ARSENIC TRIOXIDE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Arsenic (III) oxide
2) Arsenic sesquioxide
3) Arsenicum album
4) Arsenious acid
5) Arsenious oxide
6) Arsenious trioxide
7) Arsenite
8) Arsenolite
9) Arsenous acid
10) Arsenous acid anhydride
11) Arsenous anhydride
12) Arsenous oxide
13) Arsenous oxide anhydride
14) Arsodent
15) Claudelite
16) Claudetite
17) Crude arsenic
18) Diarsenic trioxide
19) White arsenic
20) CAS 1327-53-3

1.2.1) MOLECULAR FORMULA
1) As2-O3

Available Forms Sources

1) THERAPEUTIC USE

a) Arsenic trioxide injection is available as 10 mg/10 mL (1 mg/mL) sterile, clear, colorless solution in 10 mL glass, single-use ampules (Prod Info TRISENOX(R) IV injection, 2010).

1) OTHER USES

a) Arsenic trioxide is obtained as a byproduct in the smelting of copper and lead concentrates (HSDB, 2006).
b) In the United States, arsenic trioxide is mainly found in smelting of copper sulfide ores; the highest exposures are usually to roaster workers (HSDB, 2006). Arsenic trioxide in a solubilized form becomes sodium arsenite, which is more toxic than in the unsolubilized form.

1) THERAPEUTIC USE

a) Arsenic trioxide is used for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) with the presence of the t (15;17) translocation or PML/RAR-alpha gene expression, who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy (Prod Info TRISENOX(R) IV injection, 2010).

2) OTHER USES

a) Arsenic trioxide is the most important commercial arsenic compound (Clayton & Clayton, 1994). It is the primary material used to produce all arsenical compounds, and is used as an intermediate for insecticides, herbicides, and fungicides, as a wood preservative, as a decoloring and refining agent in the manufacture of glass, in pharmaceutical preparations, pigments, and in sheep and cattle dip for preserving hides, as a textile mordant, and to purify synthetic gases (EPA, 1985; Lewis, 1993; Budavari, 1996; Morgan, 1989).
b) About 85% of the pesticidal use of arsenic trioxide has been in liquid preparations intended to kill mice and rats (EPA, 1988). The remaining 15% has been used to kill moles, pocket gophers, and ants (EPA, 1988). However, many arsenic-containing pesticides have been banned in the US (Clayton & Clayton, 1994). For many years, arsenical pesticides were the most common cause of fatal poisoning in the US (Hayes & Laws, 1991).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Arsenic trioxide is used for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL). Arsenic trioxide is the primary material used to produce all arsenical compounds, and is used as an intermediate for insecticides, herbicides, and fungicides, as a wood preservative, a decoloring and refining agent in the manufacture of glass, and a textile mordant. It is also used in pharmaceutical preparations, pigments, and in sheep and cattle dip for preserving hides.
B) PHARMACOLOGY: The precise mechanism of action of arsenic trioxide in acute promyelocytic leukemia (APL) remains to be clearly defined. However, in vitro studies indicated that morphological changes and DNA fragmentation characteristic of apoptosis occur in NB4 human promyelocytic leukemia cells following arsenic trioxide administration. Selective apoptosis of APL cells mediated by activation of cysteine-proteases (caspases) may be involved. Additionally, arsenic trioxide induces damage and degradation of the fusion protein PML/RAR-alpha.
C) TOXICOLOGY: Trivalent arsenic (As3+) disrupts oxidative phosphorylation, leading to free radical formation via inhibition of pyruvate dehydrogenase, which subsequently decreases gluconeogenesis due to lack of acetyl-CoA. Chronically, arsenic may cause DNA damage, mutation in the p-53 suppressor gene, and inhibition of DNA repair mechanisms leading to cancer.
D) EPIDEMIOLOGY: INTRAVENOUS ROUTE: Overdose is rare. OTHER ROUTES: Toxicity from arsenic is uncommon and major effects are rare.
E) WITH THERAPEUTIC USE

1) INTRAVENOUS ROUTE: COMMON (greater than 20%): Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, fever, edema, rigors, chest pain, injection site pain, sore throat, hypokalemia, hypomagnesemia, hyperglycemia, elevated liver enzymes, headache, insomnia, paresthesia, dizziness, cough, dyspnea, epistaxis, hypoxia, pleural effusion, dermatitis, pruritus, ecchymosis, tachycardia, hypotension, sinusitis, arthralgia, myalgia, bone pain, leukocytosis, anemia, anxiety. OTHER ADVERSE EFFECTS: Palmar keratosis, rashes, hyperkalemia, hypocalcemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, thrombocytopenia, neutropenia, neutropenia, noncirrhotic portal hypertension, hypersensitivity reaction, tremor, peripheral neuropathy, seizure, coma, and acidosis.
2) Patients receiving arsenic trioxide may develop QT interval prolongation, complete atrioventricular block, premature ventricular contractions (PVCs), ventricular tachycardia, and a potentially fatal torsade de pointes ventricular dysrhythmia.
3) Retinoic acid syndrome (retinoic-acid-Acute Promyelocytic Leukemia, RA-APL, or APL differentiation syndrome), a serious adverse effect, may also occur. It is characterized by fever, skin rash, lower leg edema, weight gain, dyspnea, pulmonary infiltrates, and pleural or pericardial effusions, with or without leukocytosis and death.

F) WITH POISONING/EXPOSURE

1) INTRAVENOUS ROUTE

a) Data is limited. Seizures, muscle weakness, confusion may occur; other effects are similar to exposure by other routes (see below).

2) OTHER ROUTES

a) ACUTE OVERDOSE: Arsenic compounds are mainly absorbed through the gastrointestinal tract, but some absorption may occur through intact skin or inhalation. Acute arsenic ingestion generally produces signs and symptoms within 30 minutes but symptoms may be delayed for several hours if ingested with food. Many arsenic compounds are severe irritants of the skin, eye, and mucous membranes; some may be corrosive. Contact produces local hyperemia, followed by vesicular or pustular eruptions. Trivalent compounds are particularly caustic. Acute inhalation exposures have resulted in irritation of the upper respiratory tract.
b) MILD TO MODERATE TOXICITY: Gastrointestinal symptoms occur rapidly after acute ingestion. Initial signs and symptoms include burning lips, throat constriction, and dysphagia. Excruciating abdominal pain, severe nausea, vomiting, and profuse "rice water-like" diarrhea that may lead to hypovolemia follows these symptoms. In addition, hypovolemia from capillary leakage (third-spacing of fluids) is a common early effect. QTc prolongation may occur. Muscle cramps, facial edema, bronchitis, dyspnea, chest pain, dehydration, intense thirst, and fluid-electrolyte disturbances are also common following significant exposures. A garlic-like odor of the breath and feces may also develop. Subacute toxicity can produce neuropathies, both motor and sensory, and can progress to a Guillain-Barre like syndrome.
c) SEVERE TOXICITY: Hypotension and tachycardia are common early signs of severe poisoning. Hypotension may be resistant to fluid resuscitation and multi-organ failure may ensue. Fever and tachypnea may occur. These patients can develop ventricular dysrhythmias including torsade de pointes. Encephalopathy, seizures and coma have been reported. Acute renal failure, hemolytic anemia, rhabdomyolysis, and hepatitis may occur several days after ingestion.
d) CHRONIC TOXICITY: Inhalation is the most common route of exposure in arsenic workers. The sequence of chronic poisoning involves weakness, anorexia, hepatomegaly, jaundice, and gastrointestinal complaints, followed by conjunctivitis, irritation of the upper respiratory tract, hyperpigmentation, and eczematoid and allergic dermatitis. A hoarse voice and chronic upper respiratory septum is a common result after prolonged inhalation of white arsenic dust or fume. Peripheral nervous system symptoms may include numbness, burning, and tingling of the hands and feet; pain; paresthesias; tenderness; muscle fasciculations; gross tremors; ataxia; discoloration; and mental confusion. Muscular weakness, limb tenderness and difficulty walking may follow. The final phase consists of peripheral sensory neuropathy of the hands and feet. Associated motor neuropathy may occur as well. Certain arsenic compounds are known human carcinogens. Chronic exposure in either occupational settings or by drinking contaminated groundwater can cause poisoning and carries an increased risk of skin, lung, bladder, and possibly liver cancers.

0.2.3)

A) WITH THERAPEUTIC USE

1) Tachycardia has been observed during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic or anxiety.

0.2.4)

A) WITH THERAPEUTIC USE

1) Nasal congestion, lacrimation and sore throat have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. Corneal epithelial erosion and conjunctiva injection were reported in medical staff exposed during treatment of a patient with arsenic trioxide ingestion. A garlic-like odor may be detected on the breath.

0.2.5)

A) WITH THERAPEUTIC USE

1) Tachycardia, QT prolongation and ventricular dysrhythmias have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Torsades de pointes, ventricular tachycardia and ventricular fibrillation have been described after acute arsenic ingestion. These dysrhythmias may be secondary to electrolyte imbalances or direct toxic effect of arsenic on the myocardium.

0.2.6)

A) WITH THERAPEUTIC USE

1) Cough and dyspnea have been described during therapeutic use. Respiratory failure consistent with ARDS has also been reported with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.

0.2.7)

A) WITH THERAPEUTIC USE

1) Peripheral neuropathy has been described during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common.

0.2.8)

A) WITH THERAPEUTIC USE

1) Nausea, vomiting and abdominal pain have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery ("rice-water-like") diarrhea, pain in the extremities and muscles, weakness, and flushing of the skin.

0.2.9)

A) WITH THERAPEUTIC USE

1) Elevation of hepatic transaminases may occur.

B) WITH POISONING/EXPOSURE

1) Hepatocellular damage may occur, but is not common. A common post-mortem finding is mitotic activity of hepatocytes.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been reported following acute exposure and therapeutic use.

0.2.12)

A) WITH THERAPEUTIC USE

1) Fluid retention and edema have been described with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Electrolyte imbalances may occur.

0.2.13)

A) WITH THERAPEUTIC USE

1) Anemia, neutropenia and thrombocytopenia have been seen with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.

0.2.14)

A) WITH THERAPEUTIC USE

1) Skin rash, dryness and hyperpigmentation and other dermatologic effects have been reported with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Common skin findings may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation, and exfoliative dermatitis. Transverse white striae of the nails may be seen weeks after exposure. Shingles (Herpes Zoster) may also be a complication.

0.2.16)

A) WITH THERAPEUTIC USE

1) Mild to moderate hyperglycemia has been described with therapeutic use.

0.2.20)

A) Use of arsenic trioxide during pregnancy has been associated with infant death, and conversely, normal pregnancy outcomes. Until more information is available, arsenic trioxide should not be used in pregnant women unless the maternal benefit is determined to outweigh the possible risk to the fetus. Arsenic is excreted in the breast milk in humans.
B) HUMAN STUDIES: Studies of women chronically exposed to arsenic in drinking water did not find a correlation between maternal arsenic levels and birth weight or fetal malformation. Increased rates of miscarriage and low birth weight have been described in women living near smelters releasing arsenic, lead and sulfur dioxide.
C) ANIMAL STUDIES: Arsenic trioxide has caused adverse reproductive effects in mice and accumulated in the placenta and all fetal organs, especially the liver, when fed to pregnant rats.

1) Arsenic is excreted in the breast milk in experimental animals.
2) It does not seem to have any adverse effects on fertility based on animal studies. Systemic toxicity was present before any effects were noted on the testes.

0.2.21)

A) Human carcinogenicity studies have not been performed using intravenous arsenic trioxide, however, arsenic trioxide is a known human carcinogen.
B) Excess deaths ranging from 2 to 9 times higher than expected from lung cancer have been noted in epidemiologic studies of smelter workers exposed to arsenic trioxide. An IARC review linked arsenic to skin cancer and a greater risk of lung cancer. OSHA has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow. Bladder, kidney, prostate, liver, breast and colon cancer have also been linked with arsenic exposure.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Fluid resuscitation should be initiated immediately, but care must be taken to recognize pulmonary and cerebral edema when present. When a significant acute ingestion is confirmed, chelation therapy should be initiated immediately prior to laboratory confirmation. This will minimize time delay to treatment associated with prolonged laboratory result turn around. In chronic toxicity, the decision to chelate must be based upon patient condition and laboratory evaluation. Treat persistent nausea and vomiting with several antiemetics of different classes.

B) MANAGEMENT OF SEVERE TOXICITY

1) Aggressive life support measures should be instituted immediately. Anti-arrhythmic medications that prolong the QTc should be avoided. In severely ill patients, combined therapy with both BAL and an oral agent should be considered. If renal failure exists, the dose of BAL should be decreased after the loading dose.
2) INTRAVENOUS ROUTE: Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
3) INHALATION EXPOSURE: Inhalation is the most common exposure in arsenic workers. OSHA has set an "action level" of 5 mcg/m(3) of inorganic arsenic in the air over an 8-hour period. Initial treatment should be to remove the patient from the exposure and refer the patient to an occupational specialist for 24-hour urine collection. The decision to chelate will depend upon the patient's clinical status and urine arsenic concentration.
4) DERMAL EXPOSURE: Occasionally arsenic can cause a contact dermatitis or an exfoliative rash. Wash the area thoroughly and avoid further dermal contact. Topical steroid creams may decrease inflammation in these cases.
5) EYE EXPOSURE: Copious irrigation and ophthalmology follow-up.

C) INTRATHECAL INJECTION

1) No clinical reports available, information derived from experience with other antineoplastics. Keep patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free 0.9% saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

D) DECONTAMINATION

1) PREHOSPITAL: Remove the contaminated clothing and wash the patient thoroughly.
2) HOSPITAL: ORAL ROUTE: Activated charcoal does not bind arsenic well. Gastric lavage and whole bowel irrigation should be considered for confirmed significant ingestions. INTRAVENOUS ROUTE: Decontamination is not useful.

E) AIRWAY MANAGEMENT

1) Should be considered for patients with severe CNS depression at risk of aspiration.

F) ANTIDOTE

1) BAL and succimer are chelating agents used as antidotal therapy for arsenic toxicity. BAL: Symptomatic patients unable to tolerate oral medication should be treated with BAL 3 to 5 mg/kg/dose IM every 4 to 6 hours. The dose and frequency depend on the degree of toxicity seen. Higher doses of BAL invariably cause adverse effects. SUCCIMER: Should be used as soon as the patient is able to tolerate oral medication. DOSE: 10 mg/kg every 8 hours for 5 days, then decrease dosing to every 12 hours for 14 days. It may be more effective and causes fewer side effects than BAL. Chelation therapy should be stopped when the urinary arsenic level falls below 50 mcg per 24 hours.

G) MYELOSUPPRESSION

1) Monitor CBC with differential for evidence of bone marrow suppression. If fever or infection develop during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.

H) NAUSEA AND VOMITING

1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).

I) PERIPHERAL NEUROPATHY

1) Peripheral neurotoxicity should be anticipated in overdose. Monitor and treat symptoms as indicated.

J) VENTRICULAR DYSRHYTHMIAS

1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Because arsenic can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution. Unstable rhythms require immediate cardioversion.

K) TORSADES DE POINTES

1) Treat with magnesium; atrial overdrive pacing may also be indicated. Correct electrolyte abnormalities.

L) ENHANCED ELIMINATION

1) Arsenic is poorly dialyzable. Hemodialysis should only be considered for arsenic toxicity accompanied by renal failure.

M) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management.
2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

N) PITFALLS

1) ORAL ROUTE: Failure to consider arsenic poisoning in patients with prolonged gastrointestinal illness and cardiac conduction abnormalities. Failure to remove fish or other arsenic sources from the diet prior to testing urine arsenic levels.
2) INTRAVENOUS ROUTE: Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity, cardiotoxicity).

O) PHARMACOKINETICS

1) Arsenic compounds are absorbed mainly through the GI tract, but may be absorbed through intact skin or after inhalation. Vd: 562 L. Metabolism: hepatic, extensive via methylation. Excretion: Renal: 15% as unchanged arsenious acid. Renal clearance: 9 L/hr. Total body clearance: 49 L/hr. Elimination half-life: 10 to 14 hrs. Major metabolites: Dimethylarsinic acid: 72 hours; monomethylarsonic acid: 32 hrs.

P) DIFFERENTIAL DIAGNOSIS

1) ORAL ROUTE: Infectious gastroenteritis may have a similar clinical presentation, though arsenic toxicity usually lasts longer and has more multi-organ system involvement. Toxic plant and mushroom ingestion may lead to a severe gastritis though most lack the systemic toxicity seen with arsenic. Theophylline overdose may have a similar presentation though diarrhea is not as predominant a feature as it is with arsenic poisoning.
2) INTRAVENOUS ROUTE: Includes other agents that cause myelosuppression or peripheral neuropathy.

0.4.3)

A) Inhalation is the most common exposure in arsenic workers. OSHA has set an "action level" of 5 mcg/m(3) of inorganic arsenic in the air over an 8-hour period. Initial treatment should be to remove the patient from the exposure and refer the patient to an occupational specialist for 24-hour urine collection. The decision to chelate will depend upon the patient's clinical status and urine arsenic concentration.

0.4.4)

A) Copious irrigation and ophthalmology follow-up.

0.4.5)

A) OVERVIEW

1) Occasionally arsenic can cause a contact dermatitis or an exfoliative rash. Wash the area thoroughly and avoid further dermal contact. Topical steroid creams may decrease inflammation in these cases.

0.4.6)

A) Following an overdose, discontinue arsenic trioxide injection immediately and initiate chelation therapy. Refer to TREATMENT/ORAL EXPOSURE OVERVIEW section for more information.
B) INTRATHECAL OVERDOSE: No clinical reports available, information derived from experience with other antineoplastics. Keep patient upright if possible. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or lactated ringers through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) INTRAVENOUS ROUTE

a) Data is limited. Seizures, muscle weakness, confusion may occur; other effects are similar to exposure by other routes (see below).

2) OTHER ROUTES

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Tachycardia has been observed during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic or anxiety.

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever was reported in 63% of patients (25 of 40) with relapsed or refractory acute promyelocytic leukemia (APL) who received arsenic trioxide at a dose of 0.15 mg/kg/day (Prod Info TRISENOX(R) injection, 2005).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Patients may rapidly become hypotensive after acute arsenic poisoning from "third spacing" of fluids, diarrhea, or blood loss into the GI tract (Schoolmeester & White, 1980).

a) Severe hypotension was observed in instances of arsenic trioxide ingestion (Parent et al, 2006; Levin-Scherz et al, 1987) and in a worker who died after being buried under crude arsenic trioxide at a copper smelting facility (Gerhardsson et al, 1988).

3.3.5)

A) WITH THERAPEUTIC USE

1) Tachycardia was observed in 11 of 20 (55%) patients receiving arsenic trioxide for metastatic melanoma (Kim et al, 2005).

B) WITH POISONING/EXPOSURE

1) Patients may become tachycardic secondary to pain, hypovolemia, cardiac effects of arsenic, or anxiety (Morgan, 1989).

Heent

3.4.1)

A) WITH THERAPEUTIC USE

1) Nasal congestion, lacrimation and sore throat have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

3.4.2)

A) WITH POISONING/EXPOSURE

1) ALOPECIA: Hair loss may occur with chronic exposure (Finkel, 1983).

3.4.3)

A) WITH POISONING/EXPOSURE

1) Conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur (Heyman et al, 1956; Grant, 1986).
2) MEDICAL STAFF EXPOSURE: Eye pain was reported in medical staff exposed during treatment of a patient who had ingested arsenic trioxide. Technicians managing removal of the stomach contents in this patient developed corneal epithelial erosion and conjunctiva injection. No long-term sequelae were reported (Kinoshita et al, 2004).
3) CONSTRICTED VISION: A 23-year-old man intentionally ingested 1040 mg of arsenic trioxide (approximately 5 times the lethal dose) and, eight hours later, developed severe weakness, brown watery diarrhea, vomiting, and unquenchable thirst. Over the next 5 hours, the patient consumed a total of 5 liters of water (1 liter/hour) until his abdominal symptoms resolved. Approximately 20 hours post-ingestion, he presented with constricted vision, with an ophthalmic exam confirming bilateral constricted visual fields. Laboratory analysis indicated hemoconcentration (hemoglobin 18 g/dL and hematocrit 53.3%), hyperbilirubinemia (3.1 mg/dL total bilirubin), and blood and urine arsenic concentrations of 41.5 mcg/dL and 5140 mcg/dL, respectively. Despite treatment with BAL, the patient developed, on hospital day 5, hepatic dysfunction, dermatitis, muscle weakness, and peripheral neuropathy. All of the patient's symptoms, including his visual impairment, resolved over the next 3 weeks and he was discharged without sequelae (Kamijo et al, 1998).

B) ANIMAL STUDIES

1) CORNEAL INJURY: In rabbit experiments, arsenic trioxide caused eyelid edema, corneal injury, and corneal opacity (Grant, 1986).

3.4.5)

A) WITH THERAPEUTIC USE

1) Nasal congestion was reported in 4 of 20 (20%) of patients receiving arsenic trioxide for metastatic melanoma (Kim et al, 2005).

B) WITH POISONING/EXPOSURE

1) BURNING: A sensation of burning, dryness and constriction of the oral and nasal cavities may occur (Finkel, 1983; Proctor et al, 1988).

3.4.6)

A) WITH THERAPEUTIC USE

1) Sore throat was reported in 9 of 20 (45%) of patients receiving arsenic trioxide for metastatic melanoma (Kim et al, 2005).

B) WITH POISONING/EXPOSURE

1) BREATH: A garlic-like odor may be detected on the breath (Morgan, 1989).
2) SORE THROAT: Sore throat was reported in 11 of 22 medical staff exposed during treatment of a patient with arsenic trioxide ingestion (Kinoshita et al, 2004).

Cardiovascular

3.5.1)

A) WITH THERAPEUTIC USE

1) Tachycardia, QT prolongation and ventricular dysrhythmias have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

3.5.2)

A) VENTRICULAR TACHYCARDIA

1) WITH THERAPEUTIC USE

a) Prolonged QT intervals occurred in 8 of 8 patients during induction therapy, premature ventricular contractions (PVCs) occurred during 8 of 12 courses of therapy, and 4 of 8 patients developed nonsustained ventricular tachycardia requiring treatment with antiarrhythmic medications in a phase II prospective study of 8 patients with relapsed acute promyelocytic leukemia receiving arsenic trioxide. Long QTc intervals (greater than 440 ms) were present in 4 of 8 patients before arsenic trioxide therapy; there were no prolongations of the PQ interval or QRS duration. Monomorphic ventricular tachycardia (3 or greater successive PVCs that stopped spontaneously within 30 seconds) occurred in 4 patients who received treatment with either mexiletine or lidocaine; sustained ventricular tachycardia or polymorphic ventricular tachycardia did not occur. Arsenic trioxide was administered as a 2-hour daily infusion (maximum 60 days) at a dose of 0.15 mg/kg (Ohnishi et al, 2000).
b) CASE REPORT: Refractory ventricular tachycardia, which included torsades de pointes occurred in a 29-year-old man with acute promyelocytic leukemia treated with arsenic trioxide. The patient died within 24 hours after onset of the dysrhythmias with a postmortem blood arsenic level of 69 mcg/L. No alternative cause was found by the authors to explain the cardiac effects observed (Olmedo et al, 1999).

B) TORSADES DE POINTES

1) WITH THERAPEUTIC USE

a) Torsade de pointes ventricular arrhythmias developed in 3 of 19 patients in a clinical trial of arsenic trioxide treatment of hematologic malignancies. Pretreatment QTc intervals and echocardiography were normal in all 3 patients (Unnikrishnan et al, 2001).

1) A 29-year-old man with acute myeloid leukemia (AML) in third relapse with prior anthracycline treatment (72 mg/square meter (mg/m(2)) idarubicin and 36 mg/m(2) mitoxantrone) received 20 mg of arsenic trioxide daily and developed sensory polyneuropathy, blastic leukocytosis with increased pulmonary infiltrates, fluid overload, capillary leak syndrome, and respiratory distress requiring intubation on day 42 of treatment. Premature ventricular contractions and ventricular tachycardia developed with prolongation of QTc interval on electrocardiography (ECG). ECG returned to normal after treatment with lidocaine, bretylium, magnesium, and multiple cardioversions, but ventricular tachycardia with the morphology of torsade de pointes recurred and cardioversion was unsuccessful (Unnikrishnan et al, 2001).
2) A 79-year-old woman with relapsed myelodysplastic syndrome evolving into AML (no prior anthracycline therapy) developed urosepsis, fluid overload, and dyspnea requiring intubation on day 16 of arsenic trioxide therapy (20 mg daily). The QTc interval was prolonged, cardiac enzyme levels were normal, and episodes of torsade de pointes developed, which were successfully treated with intravenous magnesium and correction of the potassium level. The patient died of hemoptysis with sinus bradycardia leading to asystole (Unnikrishnan et al, 2001).
3) A 43-year-old man with refractory AML after 4 cycles of induction (72 mg/m(2) idarubicin and 36 mg/m(2) mitoxantrone total) developed prolongation of QTc interval after 7 days of treatment with arsenic trioxide (10 mg daily). QTc intervals gradually shortened after discontinuing arsenic trioxide, but the patient was intubated for respiratory distress 12 days after the start of arsenic trioxide treatment and developed ventricular tachycardia with the morphology of torsade de pointes; multiple cardioversions were unsuccessful. The authors suggest that the delayed onset of torsade de pointes arrhythmia may result from an accumulation of arsenic trioxide in tissue. They recommend treatment with isoproterenol to shorten the QTc interval and increase the heart rate and consideration of overdrive pacing if medical therapy fails (Unnikrishnan et al, 2001).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

D) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) Myocardial congestion was found at postmortem in a 28-year-old man who ingested 75 grams of arsenic trioxide and a bottle of vodka (Jolliffe et al, 1991). Coronary circulation appeared normal.

E) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) Electrocardiographic abnormalities, including prolongation of the QTc interval, T-wave flattening, and atrioventricular (AV) block, have been occasionally observed during therapy of acute promyelocytic leukemia (Huang et al, 1998a; Shen et al, 1997a; Soignet et al, 1998a). Complete AV block requiring a permanent pacemaker was observed in one patient during induction therapy (10 mg daily); the patient died of interstitial pneumonitis after a 28-day course. Necropsy revealed high arsenic concentrations in myocardium and lung tissue (Huang et al, 1998a). However, this patient had received prior doxorubicin, therefore the role of arsenic is unclear.
b) In one study, non-sustained ventricular tachycardia occurred in 4 of 8 (50%) patients receiving 0.15 mg/kg/day of arsenic trioxide for acute promyelocytic leukemia (Ohnishi et al, 2000a).
c) CASE REPORT: A 29-year-old man was treated with 20 mg/day of arsenic trioxide for relapsed acute promyelocytic leukemia. He had received previous anthracycline treatment with idarubicin and mitoxantrone. On day 42 of treatment he was intubated for respiratory distress and had ventricular tachycardia. Potassium and magnesium levels were 3.3 mEq/L and 1.7 mg/dL, respectively. EKG normalized following cardioversion and treatment with lidocaine, bretylium and magnesium. Over the next several hours, recurrent torsades de pointes occurred, which was ultimately fatal (Unnikrishnan et al, 2001a).
d) CASE REPORT: Complete atrial-ventricular heart block requiring a permanent pacemaker was reported in a patient given arsenic trioxide in the treatment of acute promyelocytic leukemia. The patient died of idiopathic interstitial pneumonitis soon after the first course of therapy; elevated arsenic levels were found in the heart and lung tissue at necropsy (Huang et al, 1998b).

2) WITH POISONING/EXPOSURE

a) BRADYCARDIA: A 28-year-old man developed bradycardia and then asystole 16 hours after ingestion of 75 grams of arsenic trioxide and a bottle of vodka (Jolliffe et al, 1991). No dysrhythmia occurred during the previous 12 hour observation period.

F) PROLONGED QT INTERVAL

1) WITH THERAPEUTIC USE

a) In one study, QTc interval prolongation greater than 500 msec was present on at least one ECG tracing in 40% (16 of 40) of relapsed or refractory APL patients treated with arsenic trioxide (0.15 mg/kg/day). QTc prolongation occurred between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks after infusion. One patient experienced torsade de pointes ventricular arrhythmia and 2 patients experienced atrial dysrhythmias (Prod Info TRISENOX(R) injection, 2005).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: Of 7 patients with relapsed acute promyelocytic leukemia treated with arsenic trioxide, three developed prolongation of the QTc after an average of 1 to 3 treatments (Huang et al, 1998b).
b) Cardiac QT prolongation greater than 500 ms was observed following an IV infusion of arsenic trioxide for leukemia treatment (Tsuji et al, 2004).

G) EDEMA

1) WITH THERAPEUTIC USE

a) Nonspecific edema (40%) and weight gain (13%) have been reported with arsenic trioxide therapy (Prod Info TRISENOX(R) injection, 2005). Both were common (86% of patients) in another small study using doses of 10 mg daily, and were frequently associated with pleural or pericardial effusion. The onset of edema was 4 to 24 days and it tended to correlate with leukocytosis. Dexamethasone was ineffective as treatment, and symptoms subsided with continuation of arsenic trioxide following reductions in white count (Huang et al, 1998a). Weight gain and fever, attributed to the retinoic acid syndrome, have also been infrequently observed in other studies (Carlson, 1999a; Soignet et al, 1998a).

Respiratory

3.6.1)

A) WITH THERAPEUTIC USE

1) Cough and dyspnea have been described during therapeutic use. Respiratory failure consistent with ARDS has also been reported with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.

3.6.2)

A) ACUTE RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) Acute respiratory failure presumably from severe weakness of respiratory muscles has been seen in a patient with severe arsenic poisoning (Greenberg et al, 1979). The condition progressed despite dimercaprol therapy and required ventilatory assistance for one month.

B) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) A patient receiving arsenic trioxide (0.25 mg/kg/d for 5 days, repeated over 4 weeks) for a germ cell tumor with known pulmonary metastases developed an ARDS-like syndrome leading to respiratory failure and death (Beer et al, 2006).

2) WITH POISONING/EXPOSURE

a) Pulmonary edema, either noncardiogenic from capillary leaking, or cardiogenic from myocardial depression, may occur and be life-threatening (Morgan, 1989).
b) Pulmonary edema was seen at autopsy in a worker who was buried under arsenic trioxide at a smelter (Gerhardsson et al, 1988).
c) Adult respiratory distress syndrome (ARDS) has been reported (Zaloga et al, 1970; Schoolmeester & White, 1980).
d) Two adult patients simultaneously poisoned with arsenic trioxide developed respiratory distress requiring intubation and mechanical ventilation 8 days after ingestion. Chest x-ray findings and hemodynamic parameters obtained by pulmonary artery catheterization were consistent with ARDS (Bolliger et al, 1992).

C) DYSPNEA

1) WITH THERAPEUTIC USE

a) Dyspnea (53%) was reported in a study of 40 patients with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

D) EPISTAXIS

1) WITH THERAPEUTIC USE

a) Epistaxis (25%) was reported in a study of 40 patients with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

E) COUGH

1) WITH THERAPEUTIC USE

a) Cough (65%) was reported in a study of 40 patients with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

F) HYPOXIA

1) WITH THERAPEUTIC USE

a) Hypoxia (23%) was reported in a study of 40 patients with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

G) PLEURAL EFFUSION

1) WITH THERAPEUTIC USE

a) CASE SERIES: Pleural effusion associated with fluid retention occurred in 71% (5/7) of patients treated with arsenic trioxide 10 mg daily for acute promyelocytic leukemia; this complication resolved gradually (paralleling resolution of leukocytosis) (Huang et al, 1998b).
b) Pleural effusion (20%) was also reported in a study of 40 patients with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

H) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) One case of idiopathic interstitial pneumonitis with RESPIRATORY FAILURE, resulting in death, has been reported during induction therapy (10 mg daily). Complete atrioventricular (AV) block preceded pneumonitis (Huang et al, 1998a). Although high arsenic concentrations were detected in the lung, the contribution of arsenic to these complications was not clearly established.

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

1) Peripheral neuropathy has been described during therapeutic use.

B) WITH POISONING/EXPOSURE

1) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common.

3.7.2)

A) PAIN

1) WITH THERAPEUTIC USE

a) In clinical trials (n=40), non-specific pain (15%) was reported (Prod Info TRISENOX(R) injection, 2005).

B) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) Three patients developed acute encephalopathy (i.e., confusion, word-finding difficulties, and behavioral changes) and peripheral neuropathy after receiving 1 cycle of arsenic trioxide therapy, 0.24 mg/kg/day on days 1 through 6 weekly for 4 weeks, for the treatment of metastatic urothelial carcinoma. Symptoms appeared between days 21 to 27, and spontaneously resolved in 1 patient. The other two patients gradually developed paralysis of all 4 limbs and inaudible speech. They subsequently died of progressive urothelial carcinoma on day 47 and day 90, respectively (Lin et al, 2008). The authors speculated that the neurologic toxicity in these patients may have been secondary to occult thiamine deficiency exacerbated by arsenic administration.

2) WITH POISONING/EXPOSURE

a) Toxic delirium and encephalopathy are complications of acute arsenic poisoning (Jenkins, 1966).
b) The encephalopathy may be permanent and result in cortical atrophy one to six months after exposure (Fincher & Koerker, 1987). Early institution of chelation therapy may not be successful in preventing arsenic encephalopathy (Fincher & Koerker, 1987). However, BAL has been reported to reverse the encephalopathy seen after chronic arsenic exposure (Freeman & Couch, 1978; Beckett et al, 1986).

C) SECONDARY PERIPHERAL NEUROPATHY

1) WITH THERAPEUTIC USE

a) Two patients developed mixed sensory and motor neuropathy 6 to 8 weeks after initiation of arsenic trioxide therapy that were being treated for relapsed acute promyelocytic leukemia. Dosing regimen was 10 mg arsenic trioxide daily for 28 days, repeated every 2 weeks until remission occurred (Huang et al, 1998c).
b) Three patients developed lower extremity numbness and acute encephalopathy after receiving 1 cycle of arsenic trioxide therapy, 0.24 mg/kg/day on days 1 through 6 weekly for 4 weeks) for treatment of metastatic urothelial carcinoma. Symptoms appeared between days 21 to 27, and spontaneously resolved in 1 patient. The other two patients gradually developed paralysis of all 4 limbs and inaudible speech. They subsequently died of progressive urothelial carcinoma on day 47 and day 90, respectively (Lin et al, 2008). The authors speculated that the neurologic toxicity in these patients may have been secondary to occult thiamine deficiency exacerbated by arsenic administration.

2) WITH POISONING/EXPOSURE

a) Peripheral neuropathy is common after acute arsenic poisoning. After acute exposure, it commonly begins one to 3 weeks later (Kamijo et al, 1998; Le Quesne & McLeod, 1977; Heyman et al, 1956). It usually begins as paresthesias of the soles of the feet, then the hands, progressing proximally over the next few days (Heyman et al, 1956).
b) Severe muscle weakness and wasting then develops, causing severe disability (Le Quesne & McLeod, 1977). It may initially be confused with Guillain-Barre syndrome (Donofrio et al, 1987). The paresthesias may be painful and are frequently described as severe burning pain in a stocking and glove distribution.
c) SYMPTOMS can persist one to two years following acute poisoning (Vantroyen et al, 2004).
d) PHYSICAL FINDINGS of arsenic neuropathy usually include prominently decreased sensation to touch, pinprick, and temperature, frequently in a stocking and glove distribution (Heyman et al, 1956). Loss of vibration sense is also common. Profound muscle weakness and wasting, distal more so than proximal, is also seen (Donofrio et al, 1987; Heyman et al, 1956). Wrist drop, foot drop, and fasciculations may be seen (Heyman et al, 1956).
e) ELECTRODIAGNOSTIC STUDIES of arsenic neuropathy have shown a reduction of motor conduction velocity and marked abnormalities of sensory nerve action potentials (Le Quesne & McLeod, 1977).
f) NERVE BIOPSY may demonstrate various stages of axonal degeneration without demyelination (Le Quesne & McLeod, 1977) or with demyelination (Donofrio et al, 1987).
g) DIMERCAPROL (BAL) does not seem to be able to reverse arsenic neuropathy (Donofrio et al, 1987; Heyman et al, 1956; Le Quesne & McLeod, 1977); recovery is usually very slow and incomplete. It has been claimed that if BAL is administered within hours of ingestion, however, that neuropathy may be prevented (Jenkins, 1966); although this may not always be true (Marcus, 1987a).
h) DMPS (dimercaptopropanesulfonic acid) may be superior to dimercaprol (BAL) in the treatment or prevention of neuropathy, according to case reports (Wax & Thornton, 2000; Moore et al, 1994).

D) TREMOR

1) WITH THERAPEUTIC USE

a) In clinical trials, tremor occurred in 5 (13%) of 40 patients with refractory or relapsed APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

E) COMA

1) WITH THERAPEUTIC USE

a) In clinical trials, coma occurred in 2 (5%) of 40 patients with refractory or relapsed APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005)

F) SEIZURE

1) WITH THERAPEUTIC USE

a) In clinical trials, seizures occurred in 3 (8%) of 40 patients with refractory or relapsed APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

2) WITH POISONING/EXPOSURE

a) Seizures may occur following an overdose (Prod Info TRISENOX(R) injection, 2005).

G) CEREBRAL ARTERY OCCLUSION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Cerebral infarct, hyperleukocytosis, and death occurred in a 27-year-old woman with relapsed acute promyelocytic leukemia who received arsenic trioxide (0.15 mg/kg/day intravenously) (Roberts et al, 2000).

H) DIZZINESS

1) WITH THERAPEUTIC USE

a) Lightheadedness (during infusion) occurred with variable frequency of arsenic trioxide. Dizziness (23% in n=40) has also been reported with therapeutic use (Prod Info TRISENOX(R) injection, 2005; Shen et al, 1997a; Soignet et al, 1998a).

I) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache has occurred with variable frequency (Soignet et al, 1998a; Shen et al, 1997a) and appeared to be causally related to arsenic trioxide therapy. In a manufacturer's report headache (60%) and insomnia (43%) were reported in patients (n=40) with refractory or relapsed APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

J) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM

1) WITH THERAPEUTIC USE

a) Peripheral neuropathy (or polyneuropathy) has been described in some patients, usually after chronic administration (approximately 10 mg daily for 1 to 2 months) of arsenic trioxide (Huang et al, 1998a; Soignet et al, 1998a). Neuropathy was not completely reversible during follow-up (2 months) in one study. Paresthesia (33%) was also reported in (n=40) patients with refractory or relapsed APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

K) BENIGN INTRACRANIAL HYPERTENSION

1) WITH THERAPEUTIC USE

a) Pseudotumor cerebri (benign intracranial hypertension) or elevated intracranial pressure was observed in a patient with acute promyelocytic leukemia after treatment of a medullary relapse with intravenous arsenic trioxide (10 mg/day). The patient had previously undergone several courses of all-trans retinoic acid treatment without incident prior to relapse. Symptoms of PTC were confined to headache, diplopia, and blurred vision associated with bilateral papilledema and electrophysiological signs of discrete polyneuropathy. Cranial magnetic resonance imaging revealed only the presence of a mild distension of the perioptic subarachnoid space. All signs and symptoms of PTC resolved within 3 weeks of discontinuing arsenic trioxide (Galm et al, 2000).

L) FATIGUE

1) WITH THERAPEUTIC USE

a) Fatigue was reported in 63% of patients (25 of 40) with relapsed or refractory acute promyelocytic leukemia (APL) who received arsenic trioxide at a dose of 0.15 mg/kg/day (Prod Info TRISENOX(R) injection, 2005). Other studies report fatigue has occurred with variable frequency and appears to be causally related to arsenic trioxide therapy (Soignet et al, 1998a; Shen et al, 1997a).

2) WITH POISONING/EXPOSURE

a) General fatigue was reported in 12 of 22 medical staff exposed during the treatment of a patient with arsenic trioxide ingestion (Kinoshita et al, 2004).

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Nausea, vomiting and abdominal pain have been described during therapeutic use.

B) WITH POISONING/EXPOSURE

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH THERAPEUTIC USE

a) Nausea, vomiting, anorexia, diarrhea, constipation, and abdominal pain have been common (27% to 86% of patients) with therapeutic use of arsenic trioxide. These complications have generally been tolerable and amenable to treatment, not requiring discontinuation of therapy (Beer et al, 2006; Prod Info TRISENOX(R) injection, 2005; Shen et al, 1997a; Bergstrom et al, 1998; Huang et al, 1998a).

2) WITH POISONING/EXPOSURE

a) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery diarrhea (sometimes described as "rice-water-like"), pain in the extremities and muscles, weakness, and flushing of the skin (Yilmaz et al, 2009; Parent et al, 2006; Kamijo et al, 1998; Gilman et al, 1985; Finkel, 1983). Gastric ulcerations and erosive gastritis have been observed by autopsy and endoscopy following acute ingestions (Yilmaz et al, 2009; Vantroyen et al, 2004; Michaux et al, 2000; Jolliffe et al, 1991a). Ulceration with bowel wall perforation may also occur in the small intestine and colon (Fanton et al, 1999).
b) CASE SERIES: Vomiting was reported in 6 children following ingestion of all or part of an ant bait gel bar containing 0.46% arsenic trioxide (estimated total dose ranging from 5 to 45 mg). One of the children (a 20-month-old girl) also experienced several episodes of diarrhea. Initial urine arsenic concentrations ranged from 1,858 to 13,981 mcg/L. All 6 children recovered following chelation therapy with succimer (Yarris et al, 2008).

Hepatic

3.9.1)

A) WITH THERAPEUTIC USE

1) Elevation of hepatic transaminases may occur.

B) WITH POISONING/EXPOSURE

1) Hepatocellular damage may occur, but is not common. A common post-mortem finding is mitotic activity of hepatocytes.

3.9.2)

A) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) Elevated transaminases were measured in 29 of 76 (38%) patients receiving 10 mg/d of arsenic trioxide for up to 60 days for acute promyelocytic leukemia. Four patients (5.3%) experienced grade 4 toxicity (transaminase levels > 20 times upper normal limit). Transaminase levels normalized upon discontinuation of therapy (Mathews et al, 2006).
b) CASE SERIES: Elevated serum transaminase levels were reported in 19% (2/7) of patients treated with arsenic trioxide for acute promyelocytic leukemia (Huang et al, 1998b).

2) WITH POISONING/EXPOSURE

a) Hepatic dysfunction may occur after acute arsenic poisoning (Kamijo et al, 1998), but is not common (Donofrio et al, 1987). Elevated transaminases can be seen in the context of multi-organ failure following severe acute poisoning (Parent et al, 2006; Bolliger et al, 1992). Mitotic activity of hepatocytes may be a common post-mortem finding in arsenic poisoning (Mackell et al, 1985). Liver enlargement with fatty infiltration has also been reported postmortem (Fanton et al, 1999; Jolliffe et al, 1991a).

B) INCREASED LIVER ENZYMES

1) WITH THERAPEUTIC USE

a) Serum transaminase elevation, alkaline phosphatase elevation, and elevated bilirubin have been observed in approximately 15% to 20% of acute promyelocytic leukemia patients (Prod Info TRISENOX(R) injection, 2005; Shen et al, 1997a; Huang et al, 1998a). These changes were not severe enough to warrant discontinuation of therapy.

C) INJURY OF LIVER

1) WITH THERAPEUTIC USE

a) Severe hepatotoxicity occurred in 63.7% (7 of 11) of newly diagnosed acute promyelocytic leukemia (APL) patients receiving a 10-mg daily intravenous infusion of arsenic trioxide and was fatal in two of the cases. Serum glutamic pyruvic transaminase (SGPT) ranged from 82 to 918 International Units/Liter; serum glutamic oxaloacetic transaminase (SGOT) ranged from 58 to 934 International Units/L. Discontinuance of arsenic trioxide and symptomatic treatment led to recovery in 5 patients; 2 patients developed lethal hepatic damage despite intensive supportive care. A 33-year-old woman with no previous history of hepatitis continued treatment for 10 days, and died on day 15 with an SGPT of 918 International Units/L and SGOT of 934 International Units/L. A 34-year-old woman with no prior liver dysfunction developed liver toxicity one week after induction therapy; she died of cerebral hemorrhage and severe liver impairment with SGPT of 900 International Units/L and SGOT 905 International Units/L. In the same study, 32% (15 of 47) of relapsed APL patients developed modest hepatotoxicity (14 grade 1; 1 grade 2) which responded to symptomatic treatment (Niu et al, 1999).
b) In one study, in a cohort of patients (n=73) with newly diagnosed APL, the effect of genetic polymorphisms on the incidence of hepatotoxicity was evaluated. Arsenic trioxide was associated with minimal hepatic toxicity. However, in patients with homozygous mutation polymorphism of methylene tetrahydrofolate reductase (MTHFR) 1298 (C/C), the risk of developing hepatotoxicity was significantly higher (P=0.004). It was hypothesized that polymorphisms of the MTHFR gene have an effect on arsenic trioxide methylation, which is an important pathway of biotransformation. Additionally, glutathione S-transferase (GST) M1 null genotype was associated with a 3.28-fold increased risk of hepatotoxicity (P=0.06) (Mathews et al, 2006a).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.

3.10.2)

A) INCONTINENCE

1) WITH THERAPEUTIC USE

a) In clinical trials, (n=40), 5% of patients developed incontinence after receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

B) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) In clinical trials, (n=40), renal failure (8%), renal impairment (8%), and oliguria (5%) occurred after patients received arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

2) WITH POISONING/EXPOSURE

a) Anuria, hematuria, proteinuria (Zaloga et al, 1970; Schoolmeester & White, 1980), acute tubular necrosis, renal failure (Giberson et al, 1976; Vaziri et al, 1980), and chronic renal insufficiency from cortical necrosis have been described (Gerhardt et al, 1978). Renal failure may also occur as a complication of rhabdomyolysis (Fanton et al, 1999).
b) CASE REPORT: Acute renal failure secondary to acute tubular necrosis was suspected in a 77-year-old man who ingested 4 grams of arsenic trioxide in a suicide attempt. Five hours post-ingestion, the patient presented with nausea and vomiting. An initial abdominal radiograph showed the presence of radiopaque material in his stomach and small intestine, and initial laboratory data revealed elevated BUN and serum creatinine concentrations (62 mg/dL, and 1.6 mg/dL, respectively). On day 1, urinalysis demonstrated pyuria, proteinuria, and microscopic hematuria, and on day 5, the 24-hour urine arsenic concentration was 99.5 mcg/day (normal less than 50 mcg/day), with a creatinine clearance of 53.47 mL/min. With supportive care, the patient's renal function gradually normalized within 2 months post-ingestion (Yilmaz et al, 2009).

C) TOXIC NEPHROPATHY

1) WITH THERAPEUTIC USE

a) Although isolated cases of renal failure have been reported during arsenic trioxide therapy of acute promyelocytic leukemia, a clear relationship to arsenic trioxide could not be established (Soignet et al, 1998a; Huang et al, 1998a).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been reported following acute exposure and therapeutic use.

3.11.2)

A) ACIDOSIS

1) WITH THERAPEUTIC USE

a) Acidosis was reported in 5% of patients (n=40) receiving arsenic trioxide (0.15 mg/kg/day) for relapsed or refractory APL (Prod Info TRISENOX(R) injection, 2005).

2) WITH POISONING/EXPOSURE

a) Metabolic acidosis was noted prior to death in a worker who died from acute arsenic poisoning after being buried in crude arsenic trioxide at a copper smelting facility (Gerhardsson et al, 1988).

Hematologic

3.13.1)

A) WITH THERAPEUTIC USE

1) Anemia, neutropenia and thrombocytopenia have been seen with therapeutic use.

B) WITH POISONING/EXPOSURE

1) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.

3.13.2)

A) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Hemolysis may occur after acute arsenic poisoning (Kyle & Pease, 1965).

B) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Anemia has been reported in 35% to 45% of patients receiving therapeutic doses of arsenic trioxide. Neutropenia has been reported in up to 55% of patients. Thrombocytopenia appears to occur less commonly (Beer et al, 2006; Kim et al, 2005).

2) WITH POISONING/EXPOSURE

a) After either acute or chronic arsenic exposure, pancytopenia may be seen (Kyle & Pease, 1965; Kjeldsberg & Ward, 1972). However, isolated leukopenia or anemia may also be seen. The anemia is usually normochromic and normocytic, but may be hypochromic and microcytic (Kyle & Pease, 1965).
b) Bone marrow aspirate may demonstrate pronounced erythroid hyperplasia similar to that seen with pernicious anemia (Selzer & Ancel, 1983). Basophilic stippling and rouleau formation of red cells may also be seen (Kyle & Pease, 1965).

C) LEUKOCYTOSIS

1) WITH THERAPEUTIC USE

a) A marked leukocytosis has been observed in up to 50% of patients with acute promyelocytic leukemia (APL) during arsenic trioxide therapy (Prod Info TRISENOX(R) injection, 2005; Niu et al, 1999; Shen et al, 1997a; Soignet et al, 1998a; Huang et al, 1998a). This "hyperleukocytosis" is seen as early as one week after initiation of therapy, and is similar to that observed with tretinoin, although it is less common with arsenic trioxide. The Sloan-Kettering protocol is to withhold therapy in these patients, which has resulted in resolution of leukocytosis as patients entered remission (Soignet et al, 1998a; Carlson, 1999a). Hyperleukocytosis was associated with cerebral infarct and death in a single case study (Roberts et al, 2000).
b) HYPERLEUKOCYTOSIS, cerebral infarct, and death occurred in a 27-year-old woman with relapsed acute promyelocytic leukemia who received arsenic trioxide (0.15 mg/kg/day intravenously). The patient presented with a white blood cell (WBC) count of 21.2 X 10(3)/microliter (mcL) and a platelet count of 19 X 10(3)/mcL six months after completion of consolidation treatment with idarubicin, cytarabine, and all-trans-retinoic acid (ATRA) preceded by induction with ATRA. At the initiation of arsenic trioxide treatment, her WBC count was 8.2 X 10(3)/mcL; after three doses of arsenic trioxide, WBC count was 20.9 X 10(3)/mcL and corticosteroid therapy was started. Arsenic trioxide was discontinued following the 8th dose with a WBC count of 212.6 X 10(3)/mcL, a platelet count of 30 X 10(3)/mcL, and the first evidence of DISSEMINATED INTRAVASCULAR COAGULATION (DIC). The patient exhibited slurred speech, right-sided weakness, and confusion and was found to have a cerebral infarct. She was treated with Decadron(R) (dexamethasone) and platelet transfusions, but had a seizure, diffuse cerebral edema, and signs of central herniation. Chemotherapy with idarubicin and cytarabine was unsuccessful and the patient died on the 15th day of hospitalization (Roberts et al, 2000).
c) Hyperleukocytosis (white blood cell (WBC) count equal to or greater than 10 X 10(3)/microliter) developed in 20 of 40 patients receiving arsenic trioxide (15 mg/kg/day). WBC counts were higher during induction treatment than during consolidation. Hyperleukocytosis was not treated with additional chemotherapy. Hyperleukocytosis was considered a serious adverse event (grade 3 or 4 of the NCI Common Toxicity Criteria) in 3 of 40 patients evaluated for safety (Prod Info TRISENOX(R) injection, 2005).
d) Hyperleukocytosis occurred in 55% (26 of 47) of relapsed acute promyelocytic leukemia (APL) patients after 1 to 43 days of treatment, and in 72.7% (8 of 11) of newly diagnosed APL patients before, or 5 to 20 days after, receiving a 10 mg daily intravenous dose of arsenic trioxide. In the 26 relapsed APL patients with hyperleukocytosis, spontaneous decline of WBC occurred in 14, decline of WBC following chemotherapy occurred in 4 (including one patient who developed ARDS on day 22 of treatment), and 1 patient died of cerebral hemorrhage. In the 8 newly diagnosed patients, spontaneous decline of WBC occurred in 4, WBC decline following chemotherapy occurred in 2, and 2 patients died (Niu et al, 1999).
e) RETINOIC ACID SYNDROME (RAS) with leukocytosis (36.65 X 10(9)/L), fever, skin rash, and lower leg edema was observed in a 37 year-old female receiving arsenic trioxide at a dose of 10 mg/day for relapsed acute promyelocytic leukemia (APL); the patient had previously experienced RAS when all-trans retinoic acid (ATRA) was used as remission induction therapy. All symptoms resolved after 7 days of treatment with prednisolone (30 mg/day in divided doses), and arsenic trioxide therapy was continued for 2 courses of 30 days each (Lin et al, 2000).

D) MYELOSUPPRESSION

1) WITH THERAPEUTIC USE

a) Anemia (20%), thrombocytopenia (18%), neutropenia (10%), and febrile neutropenia (13%) were reported in patients (n=40) with relapsed or refractory APL receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

1) Compared to APL patients treated with tretinoin (indirect comparison), delays in platelet count recovery and resolution of coagulopathy have been evident with arsenic trioxide therapy (Carlson, 1999a).

E) COAG./BLEEDING TESTS ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old man developed coagulation abnormalities with an activated partial thrombin time of 95 sec (normal 29 to 35 sec), an INR of 1.97, and decreased coagulation factors II, VII, and X following ingestion of up to 10 grams of arsenic trioxide (Parent et al, 2006).

F) ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Anemia was reported in a 77-year-old man following intentional ingestion of 4 grams of arsenic trioxide. Initial laboratory data, obtained approximately 5 hours post-ingestion, revealed a hemoglobin level of 13.5 g/dL; however, by day 7, the patient's hemoglobin had decreased to 8.7 g/dL, although he did not show any signs of hemolysis. With supportive care, the patient's anemia gradually resolved, with a hemoglobin level of 13.7 g/dL at his 5-month follow-up appointment (Yilmaz et al, 2009). The authors speculated that inhibition in erythroid colony formation by arsenic may have been a cause of the patient's anemia.

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

1) Skin rash, dryness and hyperpigmentation and other dermatologic effects have been reported with therapeutic use.

B) WITH POISONING/EXPOSURE

3.14.2)

A) DISORDER OF SKIN

1) WITH THERAPEUTIC USE

a) A non-specific rash developed in 13 of 20 (65%) patients receiving therapeutic doses of arsenic trioxide (Kim et al, 2005). Typical palmar keratosis and hyperpigmentation have also been described during therapy (Huang et al, 1998c).

2) WITH POISONING/EXPOSURE

a) Common skin findings after either acute or chronic arsenic poisoning may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation(Heyman et al, 1956), and exfoliative dermatitis (Parent et al, 2006; Kamijo et al, 1998; Hutton & Christians, 1983; Schoolmeester & White, 1980; Zaloga et al, 1970) .

B) DRY SKIN

1) WITH THERAPEUTIC USE

a) Skin dryness has occurred relatively frequently during therapy with recommended doses arsenic trioxide (i.e., approximately 10 mg daily), usually during induction (Shen et al, 1997a; Huang et al, 1998a; Bergstrom et al, 1998). In clinical trials, (n=40) 15% of patients reported dry skin after receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005). FLUSHING has also occurred during intravenous infusion (Carlson, 1999a)

C) ARSENICAL KERATOSIS

1) WITH THERAPEUTIC USE

a) Palmar keratosis and skin hyperpigmentation have occurred in some patients (Huang et al, 1998a). All cutaneous effects were either tolerable or resolved with local treatment, and did not require interruption of arsenic trioxide therapy.

D) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) Pruritus and rashes have occurred relatively frequently during therapy with recommended doses (i.e., approximately 10 mg daily), usually during induction (Shen et al, 1997a; Huang et al, 1998a; Bergstrom et al, 1998). In another study (n=40) 33% of patients reported pruritus after receiving arsenic trioxide (0.15 mg/kg/day) (Prod Info TRISENOX(R) injection, 2005).

E) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Contact dermatitis, and reddish and swollen skin without blister formation were reported in medical staff exposed during treatment of a patient who had ingested arsenic trioxide. No long-term sequelae were reported (Kinoshita et al, 2004).
b) SENSITIZATION: Arsenic trioxide can cause contact dermatitis (OSHA, 1988).

F) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) Stevens Johnson syndrome developed in a 42-year-old woman 4 days after the application of arsenic trioxide for devitalization of a gangrenous tooth pulp (Vassileva et al, 1990).

G) MEE'S LINE

1) WITH POISONING/EXPOSURE

a) Transverse white striae of the nails may be seen after acute exposure. Mee's lines commonly take 5 weeks to appear above the cuticle and advance 1 mm per week afterwards, allowing an approximation of the time of acute exposure (Heyman et al, 1956).

Musculoskeletal

3.15.2)

A) PAIN

1) WITH THERAPEUTIC USE

a) Myalgia, arthralgia, and bone pain have been reported with variable frequency during therapy (Prod Info TRISENOX(R) injection, 2005; Shen et al, 1997a; Soignet et al, 1998a).

B) MUSCLE ATROPHY

1) WITH THERAPEUTIC USE

a) Muscular weakness with atrophy of the hands and legs has been described rarely in association with polyneuropathy related to chronic arsenic trioxide administration; muscle biopsy has revealed changes consistent with arsenic toxicity (denervated and degenerated myopathy) (Huang et al, 1998a). Non-specific weakness has also been reported (10%) (Prod Info TRISENOX(R) injection, 2005).

2) WITH POISONING/EXPOSURE

a) Muscle weakness with bilateral footdrop was reported in a 23-year-old man who intentionally ingested 1040 mg of arsenic trioxide (Kamijo et al, 1998).

C) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 30-year-old man developed severe rhabdomyolysis within 48 hours of ingesting 8 g of arsenic trioxide. CK level reached 125,500 International Units/L with a potassium level of a 6.74 mEq/L (Fanton et al, 1999).
b) CASE REPORT: After ingestion of 20 g of arsenic trioxide, a 23-year-old man developed rhabdomyolysis and multi-organ failure and died 80 hours after ingestion (Sanz et al, 1989). Autopsy demonstrated loss of striation and centralization of the nuclei in pectoral muscles.

Endocrine

3.16.1)

A) WITH THERAPEUTIC USE

1) Mild to moderate hyperglycemia has been described with therapeutic use.

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hyperglycemia was reported in 45% of patients (18 of 40) receiving arsenic trioxide (0.15 mg/kg/day) for relapsed or refractory APL and was a serious adverse event (grade 3 or 4 of the NCI Common Toxicity Criteria) in the safety evaluation of 52 patients. Hypoglycemia was reported in 8% (3 of 40) of patients (Prod Info TRISENOX(R) injection, 2005). Mild hyperglycemia was a common complication of arsenic trioxide therapy in one study (Soignet et al, 1998a).

Immunologic

3.19.2)

A) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Arsenical compounds may act as contact allergens in doses too low to produce direct local irritation (HSDB, 2006).

B) LYMPHADENOPATHY

1) WITH THERAPEUTIC USE

a) A single case of angioimmunoblastic lymphadenopathy has been associated with long-term ingestion of an asthma preparation (Gay's solution) containing arsenic trioxide (HSDB, 2006). An elevated serum arsenic level was present. Improvement followed discontinuation of the medication and administration of prednisone (HSDB, 2006).

C) HYPERSENSITIVITY REACTION

1) WITH THERAPEUTIC USE

a) Drug hypersensitivity was reported in 5% of patients (2 of 40) with relapsed or refractory Acute Promeylocytic Leukemia (APL) receiving arsenic trioxide (0.15 mg/kg/day). This was a serious adverse event (grade 3 or 4 of NCI Common Toxicity Criteria) in one patient (Prod Info TRISENOX(R) injection, 2005).
b) A single case of angioimmunoblastic lymphadenopathy has been associated with long-term ingestion of an asthma preparation (Gay's solution) containing arsenic trioxide (HSDB, 2006). An elevated serum arsenic level was present. Improvement followed discontinuation of the medication and administration of prednisone (HSDB, 2006).

Reproductive

3.20.1)

3.20.2)

A) SUMMARY

1) Arsenic is NOT likely to be a significant risk to human reproduction at permissible occupational exposure limits (Council on Scientific Affairs, 1985).
2) While arsenic is likely fetotoxic in humans, data are currently inadequate to determine whether or not such effects could occur in the absence of maternal toxicity (Council on Scientific Affairs, 1985).
3) A study of 11 pregnant women chronically exposed to arsenic through drinking water (200 mcg/L) did not report any fetal malformations (Concha et al, 1998)

B) ANIMAL STUDIES

1) Arsenic compounds have caused teratogenic and embryotoxic effects in the offspring of pregnant mice, rats, hamsters, and primates when administered orally or parenterally (Prod Info TRISENOX(R) intravenous injection, 2015; RTECS, 2006; Schardein, 1985; Council on Scientific Affairs, 1985; Hood, 1972; Baxley et al, 1981). In some hamster experiments, no teratogenic effects were noted (Schardein, 1985; Hood & Harrison, 1982).
2) In rats studies, an increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were noted following arsenic trioxide doses approximately 10 times the recommended human daily dose on a mg/m(2) basis given on gestation day 9. Similar findings were observed in mice given trivalent arsenic, sodium arsenite doses 5 times the projected human dose on a mg/m(2) basis on gestation days 6, 7, 8, or 9. Neural-tube defects occurred in hamsters after intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m(2) basis) on gestation day 7 (Prod Info TRISENOX(R) intravenous injection, 2015).
3) Arsenic trioxide has caused adverse reproductive effects in mice when administered by the oral or inhalation routes (RTECS, 2006).
4) Arsenic trioxide accumulated in the placenta and all fetal organs, especially the liver, when fed to pregnant rats from days 0 through 20 of gestation (Tanaka, 1976).

3.20.3)

A) ACUTE TOXICITY

1) CASE REPORT

a) Use of arsenic trioxide during pregnancy has been associated with infant death, and conversely, normal pregnancy outcomes. Until more information is available, arsenic trioxide should not be used in pregnant women unless the maternal benefit is determined to outweigh the possible risk to the fetus.
b) NEONATAL DEATH: Acute ingestion of arsenic trioxide in a woman with a 30 week pregnancy has been reported to result in the death of the infant born 4 days after the poisoning. The child apparently died of hyaline membrane disease, but did have elevated tissue levels of arsenic. It seems apparent that arsenic can cross the placenta (Lugo et al, 1969).
c) FETAL DEATH: A 39-year-old woman was poisoned by an unknown dose of arsenic trioxide at 28 weeks gestation. The patient suffered multi-organ failure and peripheral neuropathy. Fetal death occurred; the fetus was delivered through prostaglandin-induced abortion 4 weeks after poisoning (Bolliger et al, 1992).
d) One pregnant woman had a miscarriage after receiving arsenic trioxide (Prod Info TRISENOX(R) intravenous injection, 2015).

2) LACK OF EFFECT

a) Six women developing arsenical encephalopathy during the fourth to eighth months of pregnancy delivered normal children (Schardein, 1985).
b) A study of 11 women in late gestation who were chronically exposed to arsenic through drinking water (200 mcg/L). Median blood arsenic level was 11 mcg/L, significantly increasing to 16 mcg/L by 4.4 months postpartum. Median urine total arsenic was 335 mcg/L before delivery, but did not change significantly postpartum. Median cord blood arsenic level was 9 mcg/L and correlated to maternal blood levels. At birth, newborn urine arsenic levels were 23% of maternal levels. This percentage decreased to 9% by age 4.4 months. There was no correlation between maternal arsenic levels and birth weight (Concha et al, 1998).

B) RISK SUMMARY

1) There are no adequate or well controlled studies of arsenic trioxide use during human pregnancy. Arsenic trioxide has been deemed embryolethal and teratogenic following administration in rats at doses approximately 10 times the recommended human dose. Adequate contraception is required for male and female patients of reproductive potential during and after treatment with arsenic trioxide. If pregnancy occurs, apprise patient of the potential for fetal harm (Prod Info TRISENOX(R) intravenous injection, 2015).

C) EPIDEMIOLOGICAL STUDIES

1) Increased rates of spontaneous abortions and decreased birth weights in the offspring were found in a study of women living near a smelter in Sweden which emitted lead, sulfur dioxide, and arsenic (Schardein, 1985). There was no increased incidence of congenital malformations in this group (Schardein, 1985). The significance of this study to pure chronic arsenic exposure during pregnancy is unclear.

D) OCCUPATIONAL EXPOSURE

1) AMA COUNCIL ON SCIENTIFIC AFFAIRS: Although arsenic compounds are likely fetotoxic in humans, exposure at permissible occupational levels is not likely to present a significant risk to human reproduction (Council on Scientific Affairs, 1985).

E) ANIMAL STUDIES

1) Arsenic trioxide accumulates in the placenta and all fetal organs, especially the liver, when fed to pregnant rats from days 0 through 20 of gestation (Tanaka, 1976a).

3.20.4)

A) BREAST MILK

1) No reports describing the use of arsenic trioxide during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. Arsenic is excreted in human milk and may cause serious adverse reactions in nursing infants (Prod Info TRISENOX(R) intravenous injection, 2015; Barlow & Sullivan, 1982a). Due to the potential for adverse effects in the nursing infant, a decision should be made to discontinue treatment or discontinue breastfeeding (Prod Info TRISENOX(R) intravenous injection, 2015). Women chronically exposed to arsenic through drinking water (200 mcg/L) had a median breast milk concentration of 3.1 mcg/kg (Concha et al, 1998).

B) ANIMAL STUDIES

1) Arsenic is excreted in the breast milk in experimental animals (Barlow & Sullivan, 1982).

3.20.5)

A) LACK OF INFORMATION

1) Studies in humans have not been performed.

B) ANIMAL STUDIES

1) RATS: In rats, doses high enough to produce systemic toxicity were necessary, before any effects were observed on the testes. Continuous dietary administration of up to 215 mg/kg of arsenic did not have adverse effects on fertility in male or female rats (Barlow & Sullivan, 1982).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1327-53-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Arsenic trioxide
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

3.21.3)

A) ARSENIC TRIOXIDE INJECTION

1) Human carcinogenicity studies have not been performed using intravenous arsenic trioxide, however, arsenic trioxide is a known human carcinogen (Prod Info TRISENOX(R) intravenous injection, 2015).

B) IARC REVIEW

1) IARC REVIEW - An IARC review found that there is a causal relationship between medicinal, drinking water, or occupational heavy arsenic exposure and skin cancer (IARC, 1973). There is also a clearly increased risk of lung cancer in workers inhaling high levels of arsenic trioxide (IARC, 1973).
2) IARC CANCER REVIEW - Limited Evidence in Humans (1973); Sufficient Evidence in Humans (1980) (RTECS, 2006)
3) IARC CANCER REVIEW - Inadequate Evidence in Animals (1973; 1980) (RTECS, 2006)
4) IARC CANCER REVIEW - Group 1 (RTECS, 2006)
5) NTP LISTING - Arsenic trioxide is listed in the National Toxicology Program (NTP) 11th Annual Report on Carcinogens (RTECS, 2006).
6) OSHA - The Occupational Safety and Health Administration (OSHA) has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow (Anon, 1979). A study of a population in Taiwan drinking high-arsenic concentration artesian well water found a dose-response relationship between the amount of arsenic in the water and the incidence of mortality from bladder, kidney, skin, prostate, lung, and liver cancer (Chen et al, 1988).
7) One worker who was exposed to arsenious oxide and sodium arsenite for 20 years developed cirrhosis of the liver and primary liver carcinoma (Finkel, 1983).

C) EPIDEMIOLOGICAL STUDIES

1) Excess deaths ranging from 2 to 9 times higher than expected from lung cancer have been noted in epidemiologic studies of smelter workers exposed to arsenic trioxide (Enterline & Marsh, 1980; Enterline & Marsh, 1982; Lee-Feldstein, 1986; Lee-Feldstein, 1983). Earlier studies had noted a 12.2 percent higher overall mortality for smelter workers than matched controls living in the same area, with the excess largely due to lung cancer (Pinto et al, 1977; Pinto et al, 1978).

a) Cigarette smoking was ruled out as a contributing factor in some studies (Pinto et al, 1978; Enterline & Marsh, 1980).
b) One study suggested that there is a threshold exposure below which adverse effects are unlikely to be seen (Pinto et al, 1977).
c) Length and degree of exposure were related to the likelihood of developing lung cancer in arsenic-exposed workers (Enterline & Marsh, 1982; Lee-Feldstein, 1986; Lee-Feldstein, 1983).
d) Excess digestive system cancers were also suggested in some studies (Pinto et al, 1977; Enterline & Marsh, 1982).
e) Concurrent moderate to heavy sulfur dioxide exposure may also be required for the development of lung cancer (Lee-Feldstein, 1983; Enterline & Marsh, 1982).

D) SKIN CARCINOMA

1) Basal cell and squamous cell carcinomas of the skin have been described after both acute (Renwick et al, 1981) and chronic (Jackson & Grainge, 1975; Wagner et al, 1979) arsenic exposure. Skin cancers may be of various types, and either multiple sites or multiple types may be seen in the same patient (Sommers & McManus, 1953).
2) Two patients with arsenic-induced basal cell carcinomas of the skin also developed malignancies of other organs (breast and colon) (Jackson & Grainge, 1975).

E) ANIMAL STUDIES

1) RATS - Equivocal tumorigenic agent by RTECS criteria when administered by the intratracheal route (RTECS , 1991).
2) HAMSTERS - Equivocal tumorigenic agent in some studies and neoplastic in others by RTECS criteria when administered by the intratracheal route (RTECS , 1991).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) INTRAVENOUS ROUTE: Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving IV arsenic trioxide. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor the patient for signs of bleeding.
B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
C) Monitor serum electrolytes, liver enzymes, renal function tests, and a blood arsenic concentration in symptomatic patients.
D) OTHER ROUTES: Arsenic testing must be correlated with the time of exposure and care must be taken to eliminate possible confounding factors such as food-derived arsenic (fish) or accumulated arsenic in those with chronic renal failure.
E) Diagnosis is based on elevated urinary arsenic levels. A spot urine may be done as a screen prior to chelation but arsenic excretion is intermittent, therefore a 24-hour urine arsenic collection is necessary for definitive diagnosis. A 24-hour urinary arsenic collection exceeding 100 mcg is usually abnormal, even after chelation.
F) Serial ECGs should be obtained to follow the QTc interval and continuous cardiac monitoring should be instituted in symptomatic patients.
G) Most arsenic compounds are radio-opaque, therefore abdominal X-rays may confirm acute ingestions and guide decontamination.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) An arsenic blood level below 7 mcg/100 mL is considered in the normal range. Levels may be higher in populations with chronic exposure to arsenic. Blood levels are highly variable and may be useful only after acute exposure to confirm the diagnosis; they may become undetectable following acute poisoning at times when urinary arsenic excretion remains substantial (Fesmire et al, 1988). Arsenic moves rapidly from the blood to body tissues, with an estimated distribution half-life of 2 hours (Caravati, 2004).

B) HEMATOLOGY

1) CHRONIC TOXICITY: The following findings were reported following chronic arsenic exposure: leucocytosis followed by leucopenia with depressed neutrophils; thrombocytopenia; rapidly decreasing hemoglobin indicating hemolytic anemia or GI bleed; aplastic anemia; basophilic stippling of erythrocytes; macrocytosis. Also, a reduction in hemoglobin concentration, reduction in total cell counts, and a rise of mean corpuscular volume (MCV) and hemoglobin mass (MCH), indicating an alteration of heme biosynthetic pathways were present (Rahman et al, 2001).

C) BIOCHEMISTRY

1) CHRONIC TOXICITY: Monitor hepatic enzymes and renal function. Elevated serum creatinine transaminases and bilirubin, and depressed haptoglobin levels have been reported following chronic arsenic exposure. Liver histology has shown cirrhosis and noncirrhotic portal fibrosis (Rahman et al, 2001).

D) OTHER

1) CHRONIC TOXICITY: Obtain a skin biopsy as indicated. Carcinomatous changes or Bowen's disease have been described following chronic arsenic exposure (Rahman et al, 2001).

4.1.3)

A) URINARY LEVELS

1) 24-hour urine collections for total arsenic excretion or spot specimens measured as concentration of arsenic (in micrograms or milligrams) per gram of urinary creatinine are generally the preferred samples, as they balance out the effects of varying urine volume and concentration.
2) Ideally, seafood should be avoided for at least several days prior to urine collection.

a) Following a seafood meal, urine arsenic levels may temporally rise to 200 to 1700 mcg/L (Baselt & Cravey, 1989; Baselt, 1988), due to the presence of nontoxic organic arsenic in certain seafoods.

3) A method for a quick urine spot test (Reinsch test) has been described (Grande et al, 1987) but its clinical utility is uncertain. Even with chelation, an unexposed individual should not have more than 100 mcg of arsenic per 24 hour total urine output. Urinary arsenic may be elevated up to 200 to 1700 mcg/L within 4 hours after eating some seafoods (Baselt & Cravey, 1989; Baselt, 1988; Proctor et al, 1988).

a) Samples can be tested (speciation) for various forms of arsenic: inorganic arsenic, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and arsenobetaine. Arsenobetaine is an organic, arsenic-containing compound found in seafood that is non-toxic. MMA and DMA are metabolites of inorganic arsenic (Ford, 2006a). Predominance of arsenobetaine indicates dietary seafood as the source of elevated total arsenic levels.
b) Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure (Proctor et al, 1988).
c) Urine levels are generally below 100 mcg/gram of creatinine, and generally below 20 mcg/gram of creatinine in unexposed individuals (Proctor et al, 1988).

4) A recommended maximum permissible value for arsenic in the urine of exposed workers is 200 micrograms/gram creatinine (HSDB , 1991).

4.1.4)

A) OTHER

1) HAIR

a) Arsenic has been demonstrated in hair and nails within hours after exposure (Lander et al, 1965). Normal concentration of arsenic in hair and nails is less than 1 mg/kg (Baselt & Cravey, 1989; Baselt, 1988).

1) However, many commercial laboratories performing hair analyses for consumers have not been shown to yield consistent and reliable results (Barrett, 1985), and such levels cannot be interpreted in individual patients. Hair samples are prone to external contamination following collection. Hair or nail analysis is only useful in epidemiologic studies to distinguish potentially exposed from unexposed groups.

2) OTHER

a) SPUTUM CYTOLOGY: Periodic sputum cytology examinations have been recommended for workers with chronic arsenic exposure (HSDB , 1991).

Radiographic Studies

1) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected (Hilfer & Mendel, 1962; Gousios & Adelson, 1959).

1) Monitor the chest x-ray in patients who develop pulmonary edema.

Treatment

Life Support

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) There is no data to support home management.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.

6.3.2.4) PATIENT TRANSFER/PARENTERAL

A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Remove the contaminated clothing and wash the patient thoroughly.

6.5.2)

A) SUMMARY: ORAL ROUTE: Activated charcoal does not bind arsenic well. Gastric lavage and whole bowel irrigation should be considered for confirmed significant ingestions. INTRAVENOUS ROUTE: Decontamination is not necessary.
B) GASTRIC LAVAGE

1) Aggressive decontamination with gastric lavage is recommended. If X-ray demonstrates arsenic in the lower GI tract, whole bowel irrigation should be considered. Activated charcoal may not bind significant amounts, but is recommended until definitive quantitative data are available. Fluid repletion should be begun as soon as possible.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) WHOLE BOWEL IRRIGATION (WBI)

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

D) ACTIVATED CHARCOAL

1) Preliminary results suggest that activated charcoal may not be of therapeutic value in the treatment of acute arsenic poisoning (Al-Mahasneh QM & Rodgers GC, 1990).

a) One study has reported no significant adsorption to activated charcoal, but specific quantities bound were not stated (Mitchell et al, 1989).
b) Sodium arsenite (0.65 millimolar) and sodium arsenate (1.7 millimolar) were NOT adsorbed to activated charcoal (in a ratio of 1:10) to any measurable extent in an aqueous acidic solution (simulated gastric juice) that was incubated at 37 degrees C for 30, 60, 120, and 240 minutes in an in vitro model (Al-Mahasneh QM & Rodgers GC, 1990).
c) Solutions incubated for 120 and 240 minutes at pH 10 to 12 (simulated intestinal juices) showed adsorption of 75% to 80% (Al-Mahasneh QM & Rodgers GC, 1990).

E) ENDOSCOPY

1) Endoscopic removal of adherent arsenic was performed in an adult with acute arsenic poisoning. Attempts to remove arsenic from the stomach were unsuccessful, but colonoscopy was reported successful in removal of arsenic from the ascending colon(Duenas-Laita et al, 2005a).

F) GASTROTOMY

1) Gastrotomy with manual removal of adherent arsenic was performed on a patient with persistent evidence of a radio-opaque mass in the stomach, despite gastric lavage and attempted endoscopic removal, after acute arsenic poisoning(Duenas-Laita et al, 2005a). It is unclear how much arsenic was removed.

6.5.3)

A) MONITORING OF PATIENT

1) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving IV arsenic trioxide. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor the patient for signs of bleeding.
2) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
3) Monitor serum electrolytes, liver enzymes, renal function tests, and a blood arsenic concentration in symptomatic patients.
4) Arsenic testing must be correlated with the time of exposure and care must be taken to eliminate possible confounding factors such as food-derived arsenic (fish) or accumulated arsenic in those with chronic renal failure.
5) Diagnosis is based on elevated urinary arsenic levels. A spot urine may be done as a screen prior to chelation but arsenic excretion is intermittent, therefore a 24-hour urine arsenic collection is necessary for definitive diagnosis. A 24-hour urinary arsenic collection exceeding 100 mcg is usually abnormal, even after chelation.
6) Serial ECGs should be obtained to follow the QTc interval and continuous cardiac monitoring should be instituted in symptomatic patients.
7) Most arsenic compounds are radio-opaque, therefore abdominal X-rays may confirm acute ingestions and guide decontamination.

B) CHELATION THERAPY

1) The use of chelation therapy depends on the clinical condition of the patient and arsenic concentrations in urine. BAL and succimer are chelating agents used as antidotal therapy for arsenic toxicity. Begin chelation therapy immediately in a severely ill patient with known or suspected acute arsenic poisoning (Ford, 2006).
2) END POINT: Repeat courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 mcg/L (Ford, 2006).

C) DIMERCAPROL

1) Dimercaprol (BAL) is an effective arsenic chelator but has the disadvantages of requiring painful intramuscular injections and having numerous side effects.
2) DOSE: The dose used is dependent on the severity of the patient's symptoms and the urinary arsenic levels.

a) DIMERCAPROL/BAL IN OIL: INDICATIONS: Used for the treatment of mercury (inorganic and elemental), arsenic, and gold poisoning. It is also used in combination with Edetate Calcium Disodium injection to treat patients with severe lead poisoning (Prod Info BAL In Oil intramuscular injection, 2008). Dimercaprol is contraindicated in methyl mercury poisoning (Howland, 2002; Clarkson, 1990).
b) MILD ARSENIC OR GOLD POISONING: DOSE: 2.5 mg/kg 4 times daily for 2 days, 2 times on the third day, and once daily thereafter for 10 days. SEVERE ARSENIC OR GOLD POISONING: DOSE: 3 mg/kg every 4 hours for 2 days, 4 times on the third day, then twice daily thereafter for 10 days. Administered by deep intramuscular injection only (Prod Info BAL In Oil intramuscular injection, 2008).
c) MERCURY POISONING: DOSE: 5 mg/kg initially, then 2.5 mg/kg 1 or 2 times daily for 10 days. Administered by deep intramuscular injection only (Prod Info BAL In Oil intramuscular injection, 2008).
d) ACUTE LEAD ENCEPHALOPATHY: DOSE: 4 mg/kg is given alone in the first dose and thereafter at 4-hour intervals with Edetate Calcium Disodium injection administered at a separate site. For less severe poisoning, dimercaprol dose can be decreased to 3 mg/kg after the first dose. Administered by deep intramuscular injection only. Continue the treatment for 2 to 7 days depending on clinical response (Prod Info BAL In Oil intramuscular injection, 2008). Therapy is generally switched to a less toxic oral chelator as soon as tolerated.
e) ADVERSE EFFECTS: Common effects include pain at the injection site and fever (especially in children). Other effects include hypertension, tachycardia, nausea, vomiting, headache, burning sensations of the mouth and throat, a sensation of constriction in the throat, chest, or hands, conjunctivitis, lacrimation, salivation, tingling of the extremities, diaphoresis, abdominal pain, and anxiety. Dimercaprol injection contains peanut oil. Avoid in patients with peanut allergy (Prod Info BAL In Oil intramuscular injection, 2008). Adverse effects are dose related; they develop in 1% of patients receiving 2.5 mg/kg every 4 to 6 hours, 14% of patients receiving 4 mg/kg every 4 to 6 hours and 65% of patients receiving 5 mg/kg every 4 to 6 hours (Eagle & Magnuson, 1946).
f) PRECAUTIONS: It is generally contraindicated in patients with hepatic insufficiency, with the exception of postarsenical jaundice (Prod Info BAL In Oil intramuscular injection, 2008). May cause hemolysis in G6PD deficient patients. BAL metal chelate disassociates in acid environment; urinary alkalinization is usually recommended. Do not administer with iron therapy as BAL iron complex may cause vomiting (Howland, 2002).

3) EFFICACY

a) CHILDREN: BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948). It has also been reported to effect complete recovery in a woman and her 20-week fetus after an acute ingestion of inorganic arsenic by the mother (Daya et al, 1989).
b) ANIMAL DATA: BAL has been shown to reduce the organ deposition of arsenic in a rabbit model using subcutaneous injections of Lewisite at the LD10 and LD40 and 4 doses of BAL of 35 mg/kg each (Snider et al, 1990).

D) SUCCIMER

1) INDICATIONS: Succimer is an orally administered chelator approved for use in children with lead poisoning (Prod Info CHEMET(R) oral capsules, 2005). Succimer has been efficacious in children and adults with arsenic poisoning (Cullen et al, 1995; Fournier et al, 1988; Kosnett & Becker, 1987; Lenz et al, 1981).
3) SUCCIMER/DOSE/ADMINISTRATION

a) PEDIATRIC: Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval is then increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless blood lead concentrations indicate the need for prompt retreatment.
2) Succimer capsule contents may be administered mixed in a small amount of food (Prod Info CHEMET(R) oral capsules, 2011).

b) ADULT: Succimer is not FDA approved for use in adults, however it has been shown to be safe and effective when used to treat adults with poisoning from a variety of heavy metals (Fournier et al, 1988a). Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval then is increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless the patient's symptoms or blood concentrations indicate a need for more prompt treatment (Prod Info CHEMET(R) oral capsules, 2011).

4) MONITORING PARAMETERS

a) The manufacturer recommends monitoring liver enzymes and complete blood count with differential and platelet count prior to the start of therapy and at least weekly during therapy (Prod Info CHEMET(R) oral capsules, 2011).
b) Succimer therapy did not worsen preexisting borderline abnormal liver enzyme levels in a prospective evaluation of 15 children with lead poisoning (Kuntzelman & Angle, 1992).

5) SUCCIMER/ADVERSE EFFECTS: The following adverse events have occurred in children and adults during clinical trials: nausea, vomiting and diarrhea; transient liver enzyme elevations; rash, pruritus; drowsiness and paresthesia. Events reported infrequently include: sore throat, rhinorrhea, mucosal vesicular eruption, thrombocytosis, eosinophilia, and mild to moderate neutropenia (Prod Info CHEMET(R) oral capsules, 2011).
6) ODOR: Succimer has a sulfurous odor that may be evident in the patient's breath or urine (Prod Info CHEMET(R) oral capsules, 2005).
7) HYPERTHERMIA: One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension (Marcus et al, 1991).
8) AVAILABLE FORMS: Succimer (Chemet (R)), 100 mg capsules (Prod Info CHEMET(R) oral capsules, 2011).
9) EFFICACY

a) Succimer has been shown to have a safety ratio of 20 times greater than BAL. The total dosage of BAL is limited by its intrinsic toxicity, and the greater safety ratio of succimer allows for longer and more prolonged dosing of succimer(Inns & Rice, 1993).
b) CHRONIC ENVIRONMENTAL ARSENIC POISONING: In a randomized placebo-controlled clinical trial, succimer was NOT EFFICACIOUS in improving a clinical scoring system, skin lesions, or various biochemical laboratory measurements when administered to patients in India with chronic arsenic poisoning from drinking contaminated groundwater (Guha Mazumder et al, 1998).
c) CASE REPORT: In a patient treated with succimer (30 mg/kg/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal excretion of arsenic increased 1.5-fold (Fournier et al, 1988).
d) CASE REPORT: A 39-year-old woman developed progressive weakness and peripheral neuropathy leading to quadriplegia and requiring mechanical ventilation following an unknown type of exposure to arsenic. Analysis of her serum and urine revealed elevated arsenic (As) concentrations (290 mcg As/kg [normal less than 2 mcg/kg] and 2000 mcg As/L [normal less than 10 mcg/L], respectively). Despite succimer therapy, 10 mg/kg administered 3 times daily for a total of 33 days over a 45-day period, the patient only showed slow clinical improvement with continued residual paresthesias and weakness in her hands and distal lower extremities 5 years following intoxication(Stenehjem et al, 2007).
e) CASE REPORT: An intravenous preparation of succimer was used to treat a 26-year-old man with multi organ system failure after acute trivalent arsenic overdose. A solution was prepared with 1.6 grams of succimer diluted in 50 mL of sterile water and titrated with 10 N NaOH to pH 7.2 to 7.4 and filtered through a 0.22 micron filter. The solution was administered in 500 mL of 0.9% saline solution as an infusion over 1 hour at a dose of 20 mg/kg/day for 5 days followed by 10 mg/kg/day. The succimer solution was also given via peritoneal dialysis, 20 milligrams/liter of dialysate with 12 L exchanged daily for 5 days (Hantson et al, 1995).

E) PENICILLAMINE

1) USUAL ADULT DOSE

a) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).

2) USUAL PEDIATRIC DOSE

a) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004a; Prod Info DEPEN(R) titratable oral tablets, 2009).

3) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
4) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
5) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).
6) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).

a) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).

7) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
8) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.
9) EFFICACY

a) CHILDREN: D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977a; Kuruvilla et al, 1975; Watson et al, 1981).
b) ANIMALS: In an experimental animal model, mice and guinea pigs were injected subcutaneously with 8.4 milligrams/kilogram arsenic trioxide and 30 minutes later 0.7 millimole/kilogram (104.5 milligrams/kilogram) of d-penicillamine was administered. D-penicillamine was found to lack effectiveness in this model (Kreppel et al, 1989).

F) UNITHIOL

1) EFFICACY

a) SUMMARY: Unithiol (DMPS) is used in Europe as a chelating agent for heavy metal poisonings (Kruszewska et al, 1996). It appears to be an effective chelator of arsenic in experimental animals (Inns et al, 1990; Kreppel et al, 1990; Aposhian et al, 1984; Hsu et al, 1983; Aposhian et al, 1981) and humans (Goebel et al, 1990; Kew et al, 1993; Moore et al, 1994a; Zilker et al, 1999).
b) INTRAVENOUS DOSING: The dosing regimen depends on the severity of poisoning (Prod Info DIMAVAL(R) IV, IM injection, 2004). See UNITHIOL MANAGEMENT for further information.
c) DMPS/INDICATIONS: Chelating agent for heavy metal toxicities associated with arsenic, bismuth, copper, lead and mercury (Blanusa et al, 2005).
d) DMPS/DOSING

1) ACUTE TOXICITY

a) ADULT ORAL DOSE:

1) 1200 to 2400 mg/day in equally divided doses (100 to 200 mg 12 times daily) (Prod Info DIMAVAL(R) oral capsules, 2004).

b) ADULT INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

1) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
2) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
3) First 24 hours: 250 mg intravenously every 3 to 4 hours (1500 to 2000 mg total).
4) Day two: 250 mg intravenously every 4 to 6 hours (1000 to 1500 mg total).
5) Day three: 250 mg intravenously every 6 to 8 hours (750 to 1000 mg total).
6) Day four: 250 mg intravenously every 8 to 12 hours (500 to 750 mg total).
7) Subsequent days: 250 mg intravenously every 8 to 24 hours (250 to 750 mg total).
8) Depending on the patient's clinical status, therapy may be changed to the oral route.

c) PEDIATRIC ORAL DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005):

1) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
2) Initial dose: 20 to 30 mg/kg/day orally in many equal divided doses.
3) Maintenance dose: 1.5 to 15 mg/kg/day.

d) PEDIATRIC INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

1) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
2) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
3) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
4) First 24 hours: 5 mg/kg intravenously every four hours (total 30 mg/kg).
5) Day two: 5 mg/kg intravenously every six hours (total 20 mg/kg).
6) Days three and four: 5 mg/kg intravenously every 8 to 24 hours (total 5 to 15 mg/kg).

2) CHRONIC TOXICITY

a) ADULT DOSE

1) 300 to 400 mg/day orally (in single doses of 100 to 200 mg). The dose may be increased in severe toxicity (Arbeitsgruppe BGVV, 1996; Prod Info DIMAVAL(R) oral capsules, 2004).

3) DMPS/ADVERSE REACTIONS

a) Chills, fever, and allergic skin reactions such as itching, exanthema or maculopapular rash are possible (Hla et al, 1992; Prod Info DIMAVAL(R) oral capsules, 2004). Cardiovascular effects such as hypotension, nausea, dizziness or weakness may occur with too rapid injection of DMPS. Hypotensive effects are irreversible at very high doses (300 mg/kg) (Prod Info DIMAVAL(R) oral capsules, 2004; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013).

e) SOURCES

1) DMPS is not FDA-approved, but is available outside of the US from Heyl Chem-pharm Fabrik in Germany (Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013; Prod Info DIMAVAL(R) oral capsules, 2004). In the US it may be obtained from some compounding pharmacies.

f) CASE SERIES/CHRONIC TOXICITY: In a small (n=10) prospective, randomized, placebo-controlled, single-blind study of untreated patients with chronic arsenicosis following groundwater contamination, unithiol treatment was found to improve some clinical parameters (i.e., weakness, pigmentation and lung disease), and to increase total urinary excretion of arsenic. The treatment dose was 100 mg unithiol (orally) given four times per day for 1 week and repeated in the 3rd, 5th and 7th week of the study (Mazumder et al, 2001).
g) CASE REPORT: A 33-year-old woman developed arsenic poisoning as evidenced by a 1.5 year-history of peripheral neuropathy, pancytopenia, ventricular tachycardia, skin rash, and nail changes. Laboratory data revealed a blood arsenic concentration of 5.6 mcg/dL. Despite administration of succimer, the neuropathy continued to progress to facial paresis, severe weakness in all 4 extremities, and respiratory failure. Succimer was then discontinued, and unithiol was initiated at a dosage regimen of 250 mg IV every 4 hours. Twenty-four hours after beginning unithiol therapy, urinary excretion of arsenic increased to 300 mcg/L from a baseline of 101 mcg/L. Within 48 hours, the patient's neuropathy improved and, 10 days later, she was discharged in a wheelchair. At her 3-month follow-up, the patient continued to have residual paresthesias and weakness in her lower extremities, but she was able to walk without assistance, and by 1 year she was back at work with mild residual weakness and paresthesiae(Wax & Thornton, 2000a).

G) HYPOTENSIVE EPISODE

1) Hypotension from acute arsenic ingestion is likely due to intravascular volume depletion from vomiting, diarrhea, or third spacing of fluids.
2) The initial treatment should consist of adequate volume replacement with crystalloid, with the addition of blood products in patients with significant gastrointestinal blood loss. Place the patient supine until hypotension is corrected.
3) Aggressive monitoring of volume status should be undertaken even in the absence of hypotension initially. Bladder catheterization to monitor hourly urine output, a central venous catheter, or a Swan-Ganz catheter should be used as clinically warranted.
4) Pressors should be used only if volume replacement does not reverse the hypotension.
5) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

6) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

H) TACHYCARDIA

1) Tachycardia may be a response to hypovolemia and should be treated initially with fluid replacement as clinically warranted.

I) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

J) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

K) NEUROPATHY

1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy (Jenkins, 1966). However, once neuropathy has developed (usually 1 to 3 weeks after acute exposure), chelation with BAL may not be effective in reversing it (Heyman et al, 1956; Donofrio et al, 1987; Le Quesne & McLeod, 1977).
2) Unithiol (DMPS, dimercaptopropanesulfonic acid) may be superior in the treatment of neuropathy (Wax & Thornton, 2000; Moore et al, 1994)
3) Physical therapy may be helpful for patients with established arsenical neuropathies.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
8) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) OPHTHALMIC EXAMINATION AND EVALUATION

1) SYSTEMIC TOXICITY: No cases of systemic arsenic poisoning following only eye exposure have been reported.
2) CONSULTATION: If significant eye irritation is present, prolonged initial flushing and early ophthalmologic consultation are advisable.
3) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
2) Workers with significant arsenical dermatitis, ulcerations, or dermatoses may be overexposed and may need to be precluded from further exposure.
3) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Arsenic is poorly dialyzable. Hemodialysis should only be considered for arsenic toxicity accompanied by renal failure (Giberson et al, 1976).
2) Hemodialysis was ineffective in a fatal case of ingestion of 2 grams of arsenic trioxide 26 hours prior to receiving medical attention (Levin-Scherz et al, 1987). The maximum amount of arsenic possibly removed by hemodialysis in this case was 2.9 milligrams. In a second case where greater than 1000 mg of arsenic trioxide was ingested, two courses of hemodialysis removed only 3.5 and 1.8 mg of arsenic (Mahieu et al, 1981).
3) CASE REPORTS: A 19-year-old female and a 62-year-old male each ingested 1.8 g of arsenic trioxide. In the female patient, renal arsenic clearance was calculated at 21.5 L/hr with 94 mg total arsenic excretion over 72 hours. The male patient experienced severe renal failure requiring prolonged dialysis. Arsenic clearance was estimated at 0.9 L/hr by dialysis with 23 mg total arsenic excretion over 99 hours (Blythe & Joyce, 2001). In another study, arsenic clearance of 2.25 L/hr by hemodialysis was reported. These findings suggest that dialysis is unlikely to be beneficial in patients with normal renal function (Hantson et al, 2003).
4) Mathieu et al (1992) report the effect of hemodialysis and dimercaprol on arsenic kinetics following an ingestion of 10 grams of sodium arsenate (40 to 50 percent arsenic) (Mathieu et al, 1992). During the 15 days of hospitalization, 235 milligrams of arsenic was eliminated in the urine.

a) Instantaneous hemodialysis clearance was 85 +/- 75 milliliters/minute without previous BAL and 87.5 +/- 75 milliliters/minute with a previous 250 milligram BAL injection.
b) BAL: 250 milligrams was given one time only at approximately 20 hours postingestion.
c) One month after discharge the patient was admitted to another hospital for a sensory and motor polyneuritis involving both upper and lower limbs. Arsenic concentrations in blood and urine were not detectable, however, BAL was administered for 8 days at this institution. All neurologic signs resolved over 3 months.

5) In another study, Zilker et al (1999) reported that hemodialysis and CAVHDF did not significantly alter arsenic kinetics in a 24-year-old man who had accidentally ingested arsenic residue with an initial serum arsenic level of 245.8 micrograms/liter (Zilker et al, 1999). Unithiol (Dimercaptopropane sulfonate, DMPS) 1.2 grams was also given during the first two days of enhanced elimination therapy. During the first 87 hours following admission, 89.67 mg of arsenic was recovered in the urine, while the first hemodialysis removed 0.168 mg of arsenic and 0.061 mg was found in the CAVHDF dialysate.

a) Renal function remained normal throughout the period, and the authors suggested that unithiol was an effective therapy for arsenic poisoning when no kidney failure was present. One limitation of the study, however, was that no urinary levels were obtained prior to unithiol treatment.

6) Dialysis clearance rates of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980).
7) Hemodialysis was instituted 4 hours postadmission in a 30-year-old man who ingested 6 ounces of a rodenticide containing arsenous oxide 1.5 percent (approximately 2,150 milligrams of metallic arsenic) although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988).
8) Hemodialysis and continuous arterio-venous hemodiafiltration were found to remove negligible amounts of arsenic in an adult who maintained normal renal function after poisoning with arsenic (Zilker et al, 1999).

Abstracts

Case Reports

1) INGESTION: A 30-year-old male presented to the ED 1 hour after ingesting an estimated 25 g of arsenic trioxide. He had induced vomiting immediately, bringing up some of the powder. On arrival at the ED he complained of abdominal pain, chest tightness, and the urge to defecate. He was decontaminated with activated charcoal and whole bowel irrigation with polyethylene glycol was instituted. DMSA was not available and IV N-acetylcysteine (NAC) was started (12 g over 15 min, 4 g over 4 hours, and 8 g over 16 hours), penicillamine 250 mg every 6 hours, and 1950 calcium disodium edetate over 8 hours. Abdominal pain and vomiting subsided overnight. The NAC was completed and DMSA 800 mg three times daily was started 24 hours post-ingestion.

a) He was discharged 24 hours later on DMSA 800 mg three times daily for 5 days and then 800 mg two times daily for 14 days. Follow-up at 2 weeks showed that he had no further clinical effects or evidence of peripheral neuropathy (Isbister et al, 2004).

2) INGESTION: A 30-year-old man and 39-year-old woman who was 28 weeks pregnant ingested chocolate contaminated with arsenic trioxide. Both patients presented to the emergency room with severe abdominal cramps, nausea and vomiting, diarrhea, hypotension, and increased pulse rate. Both patients were diagnosed with staphylococcal food poisoning, treated with hydration and released the following day asymptomatic.

a) On day 3 both patients were readmitted with abdominal pain, hypersalivation, heartburn, and hematemesis. On day 5 both patients exhibited signs of early peripheral neuropathy, a paralytic ileus, and generalized edema. A chest roentgenogram revealed bilateral pleural effusions. Muscle weakness increased by day 6, as well as confusion and hallucinations. On day 5 fetal death was confirmed. On day 7 sinus tachycardia and a diffuse maculopapular rash was noted. On day 8 arsenic poisoning was confirmed through toxicological examination of the chocolate and BAL, 3 mg/kg/4 hr, was begun. Also on day 8 both patients became tachypneic with development of ARDS. The patients were intubated. Other laboratory results revealed liver involvement with abnormal liver function tests, renal involvement, and bone marrow suppression.
b) Three weeks following hospital admission, the liver, renal, and hematological functions returned to normal. All toxic effects disappeared by the end of week 3 except the severe polyneuropathy which improved over the next 2 years (Bolliger et al, 1992a).

3) INHALATION/INGESTION: A Swedish worker at a copper smelter was buried in arsenic trioxide. The filter mask he was wearing became clogged so he removed it. He was promptly rescued by a coworker. In the rescue process he had inhaled and swallowed arsenic dust. He arrived at a local hospital within 40 minutes of the incident and was vomiting, coughing, and dyspneic. Decontamination of the GI tract included lavage and administration of activated charcoal. Intravenous betamethasone was given to prevent airway obstruction. Within 3 hours of admission he also received promethazine 50 mg IM, doxycycline 200 mg IV, BAL 300 mg IM, and 2,3-dimercapto-1-propanol. He deteriorated quickly despite symptomatic and supportive care. He died 6 hours after the incident (Gerhardsson et al, 1988). The authors did not report how the worker was decontaminated at the incident site.
4) A 28-year-old male presented to a psychiatric unit 3 hours after ingesting approximately 10 g of arsenic trioxide. He was decontaminated with activated charcoal and transferred to the ED with symptoms of abdominal pain and vomiting. Whole bowel irrigation was instituted at 1000 mL/hour and continued for 72 hours. DMSA was not available and the patient was treated with calcium disodium edetate 1800 mg (1000 mg/m[2]/day) over 8 hours. DMSA, 500 mg three times daily, was started 11 hours following ingestion. On day 8, he was discharged to an acute psychiatric unit on DMSA 500 mg three times daily for 34 days. At follow-up, there was no clinical evidence of peripheral neuropathy (Isbister et al, 2004).
5) A 54-year-old man ingested 20 grams of arsenic trioxide in a suicide attempt. On ED arrival 3 hours later, he was restless and complained of nausea and upper abdominal pain. He underwent gastric lavage immediately and was treated with 200 mg of British antilewisite IM every 4 hours and bowel irrigation. Abdominal x-ray taken after lavage revealed a mass of arsenic in his stomach. Endoscopy failed to remove the arsenic, and he underwent a total gastrectomy. While in the ICU, he developed ventricular tachycardia and fibrillation and was successfully resuscitated. He died on the second day from refractory hypotension (Kinoshita et al, 2004).
6) A 26-year-old man developed abdominal pain, vomiting, diarrhea, coagulation abnormalities, elevated hepatic enzymes, hepatomegaly, and renal impairment with a serum creatinine of 1.8 mg/dL and a BUN of 125 mg/dL. Following a urinalysis that detected 0.867 mg/L of arsenic trioxide, chelation therapy with dimercaprol and dimercaptosuccinic acid was started. Despite chelation and enhanced elimination with peritoneal dialysis and hemodialysis, the patient continued to deteriorate with development of generalized erythroderma, respiratory distress syndrome with evidence of an aspergillus infection, and a decline in neurological status with detection of a subarachnoid hemorrhage on hospital day 26 (approximately 30 days following onset of initial symptoms). After performing an EEG and measurement of evoked potentials, the patient was declared brain dead on that same day (day 26). Postmortem analysis of biological fluids detected significant concentrations of arsenic, including a blood arsenic concentration of 355 mcg/L. Criminal investigation of the patient's wife revealed that she had obtained 10 grams of arsenic trioxide for veterinary use. It is suspected that the patient had been given a low dose of arsenic trioxide over the two weeks prior to hospital admission and a larger dose of arsenic on the day prior to admission (Parent et al, 2006).

1) INGESTION: Marcus reported the case of a 16-year-old patient who ingested 2 ounces of technical grade arsenic trioxide in a suicide attempt that demonstrates that early chelation may not always prevent development of peripheral neuropathy(Marcus, 1987).

a) Vomiting, diarrhea, and abdominal pain occurred about 6 hours after ingestion and prompted emergency department evaluation where ipecac and activated charcoal were given. Tachycardia and hypotension developed which responded to fluid administration.
b) Chelation with BAL at 4 milligrams per kilogram every 4 hours was started immediately and continued until gastrointestinal symptoms were subsiding. The patient then received oral D-penicillamine at 30 milligrams per kilogram per day.
c) Although blood arsenic levels rapidly decreased, urine arsenic levels only gradually fell from 50,000 micrograms per day to 20 micrograms per day over a 31 day period. Elevated liver enzyme levels were found beginning on the third day after exposure. Hypoesthesias of the legs and bilateral foot drop developed with an onset two weeks after hospitalization, and significant residual muscular weakness in both lower extremities persisted one year later.

Range Of Toxicity

Therapeutic Dose

7.2.1)

A) INDUCTION TREATMENT SCHEDULE - 0.15 milligram/kilogram intravenously over 1 to 2 hours daily (may be extended up to 4 hours if acute vasomotor reactions observed) until bone marrow remission; not to exceed 60 doses (Prod Info TRISENOX(R) injection, 2005).
B) CONSOLIDATION TREATMENT SCHEDULE - Initiate 3 to 6 weeks after completion of induction therapy; 0.15 milligram/kilogram daily intravenously over 1 to 2 hours daily for 25 doses over a period of up to 5 weeks (Prod Info TRISENOX(R) injection, 2005).

7.2.2)

A) Safety and effectiveness in children in children less than 5 years of age have not been studied. Refer to adult dosing for children 5 years of age or older (Prod Info TRISENOX(R) injection, 2005).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) More than 50% of a group of 74 patients who took an antihistaminic herbal preparation (3.3 mg of arsenic trioxide daily) developed a sensorimotor peripheral neuropathy (HSDB , 1991).
2) A 43-year-old man survived after ingesting 54 g of arsenic trioxide in a suicide attempt, 200 times the lethal dose (Duenas-Laita et al, 2005).
3) A 23-year-old man intentionally ingested 1040 mg of arsenic trioxide. Clinical manifestations included severe weakness, brown watery diarrhea, vomiting, and unquenchable thirst, followed by constricted visual fields, hepatic dysfunction, dermatitis, and peripheral neuropathy. He was treated with fluid resuscitation and BAL. All of the patient's symptoms, including his visual impairment, resolved over the next 3 weeks and he was discharged without sequelae (Kamijo et al, 1998).
4) A 33-year-old woman survived ingestion of 1850 mg of arsenic trioxide following treatment with 2,3 propanesulphonate (DMPS) and hemodialysis (Kruszewska et al, 1996).
5) CASE SERIES: Vomiting was reported in 6 children following ingestion of all or part of an ant bait gel bar containing 0.46% arsenic trioxide (estimated total dose ranging from 5 to 45 mg). One of the children (a 20-month-old girl) also experienced several episodes of diarrhea. Initial urine arsenic concentrations ranged from 1,858 to 13,981 mcg/L. All 6 children recovered following chelation therapy with succimer (Yarris et al, 2008).
6) A 77-year-old man developed nausea, vomiting, renal impairment, and anemia after ingesting 4 g of arsenic trioxide in a suicide attempt. With supportive care, including chelation therapy with dimercaprol (BAL), the patient gradually recovered (Yilmaz et al, 2009).
7) A 67-year-old woman who was treated for persistent psoriasis with Fowler's solution over a 15 year period (estimated at 25 g of arsenic trioxide in all) developed noncirrhotic hepatic fibrosis as a result of the chronic arsenic poisoning (Piontek et al, 1989).

1) Acute ingestion of 9 to 14 mg of arsenic trioxide by a 16-month-old child produced classic GI signs and symptoms of arsenic poisoning (Watson et al, 1981).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) PEAK RESPONSE - ACUTE PROMYELOCYTIC LEUKEMIA, INTRAVENOUS: 24 to 83 days (Soignet et al, 1998).

a) Represents time to complete remission by all criteria (ie, no more than 5% blasts in bone marrow, normalization of peripheral blood counts); the median time was 47 days (Soignet et al, 1998). The median time to remission based on bone marrow criteria (elimination of leukemic blasts and promyelocytes) was 33 days. Patients in this study were treated with daily infusions until marrow clearance of leukemic cells; in those experiencing complete remission, additional courses were given as consolidation (25-day courses, separated by 3 to 6 weeks).

2) AUC - 35 to 40 micromols x /h/L after a 10-mg intravenous dose (Shen et al, 1997).
3) THERAPEUTIC CONCENTRATION: ACUTE PROMYELOCYTIC LEUKEMIA, not clearly established.

a) In one study, complete remissions were observed when 12-hour plasma arsenic levels exceeded 1 micromol/L during a regimen of 10 mg daily (2- to 3-hour infusion) (Shen et al, 1997). However, this observation is based solely on reported plasma levels; an attempt to correlate efficacy and plasma levels was not performed.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) The blood and urine arsenic concentrations, obtained approximately 20 hours after a 23-year-old man intentionally ingested 1040 mg of arsenic trioxide and survived, were 41.5 mcg/dL and 5140 mcg/dL, respectively (Kamijo et al, 1998).
2) Postmortem arsenic concentrations in the tissues of a 26-year-old man, who was fatally poisoned with up to 10 grams of arsenic trioxide, are as follows:

Tissue	Arsenic (mcg/g tissue)
Hair	67
Nails	13.8
Thyroid	6.6
Liver	2.6
Muscle	1.9
Skin	1.8
Brain	1.5
Heart	1.1
Kidney	1

3) CASE SERIES - Vomiting was reported in 6 children following ingestion of all or part of an ant bait gel bar containing 0.46% arsenic trioxide (estimated total dose ranging from 5 to 45 mg). One of the children (a 20-month-old girl) also experienced several episodes of diarrhea. Initial urine arsenic concentrations ranged from 1,858 to 13,981 mcg/L. All 6 children recovered following chelation therapy with succimer (Yarris et al, 2008).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Arsenic trioxide

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Category 1 ; Listed as: Arsenic and inorganic arsenic compounds: Arsenic trioxide

a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (ORAL)MOUSE:

1) 20 mg/kg (RTECS, 2006)

B) LD50- (SUBCUTANEOUS)MOUSE:

1) 9800 mcg/kg (RTECS, 2006)

C) LD50- (INTRAPERITONEAL)RAT:

1) 871 mg/kg (RTECS, 2006)

D) LD50- (ORAL)RAT:

1) 10 mg/kg (RTECS, 2006)

Summary

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

1) Arsenic trioxide occurs as colorless monoclinic, cubic, or fibrous crystals, or as white or clear amorphous lumps or powder. It is odorless and tasteless. It is sparingly soluble in cold water, soluble in 15 parts boiling water, and soluble in glycerine, dilute hydrochloric acid, or alkali hydroxide. It will corrode metals under moist conditions, and is somewhat more stable at mildly acidic pH. It sublimes upon heating. Exposure to the vapors is therefore a potential hazard (HSDB, 2006; Budavari, 1996; Lewis, 1993).

Molecular Weight

Animal Toxicology

References

General Bibliography

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ARSENIC TRIOXIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Summary

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography