15th and 16th centuries, the Italian family of Borgias used arsenic as their favorite poison for political assassinations. Some even have suggested that Napoleon was poisoned by arsenic-tainted wine served to him while in exile.
In nature, arsenic exists in the metallic state in 3 allotropic forms (alpha or yellow, beta or black, gamma or grey) and several ionic forms. Arsenic has been used as a medicinal agent, a pigment, a pesticide, and an agent of criminal intent. It is typically considered a heavy metal and shares many toxic characteristics with the other heavy metals (eg, lead, mercury). Arsenic is primarily used in the production of glass and semiconductors. It is also found in certain water supplies and seafood.
Today, arsenic poisoning occurs through industrial exposure, from contaminated wine or moonshine, or because of malicious intent. The possibility of heavy metal contamination of herbal preparations and so-called nutritional supplements must also be considered.
Because arsenic has been involved in geopolitics, an estimated 100 million people are at risk of exposure to unacceptable arsenic levels in either well water or ground water. This has become a major public health issue in the developing world, primarily Bangladesh and surrounding countries, where many thousands of individuals are suffering from precancerous arsenic-related disease.
Pathophysiology
Inorganic forms of arsenic are more toxic than organic forms. The trivalent forms are more toxic and react with thiol groups, while the pentavalent forms are less toxic but uncouple oxidative phosphorylation. Very few organ systems escape the toxic effects of arsenic.
Trivalent inorganic arsenic inhibits pyruvate dehydrogenase by binding to the sulfhydryl groups of dihydrolipoamide. Consequently, conversion of pyruvate to acetyl coenzyme A (CoA) is decreased, citric acid cycle activity is decreased, and production of cellular ATP is decreased. Trivalent arsenic inhibits numerous other cellular enzymes through sulfhydryl group binding. Trivalent arsenic inhibits cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and further production of acetyl CoA; it also blocks the production of glutathione, which prevents cellular oxidative damage.
Effects of pentavalent inorganic arsenic occur partially because of its transformation to trivalent arsenic; toxicity proceeds as outlined above. More importantly, pentavalent arsenic resembles inorganic phosphate and substitutes for phosphate in glycolytic and cellular respiration pathways. High-energy phosphate bonds are not made, and uncoupling of oxidative phosphorylation occurs. For example, in the presence of pentavalent arsenic, adenosine diphosphate (ADP) forms ADP-arsenate instead of ATP; the high-energy phosphate bonds of ATP are lost.
Arsenic is listed as a presumed carcinogenic substance based on the increased prevalence of lung and skin cancer observed in human populations with multiple exposures (primarily through industrial inhalation).
Frequency
United States
According to the American Association of Poison Control Centers' (AAPCC) Toxic Exposure Surveillance System (TESS), 989 non–pesticide-related arsenic exposures with 2 fatalities and 344 arsenic-containing pesticide exposures with no fatalities were reported in 2004.
International
Worldwide, up to 100 million people are at risk of exposure to arsenic from excessive arsenic in drinking water. In Bangladesh, more than 95% of the water supply to over 138 million people is potentially arsenic contaminated at levels exceeding the US EPA and WHO action limits. If international efforts at elimination of the risk are unsuccessful, it is estimated that a substantial proportion of the Bangladesh population will develop arsenic-related diseases such as pulmonary and skin cancers and cardiovascular and renal disease.
Mortality/Morbidity
According to the American Association of Poison Control Centers' (AAPCC) Toxic Exposure Surveillance System (TESS), 989 non–pesticide-related arsenic exposures with 2 fatalities and 344 arsenic-containing pesticide exposures with no fatalities were reported in 2004.
Sex
Men are more likely to experience industrial arsenic exposure than women.
Age
As in many reported cases of poisoning, the majority of reports of exposure to arsenic-containing pesticides occur with children younger than 6 years as the victim (251 of 344 in the TESS 2004 data), whereas, when nonpesticide arsenic exposure is involved, the majority are in adults older than 19 years (720 of 989).
History
- Arsenic exposure is usually suicidal, malicious, homicidal, or occupational.
- To reveal the exposure, record a careful work history on individuals with symptoms of a painful peripheral neuropathy. If the setting is not occupational, a careful epidemiological history of those affected and those unaffected must be undertaken.
- Exposure to arsine gas is usually the result of an occupational accident; in most cases, the worker presents rapidly and is brought in with the material safety data sheet (MSDS).
- Determining unusual cases requires a careful history regarding dietary and nutritional habits, particularly the use of nutritional supplements and ayurvedic medicines, hobbies, and alcohol abuse.
- Often, patients with neurological symptoms are subjected to "heavy metal screens" by their primary care practitioners or even neurologists. Often, the laboratories used are not the standard medical reference laboratories, and the results are of questionable reliability. In other cases, the results are reported in concentration of total arsenic in urine or blood, and this is not generally accepted as valuable in the determination of possible exposure or toxicity.
Physical
- Frequently, patients exposed to arsenic will have a garlic smell to their breath and tissue fluids.
- In trivalent arsenic poisoning, clinical effects depend on the chronicity of exposure.
- Acute exposures generally manifest with the choleralike gastrointestinal symptoms of vomiting (often times bloody) and severe diarrhea (which may be rice-watery in character and often bloody); these patients will experience acute distress, dehydration (often), and hypovolemic shock.
- Chronic toxicity is more insidious and may manifest as a classical dermatitis (hyperkeratosis with a classical "dew drops on a dusty road" appearance) or peripheral neuropathy (usually a painful paresthesia that is symmetrical and stocking-glove in distribution).
- Also, whitish lines (Mees lines) that look much like traumatic injuries are found on the fingernails.
- Multiple reports of cardiac arrhythmias exist in the literature. Reports of prolongation of the QT and ventricular fibrillation after acute arsenic intoxication make careful attention to cardiac status imperative.
- Chronic hepatic and renal damage is common with chronic exposure.
- Arsine gas exposure manifests with an acute hemolytic anemia and striking chills. Hemoglobinuria causes the urine to appear black (see Media file 1), and the patient becomes rapidly obtunded and shocky. Shaking chills are often described in these patients.
Causes
- Children may encounter arsenic trioxide as a rodenticide or herbicide. Examine for both arsenic and cholinesterase-inhibitor exposure. Possible transdermal absorption from exposure to pressure-treated wood, now banned for use by the US EPA, has been reported.
- Adults may be exposed through work in a metal foundry, mining, glass production, or the semiconductor industry.
- Arsenic has been found to contaminate such common items as wine, glues, and pigments.
Abdominal Trauma, Blunt
Anemia, Acute
Anxiety
Appendicitis, Acute
CBRNE - Botulism
Dermatitis, Atopic
Dermatitis, Contact
Dermatitis, Exfoliative
Encephalitis
Gastroenteritis
Hemolytic Uremic Syndrome
Toxicity, Caustic Ingestions
Toxicity, Iron
Toxicity, Lead
Toxicity, Mercury
Toxicity, Mushroom - Amatoxin
Toxicity, Theophylline
Other Problems to be Considered
Toxicity, colchicine, and other antimetabolites
Lab Studies
- Complete blood count
- As with all heavy metals, microcytic hypochromic anemia is common.
- Obtain a CBC with indices and a reticulocyte.
- Acute hemolytic anemia is the rule with arsine exposure.
- A test for plasma arsenic concentrations is helpful but rarely available until after the decision to treat is made. Blood arsenic concentrations should not exceed 50 mcg/L. In patients with arsenic poisoning, blood arsenic concentrations commonly range from several hundred to several thousand micrograms per liter. The reported half-life of arsenic in blood immediately following ingestion is in hours, while whole-body clearance may be in days or months and is apparently dose-related.
- Urine analyses
- A urine spot test for arsenic can be helpful.
- A 24-hour urine collection for total arsenic excretion can be diagnostic and useful following therapy. A 24-hour clearance of more than 50 mcg is unusual (be sure the patient has not consumed shellfish for at least 3 days). Because nutritional sources of arsenic are not unusual, the laboratory must "speciate" the arsenic into organic and inorganic moieties. The inorganic arsenic appears to be responsible for symptoms and signs. This point is extremely important, since using just the total arsenic level may lead to unnecessary treatment for many patients.
- Various species of arsenic may be recovered in a urine specimen. The human body begins to metabolize inorganic arsenic into various organic forms after a short period of time. Metabolites include methylarsonic acid (MMA) and dimethylarsenic acid (DMA). It should be possible for the laboratory to separate these species from the usual dietary organic forms, but it is imperative that the laboratory be asked to insure that this has been done.
- Obtain a urine pregnancy test in women of childbearing age.
Imaging Studies
- An abdominal radiograph may reveal the presence of radio-opaque densities and may resemble an upper GI series.
Other Tests
- Nerve conduction studies may confirm the peripheral neuropathy. This may be particularly important because the classic stocking-glove distribution suggests another etiology.
- Cardiac arrhythmias and, in rare cases, cardiac failure have been reported as resulting from arsenic toxicity. Electrocardiography would therefore be indicated.
Procedures
- Once arsenic distributes into the tissues, treatment may be unsuccessful. Clinical trials are not available, but attempting to remove arsenic from the plasma before it reaches the tissues makes sense. Because the clearance of arsenic by dialysis is substantial, hemodialysis may be indicated if available within a short time after exposure.
- In arsine exposure, hemolysis may be severe and life threatening, and no data suggest that chelation therapy can alter this. Arsine appears to rapidly bind to the erythrocytes, making them likely to lyse and release more toxin to contaminate other cells. The use of multiple transfusions and perhaps exchange transfusion may be necessary.
Prehospital Care
- Provide support to airway, breathing, and circulation.
Emergency Department Care
- Hemodynamic stabilization is of primary importance, and large amounts of crystalloid solutions may be required because of significant GI losses (ie, vomiting, diarrhea). In the face of acute blood loss, consideration of the use of blood products may be critical in sustaining the life of the victim.
- The use of gastrointestinal decontamination is controversial and may confuse the clinical picture. For acute arsenic ingestions, orogastric lavage is recommended if the patient presents rapidly or plain radiography indicates that arsenic is present in the stomach. Activated charcoal does not adsorb arsenic appreciably and is not recommended for patients in whom co-ingestants are not suspected. Whole bowel irrigation with polyethylene glycol may be effective to prevent GI tract absorption of arsenic. The use of invasive gastric-emptying procedures has been reported in dire cases, but these attempts do not seem to be fruitful.
- Do not delay with definitive chelation therapy and hemodialysis.
Consultations
- Consult a hematologist and nephrologist in cases of arsine exposure.
- Neurology and physiatry consultations are appropriate in cases of arsenic exposures.
- Consultation with a medical toxicologist conversant with the use of chelation therapy may be very useful.
- Psychiatric consultation is necessary before discharge if the arsenic ingestion was intentional.
Treatment of acute arsenic toxicity is supportive. Chelation therapy is imperative in all symptomatic patients; however, the use of chelators in patients exposed to arsine gas is controversial. The efficacy of chelation therapy in providing either laboratory or clinical improvement in intoxicated patients is lacking. The physician is reminded to look carefully at laboratory tests. Generally, organic arsenical compounds found in the urine are not an indication of arsenic toxicity and do not warrant therapeutical intervention. Hemodialysis, in the absence of renal failure, has not been shown to alter medical outcome. The use of extracorporeal membrane oxygenation in an infant who developed cardiovascular collapse did not result in survival.
Drug Category: Chelating agents
Bind heavy metals and to hasten excretion. By binding in plasma, they render heavy metals nontoxic.
| Drug Name | Dimercaprol (BAL in Oil) |
|---|
| Description | First-line agent available in the US for treating arsenic poisoning. Often in short supply, is one of the antidotes considered essential to be stocked by every ED.
Administered IM q4h, mixed in a peanut oil base. Excreted in urine and bile. May be administered to patients with renal failure. |
|---|
| Adult Dose | 2.5-3 mg/kg IM q4h for 2 d, then qid on day 3, then bid for 10 d; dose may be adjusted upward in severe poisoning not to exceed 5 mg/kg (Although diluted in oil, there is little use for a test dose of the drug. If it is deemed essential to use the preparation, efforts to block anaphylaxis in peanut-sensitive individuals is imperative. At least one death has been reported in which a test dose produced urticaria and the full dose then precipitated death by anaphylaxis. Thus, this effort should not be made.) |
|---|
| Pediatric Dose | 50-75 mg/m2 IM q4h; not to exceed 450 mg/d for 5 d |
|---|
| Contraindications | Documented hypersensitivity; G-6-PD deficiency; concurrent iron supplementation therapy; hypersensitivity to peanuts (because suspended in peanut oil) |
|---|
| Interactions | Toxicity may increase with coadministration of selenium, uranium, iron, or cadmium |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | May be nephrotoxic; may cause hypertension; caution when administering to patients with oliguria or G-6-PD deficiency; may induce hemolysis in G-6-PD deficient patients; may cause sterile abscesses at injection site, fever, tachycardia, CNS stimulation, headache, nausea, vomiting, urticaria, a burning sensation around the mouth, and diaphoresis |
|---|
| Drug Name | Succimer (DMSA) |
|---|
| Description | Licensed by the FDA for use only in childhood lead poisoning. Has been used worldwide as a heavy metal chelator and has been efficacious in treating arsenic intoxications. In the US, is only available in a bead-filled oral capsule of 100 mg. |
|---|
| Adult Dose | 10 mg/kg/dose PO q8h for 5 d; then q12h for 14 d |
|---|
| Pediatric Dose | Administer as in adults |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | Do not administer concomitantly with edetate calcium disodium or penicillamine |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Correct dehydration, if present, and establish adequate urine flow before and during therapy; is renally excreted and should be used with caution in those with renal insufficiency; thrombocytosis, eosinophilia, and dysrhythmias have occurred from use |
|---|
| Drug Name | Dimerval (DMPS) |
|---|
| Description | Internationally accepted DOC for treating most heavy metal poisonings. Not licensed for use in the US and must be obtained from Helytex in Houston. Available as either a parenteral or oral form. |
|---|
| Adult Dose | Not established
1 vial (200 mg) q4h until oral product can be used when parenteral form is available
1 cap (100 mg of active drug) tid/qid depending on clinical and laboratory results |
|---|
| Pediatric Dose | Administer as in adults |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | None reported |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | None reported |
|---|
Further Inpatient Care
- Many patients will develop profound peripheral motor palsies requiring extensive rehabilitation. Rehabilitation should be started as promptly as the clinical picture allows.
Further Outpatient Care
- Perform a careful neurological evaluation in follow-up of all patients because the peripheral neuropathy, which may develop after an acute exposure, may not appear for 2-3 weeks.
Complications
- Sterile abscesses after the use of dimercaprol (BAL in Oil) are not unusual. They initially may appear like erythematous macules, which spread or coalesce and may continue to drain for some time.
Patient Education
Medical/Legal Pitfalls
- Failure to immediately report all suspicious cases to an appropriate law enforcement agency (If someone presents with arsenic toxicity and the cause is not obvious, a malicious etiology may be involved.)
Special Concerns
- Checking the patient's family members for exposure is important because a good chance exists that they may also have been exposed to arsenic toxicity.
| Media file 1:
Black water urine from a patient with massive hemolysis secondary to arsine exposure at a gas tank cleaning operation. |
 |  View Full Size Image | |
Media type: Photo
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Toxicity, Arsenic excerpt Article Last Updated: Nov 6, 2007
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