SODIUM ARSENITE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1.2.1) MOLECULAR FORMULA
1) As-O2.Na

Available Forms Sources

1) Sodium arsenite is a white or greyish powder with a salty taste (HSDB , 1993). It is available in a technical grade of 90 to 95% purity and a commercial grade of 95 to 98% purity (EPA, 1985; Sax & Lewis, 1987) 1989; (Budavari, 1989).
2) Sodium arsenite is a TRIVALENT ARSENIC COMPOUND. Trivalent arsenic compounds are generally considered to be more toxic than pentavalent arsenic compounds on an equal dose basis (Finkel, 1983; Morgan, 1989). Trivalent arsenic compounds are thought to produce their toxic effects by reversibly combining with sulfhydryl groups, resulting in inhibition of various enzyme systems (Hood, 1972; Byard, 1979). Arsenic inhibits enzymes required for cellular respiration, and has the effect of depleting cellular energy stores, leading to cellular death (Schoolmeester & White, 1980).
3) OSHA considers sodium arsenite to be a human carcinogen.
4) The ACGIH has established a Biological Exposure Index (BEI) for arsenic. Refer to the BIOMONITORING section for more information.
5) The following review is based on the toxic effects of arsenic and inorganic arsenic compounds in general, with effects attributed specifically to sodium arsenite noted.

1) Sodium arsenite is formed from arsenic trioxide under moist conditions (Baselt & Cravey, 1989; Baselt, 1988). The commercial product is not a single substance, but is rather a solid solution of CAUSTIC SODA and ARSENIC TRIOXIDE (HSDB , 1993).

1) Sodium arsenite is used as a pesticide and herbicide, although it is being replaced by less toxic organic compounds for such purposes (HSDB , 1993). It is also used as a wood preservative and corrosion inhibitor, and in textile drying (HSDB , 1993).
2) Between 1966 and 1979, 61 cases of accidental sodium arsenite poisoning, including 24 fatalities, were reported to the EPA's Pesticide Incident Monitoring System (PIMS) (EPA, 1988). In 1991, a mass poisoning of 718 persons in Argentina from sodium arsenite-contaminated meat was reported (Roses et al, 1991).

Overview

Life Support

Clinical Effects

0.2.1)

A) Sodium arsenite is a trivalent, inorganic arsenical compound. It is a white or greyish powder solid.
B) Sodium arsenite can cause acute and chronic arsenic poisoning following ingestion, inhalation, or dermal exposure. It is a known human carcinogen and mutagen, and has caused teratogenicity and adverse reproductive effects in experimental animals. It is advisable to treat all arsenic compounds as highly toxic.
C) Acute arsenic ingestion generally produces symptoms within 30 to 60 minutes, but symptom onset may be delayed for several hours if ingested with food. A metallic or garlic taste, vomiting, abdominal pain, dysphagia, and profuse watery (rice-water-like) and sometimes bloody diarrhea may occur. Dehydration, intense thirst, and fluid-electrolyte disturbances are common. Hypovolemia from capillary leaking ("third spacing" of fluids) is a common early event.
D) Systemic arsenic poisoning from occupational exposure is uncommon. Arsenic workers have developed a hoarse voice, nasal irritation and possibly perforation of the nasal septum, irritation of eyes, skin, and mucous membranes, and rarely, cirrhosis of the liver. Nausea and vomiting are infrequent complaints among arsenic workers. Painful ulceration of the wrist and scrotal skin, lips, and nostrils may develop with dust exposure.
E) Initially, the primary target organs are the gastrointestinal tract, heart, brain, and kidneys. Eventually, the skin, bone marrow, and peripheral nervous system may be significantly damaged. Peripheral neuropathy appears similar regardless of the route of exposure.

0.2.3)

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

0.2.4)

A) Conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. Severe corneal injury following direct contact may occur. A garlic-like odor may be detected on the breath.

0.2.5)

A) Ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion.

0.2.6)

A) 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) Toxic delirium and encephalopathy are common complications. Peripheral neuropathy is common. Seizures may occur.

0.2.8)

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

0.2.10)

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

0.2.12)

A) Electrolyte imbalances may occur.

0.2.13)

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

0.2.14)

A) 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. Shingles (Herpes Zoster) may also be a complication.

0.2.20)

A) Sodium arsenite is teratogenic or fetotoxic in mice, rats, and hamsters. Fetotoxicity and fetal death are possible. Human reproductive data for this compound are lacking, but other arsenicals have been linked with human reproductive toxicity.
B) Arsenic can cross the placenta. Arsenic is excreted in the breast milk in both experimental animals and humans.
C) Systemic toxicity was present before any effects were noted on the testes.

0.2.21)

A) 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) GASTRIC DECONTAMINATION: 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.
B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.

1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.

C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
D) PATIENT MONITORING

1) Monitor liver, renal and cardiac functions. Maintain high urine output.

E) ALKALINIZATION OF THE URINE

1) May prevent the deposition of red cell breakdown products from hemolysis in the renal tubules.

F) URINE ALKALINIZATION

1) Administer 1 to 2 mEq/kg sodium bicarbonate bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. Adjust as needed to achieve a urine pH of at least 7.5 and a urine output of 1 to 3 mL/kg/hr.
2) Assure adequate hydration and renal function. Monitor fluid balance, serum electrolytes, and blood pH. Obtain hourly intake/output and urine pH.

G) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.

1) DIMERCAPROL (BAL) - Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose and frequency used depend on the degree of toxicity seen. Dose dependent side effects may occur.
2) D-PENICILLAMINE - The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day, adults may require larger doses (ie, up to 2 grams/day).
3) DMSA - 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug. It has the advantage of being an oral agent as well as being relatively non-toxic.
4) N-acetylcysteine (NAC) cannot presently be recommended for the treatment of arsenic poisoning.
5) THERAPEUTIC END-POINT - Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter.

H) A MOBILIZATION TEST - has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic.
I) Physical therapy may be helpful for patients with established arsenical neuropathies.
J) HEMODIALYSIS - should be performed in the presence of any degree of renal failure.
K) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
L) X-RAY - Arsenic is radiopaque. Obtain abdominal film and repeat as necessary to insure that gastric emptying maneuvers have been effective. A chest radiograph should also be obtained, as pulmonary edema may occur.
M) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) Alkalinization of the urine may prevent deposition of red cell breakdown products from hemolysis in renal tubular cells.

1) URINE ALKALINIZATION

a) Administer 1 to 2 mEq/kg sodium bicarbonate bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. Adjust as needed to achieve a urine pH of at least 7.5 and a urine output of 1 to 3 mL/kg/hr.
b) Assure adequate hydration and renal function. Monitor fluid balance, serum electrolytes, and blood pH. Obtain hourly intake/output and urine pH.

C) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.

D) A MOBILIZATION TEST - has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic.
E) Physical therapy may be helpful for patients with established arsenical neuropathies.
F) HEMODIALYSIS - should be performed in the presence of any degree of renal failure.
G) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
H) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.

0.4.4)

A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.
B) No cases of systemic arsenic poisoning following only eye exposure have been reported.
C) If significant eye irritation is present, prolonged initial flushing and early ophthalmologic consultation are advisable.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
2) Alkalinization of the urine may prevent deposition of red cell breakdown products from hemolysis in renal tubular cells.

a) URINE ALKALINIZATION

3) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.

a) DIMERCAPROL (BAL) - Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose and frequency used depend on the degree of toxicity seen. Dose dependent side effects may occur.
b) D-PENICILLAMINE - The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day, adults may require larger doses (ie, up to 2 grams/day).
c) DMSA - 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug. It has the advantage of being an oral agent as well as being relatively non-toxic.
d) N-acetylcysteine (NAC) cannot presently be recommended for the treatment of arsenic poisoning.
e) THERAPEUTIC END-POINT - Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter.

4) A MOBILIZATION TEST - has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic.
5) Physical therapy may be helpful for patients with established arsenical neuropathies.
6) HEMODIALYSIS - should be performed in the presence of any degree of renal failure.
7) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
8) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
9) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
10) Restriction from further exposure may be necessary for workers with significant arsenical dermatitis, ulcerations, or dermatoses.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

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

3.3.4)

A) HYPOTENSION - 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).

3.3.5)

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

Heent

3.4.1)

A) Conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. Severe corneal injury following direct contact may occur. A garlic-like odor may be detected on the breath.

3.4.2)

A) ALOPECIA - Hair loss may occur with chronic exposure (Finkel, 1983; ITI, 1995).

3.4.3)

A) CONJUNCTIVITIS - photophobia, dimness of vision, diplopia, and lacrimation may occur (Heyman et al, 1956; Grant, 1993).
B) CORNEAL INJURY - Direct application or intrastromal injection of sodium arsenite caused severe corneal injury in rabbits (Grant, 1986).
C) ACUTE POISONING - Acute sodium arsenite poisoning in rats and rabbits did NOT cause retinal degeneration (Grant, 1993).

3.4.5)

A) BURNING - A sensation of burning, dryness and constriction of the oral and nasal cavities may occur (Finkel, 1983; Hathaway et al, 1996). Perforation of the nasal septum may result from irritation (Clayton & Clayton, 1994).

3.4.6)

A) BREATH - A garlic-like odor may be detected on the breath (Morgan, 1993; HSDB , 1999).

Cardiovascular

3.5.1)

A) Ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion.

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) Particularly ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion (Peterson & Rumack, 1977; Goldsmith, 1980; St Peter et al, 1970).
2) These dysrhythmias may be secondary to electrolyte imbalances rather than a direct toxic effect of arsenic on the myocardium (Sittig, 1991).

B) ELECTROCARDIOGRAM ABNORMAL

1) ECG changes have included QT prolongation, left axis deviation, peaked T waves, and also deeply inverted T waves (Gousios & Adelson, 1959; Heyman et al, 1956).

a) These ECG changes may be secondary to electrolyte imbalances rather than a direct toxic effect of arsenic on the myocardium (Sittig, 1991), although a direct, reversible effect on the myocardium has been postulated from animal experiments (Massmann & Opitz, 1954).

Respiratory

3.6.1)

A) 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) APNEA

1) 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) Either noncardiogenic from capillary leaking, or cardiogenic from myocardial depression, may occur and be life-threatening (Morgan, 1989).

C) ACUTE LUNG INJURY

1) Adult respiratory distress syndrome (ARDS) has been reported (Zaloga et al, 1970; Schoolmeester & White, 1980).

Neurologic

3.7.1)

A) Toxic delirium and encephalopathy are common complications. Peripheral neuropathy is common. Seizures may occur.

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) Toxic delirium and encephalopathy are complications of acute arsenic poisoning (Jenkins, 1966).

a) 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).

B) SECONDARY PERIPHERAL NEUROPATHY

1) Peripheral neuropathy is common after acute arsenic poisoning. After acute exposure, it commonly begins one to 3 weeks later (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).
2) 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 (Harbison, 1998).
3) 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).
4) 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).
5) NERVE BIOPSY may demonstrate various stages of axonal degeneration without demyelination (Le Quesne & McLeod, 1977) or with demyelination (Donofrio et al, 1987).
6) 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, neuropathy may be prevented (Jenkins, 1966), although this may not always be true (Marcus, 1987).

a) Early and prolonged chelation therapy with BAL followed by d-penicillamine did not prevent development of a mild peripheral neuropathy in a patient who injected sodium arsenite and potassium cyanide intravenously in a suicide attempt (DiNapoli et al, 1989).

C) SEIZURE

1) Seizures may occur (Harbison, 1998; Hathaway et al, 1996).

Gastrointestinal

3.8.1)

3.8.2)

A) GASTROENTERITIS

1) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery diarrhea (sometimes described as "rice-water-like") (Gilman et al, 1985), pain in the extremities and muscles, weakness, and flushing of the skin (Sittig, 1991).

Hepatic

3.9.1)

A) 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) Hepatocellular damage may occur after acute arsenic poisoning, but is not common (Donofrio et al, 1987). Mitotic activity of hepatocytes may be a common post-mortem finding in arsenic poisoning (Mackell et al, 1985).

Genitourinary

3.10.1)

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

3.10.2)

A) RENAL FAILURE SYNDROME

1) 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).

Hematologic

3.13.1)

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

3.13.2)

A) HEMOLYSIS

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

B) PANCYTOPENIA

1) 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).
2) 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).

Dermatologic

3.14.1)

3.14.2)

A) SKIN FINDING

1) 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 (Zaloga et al, 1970; Schoolmeester & White, 1980; Hutton & Christians, 1983; Clayton & Clayton, 1994).

B) MEE'S LINE

1) 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).

C) HERPES ZOSTER

1) Shingles may also be a complication of arsenic poisoning (Jenkins, 1966; HSDB , 1999).

Reproductive

3.20.1)

3.20.2)

A) HUMANS

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) 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). Because of mixed exposures, these effects could not be attributed to arsenic alone.

B) ANIMAL STUDIES

1) Sodium arsenite has caused teratogenic and embryotoxic effects in the offspring of pregnant mice, rats, and hamsters when administered orally or parenterally (Schardein, 1993; Council on Scientific Affairs, 1985; Hood, 1972; Baxley et al, 1981). In some hamster experiments, no teratogenic effects were noted (Schardein, 1993; Hood & Harrison, 1982).
2) At doses of 10 or 12 mg/kg administered intraperitoneally to mice on days 7 through 12 of gestation, sodium arsenite caused increased fetal deaths, decreased fetal weights, and developmental abnormalities including exencephaly, micrognathia, open eyes, tail abnormalities, fused ribs, and fused or missing vertebral ossification centers (Hood, 1972).
3) Parenteral administration of high arsenic doses caused exencephaly, skeletal defects, and abnormalities of the genitourinary system. At lower doses in drinking water, only minimal fetal effects have been seen (Hathaway et al, 1996; Proctor et al, 1988).
4) Resorptions and maternal lethality were produced by sodium arsenite at an IP dose of 12 mg/kg in Swiss mice on day 9 of gestation. Maternal lethality was prevented, and embryolethality and skeletal variations were significantly reduced, by meso-2,3-mercaptosuccinate (Domingo et al, 1995).
5) In a cultured mouse embryo system, sodium arsenate and arsenite were both teratogenic, resulting in abnormalities of cranial closure, abnormalities of the eye and optic nerve, and pharyngeal arch defects. The ED50 for arsenate was about threefold higher than that for arsenite (Tabocova et al, 1996).
6) The dithiol compound meso-2,3-dimercaptosuccinic acid (DMSA) effectively prevented the teratogenic activity of sodium arsenite in pregnant mice, when given within one hour after the arsenite (Bosque et al, 1991).
7) Increased fetal deaths, lower fetal weights, and malformations of the head and musculoskeletal system were seen in mice given 10 or 12 mg/kg intraperitoneally on days 7 through 12 of gestation (Hood, 1972). In some hamster experiments, no teratogenic effects were noted (Schardein, 1985; Hood & Harrison, 1982).
8) Sodium arsenite at a concentration of 50 mcM for 2 hours also induced malformations in rat embryos in vitro. This activity was accompanied by the synthesis of two heat-shock proteins (Cornel et al, 1991).

3.20.3)

A) PLACENTAL BARRIER

1) Based on observations with arsenic trioxide, arsenic appears to cross the human placenta (Lugo et al, 1979).
2) NEONATAL DEATH - Acute ingestion of arsenic in a female with a 30 week pregnancy has been reported to result in the death of the infant born 4 days after the poisoning (Lugo et al, 1969). 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.
3) In studies of a population in Argentina exposed to environmental arsenic (drinking water arsenic approximately 200 mcg/L), cord blood concentrations (median 9 mcg/L) were almost as high as maternal blood concentrations (median 11 mcg/L). Essentially, all of the blood arsenic and about 90 percent of the urinary arsenic in both mothers and newborns was in the form of dimethylarsinic acid in comparison to 70 percent in the urine of non-pregnant women, suggesting that the methylation of arsenic may be up-regulated during pregnancy (Concha et al, 1998).
4) 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. There was no increased incidence of congenital malformations in this group (Schardein, 1993). The significance of this study to pure chronic arsenic exposure during pregnancy is unclear.
5) Six women developing arsenical encephalopathy during the fourth to eighth months of pregnancy delivered normal children (Schardein, 1993).

B) ANIMAL STUDIES

1) FERTILITY - Continuous dietary administration of up to 215 mg/kg of arsenic did not have adverse effects on fertility in female rats (Barlow & Sullivan, 1982).
2) Resorptions and maternal lethality were produced by sodium arsenite at an IP dose of 12 mg/kg in pregnant Swiss mice on day 9 of gestation. Maternal lethality was prevented, and embryolethality and skeletal variations were significantly reduced, by meso-2,3-mercaptosuccinate (Domingo et al, 1995).
3) Sodium arsenite was distributed to fetal tissues in mice, but the majority of fetal arsenic was in the less toxic methylated form (Hood et al, 1988).

3.20.4)

A) BREAST MILK

1) Arsenic is excreted in the breast milk in both experimental animals and humans (Barlow & Sullivan, 1982).
2) There may be some risk to nursing infants of mothers exposed to arsenic from evidence in Japanese children who drank arsenic-contaminated powdered milk and who may have had deficiencies in later brain development (Barlow & Sullivan, 1982).

3.20.5)

A) HUMANS

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

B) ANIMAL STUDIES

1) 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 CAS7784-46-5 (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: Sodium arsenite
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) CARCINOMA

1) An IARC review found that there is a causal relationship between medicinal, drinking water, or occupational heavy arsenic exposure and skin cancer. There is also a clearly increased risk of lung cancer in workers inhaling high levels of arsenic trioxide (IARC, 1987).
2) The Occupational Safety and Health Administration (OSHA) has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow (Anon, 1979). The US Environmental Protection Agency has classified inorganic arsenical compounds as Class A carcinogens based on sufficient human epidemiological evidence (EPA, 1988).
3) Sodium arsenite and other arsenic compounds have been linked with respiratory cancer, skin cancer and digestive system cancers (Enterline & Marsh, 1980; Lee-Feldstein, 1983) 1986; (Pinto et al, 1977; Enterline & Marsh, 1982; Wagner et al, 1979; ACGIH, 1986) IARC, 1973; (HSDB , 1993).
4) One worker who was exposed to arsenic trioxide and sodium arsenite for 20 years developed primary liver carcinoma (Finkel, 1983). Acute myelogenous leukemia has also been linked with chronic arsenic exposure (Kjeldsberg & Ward, 1972). Pre-neoplastic lesions due to sodium arsenite exposure have been found in human respiratory epithelium (Dong et al, 1995).
5) 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).
6) In additional environmental exposure studies in various regions where arsenic exposure is endemic, epidemiologic studies have suggested possible relationships of arsenic exposure to cancers of the lung (Hopenhayn-Rich et al, 1998; Smith et al, 1998), kidney (Hopenhayn- Rich et al, 1998), and bladder (Smith et al, 1998; Hopenhayn-Rich et al, 1996).
7) SKIN CARCINOMA - 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.

a) Two patients with arsenic-induced basal cell carcinomas of the skin also developed malignancies of other organs (breast and colon) (Jackson & Grainge, 1975).

8) HEPATIC CARCINOMA - 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).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Quantitative 24 hour urine collections are the most reliable laboratory measure of arsenic poisoning. Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure.
B) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
C) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected.
D) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.
E) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
F) Monitor arterial blood gases and chest x-ray in patients who develop pulmonary edema.
G) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) An arsenic blood level below 7 mcg/100 mL is considered in the normal range. 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).
2) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
3) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
4) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."

B) ACID/BASE

1) Monitor arterial blood gases in patients who develop pulmonary edema.

C) HEMATOLOGIC

1) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.

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) 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, 2000; Proctor et al, 1988).

a) Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure (Proctor et al, 1988).
b) Urine levels are generally below 100 mcg/gram of creatinine, and generally below 20 mcg/gram of creatinine in unexposed individuals (Hathaway et al, 1996).

4.1.4)

A) OTHER

1) HAIR

a) Arsenic has been found in hair and nails within hours after exposure (Lander et al, 1965). Normal concentration of arsenic in hair and nails is less than 1 mcg/gram (Baselt, 2000).

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 or nail analysis is only useful in epidemiologic studies to distinguish potentially exposed from unexposed groups.

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

Monitoring

Oral Exposure

6.5.2)

A) GASTRIC EMPTYING

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 begin 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.

B) ACTIVATED CHARCOAL

1) Preliminary results suggest that activated charcoal may not be of therapeutic value in the treatment of acute arsenic poisoning (pp 5-1990).

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 (pp 5-1990).
c) Solutions incubated for 120 and 240 minutes at pH 10 to 12 (simulated intestinal juices) showed adsorption of 75 to 80 percent (pp 5-1990).

2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) WHOLE BOWEL IRRIGATION (WBI)

1) Whole bowel irrigation with polyethylene glycol electrolyte lavage solution may be a relatively safe and effective means of rapid gastrointestinal decontamination (Lee et al, 1995).

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.

6.5.3)

A) 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 or blood products. Placing the patient in Trendelenburg and using MAST trousers may also be useful.
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).

B) TACHYARRHYTHMIA

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

C) VENTRICULAR ARRHYTHMIA

1) Ventricular tachycardia or ventricular fibrillation may occur after acute arsenic poisoning and should be treated with DC countershock and standard antiarrhythmic agents.
2) LIDOCAINE

a) 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).

b) 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).

c) LIDOCAINE/MONITORING PARAMETERS

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

3) PROCAINAMIDE

a) PROCAINAMIDE/ADULT LOADING DOSE

1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).

b) PROCAINAMIDE/CONTROLLED INFUSION

1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)

c) PROCAINAMIDE/ADULT MAINTENANCE DOSE

1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).

d) PROCAINAMIDE/PEDIATRIC LOADING DOSE

1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).

e) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE

1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

f) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE

1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

g) MONITORING PARAMETERS

1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).

h) AVOID

1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

4) BRETYLIUM

a) ADULTS: 5 milligrams/kilogram in 50 milliliters D5W over 10 minutes; can repeat dose at 10 minutes with 10 milligrams/kilogram; may also infuse at 1 to 2 milligrams/minute. CHILDREN: 5 to 10 milligrams/kilogram intravenously over 10 minutes, up to 30 milligrams/kilogram; maintenance: 5 milligrams/kilogram intravenously every 6 to 8 hours.

D) ALKALINE DIURESIS

1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
2) SODIUM BICARBONATE/INITIAL DOSE

a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.

3) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

4) CAUTION

a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.

E) CHELATION THERAPY

1) INDICATIONS

a) Begin chelation therapy in symptomatic patients. The urine arsenic level which should prompt chelation in an asymptomatic patient has been recommended as 200 micrograms/liter (Kersjes et al, 1987).

2) THERAPEUTIC END-POINT

a) Repeat courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter (Goldfrank et al, 1986; AMA, 1986). Observation for return of symptoms is strongly recommended.

3) MOBILIZATION TEST

a) Diagnosis for mild or chronic exposure can be aided by the following procedure:

1) BASELINE COLLECTION - A 24-hour urine collection for baseline arsenic excretion (Normal less than 100 micrograms/24 hours).
2) CHELATED COLLECTION - Following the baseline 24-hour collection, a second 24-hour urine collection should be performed while the patient receives 4 doses, every 6 hours of D-penicillamine (25 milligrams/kilogram/dose up to 250 milligrams/dose). Other chelators have been used in similar tests.
3) INTERPRETATION - Either urine collection showing arsenic excretion greater than 100 micrograms/24 hours is diagnostic and should be followed by a 5 day course of D-penicillamine or another chelator. 24-hour urine collections to measure arsenic excretion during chelation are recommended.

b) SEAFOOD - During the mobilization test the patient should avoid seafood. Ingestion of seafood, particularly shellfish, may transiently increase urinary arsenic levels to 200 to 1700 micrograms/liter (Baselt & Cravey, 1989).
c) SPOT SAMPLES - For diagnostic purposes, a spot urine arsenic, blood arsenic (normal less than 7 micrograms/deciliter), pubic hair arsenic (normal less than 1 microgram/gram), and nail arsenic (normal less than 1.7 micrograms/gram) may be helpful, but results must be carefully interpreted.

F) DIMERCAPROL

1) DOSE: Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose used is dependent on the severity of the patient's symptoms and the urinary arsenic levels.

a) Limited supplies of dimercaprol following an acute massive epidemic (N=718) of sodium arsenite poisoning prompted health care providers to modify the dosing regimen of dimercaprol (Roses et al, 1991). The study population (N=307) was divided into 3 treatment groups based on urinary arsenic concentrations. All subjects in all treatment groups were free of arsenic related symptomatology at 1 or 2 year follow-up.

1) Two hundred forty-six subjects with urinary arsenic concentrations up to 75 micrograms/deciliter were given no dimercaprol.
2) Forty-nine subjects with urinary arsenic concentrations from 76 to 500 micrograms/deciliter received dimercaprol 2 milligrams/kilogram intramuscularly once daily for 10 days.
3) Twelve subjects with urinary arsenic concentrations greater than 500 micrograms/deciliter were administered dimercaprol 2 milligrams/kilogram intramuscularly every 8 hours on days 1 and 2, every 12 hours on days 3 and 4, and every 24 hours from day 5 to 10. Three subjects in this group also received supportive treatment.

2) ADVERSE EFFECTS: Typical side effects which are dose related include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, seizures, "leukotoxic effect", and reducing substances in the urine (Woody & Kometani, 1948).
3) EFFICACY

a) Dimercaprol (BAL) is an effective arsenic chelator but has the disadvantages of requiring painful intramuscular injections and having numerous side effects.
b) CHILDREN:

1) 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 affect complete recovery in a woman and her 20-week fetus after an acute ingestion of inorganic arsenic by the mother (Daya et al, 1989).

c) ANIMALS: 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).

G) PENICILLAMINE

1) DOSE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day (Peterson & Rumack, 1977), but larger doses may be required in adults.
2) ADVERSE EFFECTS: Long term therapy for the treatment of arthritis or Wilson's disease has resulted in fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity, but this has not been reported when the drug is used short term for heavy metal chelation.
3) EFFICACY

a) CHILDREN:

1) D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977; Kuruvilla et al, 1975; Watson et al, 1981).

b) ANIMALS:

1) 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).

c) DISADVANTAGES - It has the advantage of being an oral agent, but the disadvantages of not being able to be given to patients allergic to penicillin, not being retained well if patients are vomiting, and the theoretical problem of enhancing absorption of the arsenic-chelator complex.
d) It does not appear to result in depletion of zinc and copper when given for several weeks (Peterson & Rumack, 1977).

H) SUCCIMER

1) EFFICACY

a) SUMMARY: 2,3-Dimercaptosuccinic acid (DMSA, Succimer), is currently approved for the treatment of childhood lead poisoning. It appears to be an effective chelator of arsenic in experimental animals (Graziano et al, 1978; Hannemann et al, 1995) and man (Lenz et al, 1981; Kosnett & Becker, 1987; Fournier et al, 1988).

1) DMSA 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 DMSA allows for longer and more prolonged dosing of DMSA (Inns & Rice, 1993).
2) In a double-blind, randomized, crossover, placebo-controlled study of patients with chronic environmental arsenical disease in West Bengal, patients were given placebo or DMSA 1400 mg/day for one week followed by 1050 mg/day for two additional weeks. The alternative treatment was then administered following a three week delay. Although both groups reported clinical improvement, treatment was no better than control (Guha Mazumder et al, 1998).

b) DOSE: The recommended initial dose is 10 milligrams/kilogram or 350 milligrams/square meter every 8 hours for 5 days, followed by 10 milligrams/kilogram every 12 hours for 14 days (Prod Info, 1991).
c) ADVERSE EFFECTS

1) During clinical trials in children the following adverse reactions were reported (Prod Info, 1991):

1) Transient LFT increase: 6 to 10%
2) Mucosal vesicular eruptions: 1 case
3) Rash, pruritus: 2.6%
4) Nausea, vomiting, diarrhea: 12%
5) Drowsiness, paresthesia: 1%
6) Sore throat, rhinorrhea: 3.7%
7) Thrombocytosis, eosinophilia: 0.5%

2) Succimer has a sulfurous odor that may be evident in the patients' breath and urine (Prod Info, 1991a).

d) CASE REPORT - In a patient treated with DMSA (30 milligrams/kilogram/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).
e) DMSA has the advantage of being an oral agent as well as being relatively non-toxic.
f) An intravenous preparation of DMSA was used to treat a 26-year-old man with multi organsystem failure after acute trivalent arsenic overdose (Hantson et al, 1995).

1) A solution was prepared with 1.6 grams of DMSA diluted in 50 milliliters of sterile water and titrated with 10N NaOH to pH 7.2 to 7.4 and filtered through a 0.22 micron filter. The solution was administered in 500 milliliters of 0.9% saline solution as an infusion over 1 hour at a dose of 20 milligram/kilogram/day for 5 days followed by 10 milligram/kilogram/day. The DMSA solution was also given via peritoneal dialysis, 20 milligrams/liter of dialysate with 12 liters exchanged daily for 5 days.

I) UNITHIOL

1) EFFICACY

a) SUMMARY: 2,3-dimercapto-1-propanesulphonic acid (DMPS) is used in Europe as a chelating agent for heavy metal poisonings. 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 man (Goebel et al, 1990; Kew et al, 1993).
b) DOSE: DMPS has been given to adults in a dosage of 100 mg orally three times daily for 3 weeks (Kew et al, 1993) and up to 9 months (Goebel et al, 1990).

J) EXPERIMENTAL THERAPY

1) N-ACETYLCYSTEINE - N-acetylcysteine (NAC) has been shown to increase the LD50 of mice poisoned with sodium arsenite (Shum et al, 1981). NAC has the advantage of being both an oral and an intravenous agent, and so may become the only chelator which can be given intravenously for acute arsenic poisoning.
2) METHYL GROUP DONORS - Sulfo-adenosyl-L-methionine (Samyr(R), Bio-research, Milan) has been proposed as an agent which may promote methylation and subsequent urinary elimination of arsenic (Mahieu et al, 1987).

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).

L) EXPERIMENTAL THERAPY

1) IMMUNOTHERAPY - Use of immunotherapy for the treatment of sodium arsenite toxicity is being investigated in animal models. Leikin et al (1991) demonstrated a protective effect of anti-arsenic reactive serum female balb/c mice. Applicability of immunotherapy to treatment of human poisonings has not been determined.
2) 2,3-DITHIOERYTHRITOL - Is a synthesized derivative of BAL. Preliminary laboratory evidence indicates that it is less toxic than BAL or DMSA (Boyd et al, 1989).

M) CORTICOSTEROID

1) MELARSOPROL ENCEPHALOPATHY - Only 4 percent of those patients given corticosteroids (prednisolone, not more than 40 milligrams daily) developed melarsoprol encephalopathy compared to approximately 33 percent in those patients receiving no steroids in a prospective randomized trial involving 600 patients with parasitology-confirmed Trypanosoma brucei gambiense infections (Pepin et al, 1989).

N) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

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) ALKALINE DIURESIS

1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
2) SODIUM BICARBONATE/INITIAL DOSE

3) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

4) CAUTION

B) CHELATION THERAPY

1) The urine arsenic level which should prompt chelation in an asymptomatic patient has been said to be 200 micrograms/liter (Kersjes et al, 1987).
2) MOBILIZATION TEST

a) Diagnosis for mild or chronic exposure can be aided by the following procedure, although some authorities doubt its usefulness because of the relatively rapid excretion of absorbed arsenic:

1) Collect a 24 hour urine for baseline arsenic excretion (normal less than 100 micrograms/24 hours).
2) Following the baseline 24 hour collection, a second 24 hour urine collection should be performed while the patient receives 4 doses, every 6 hours, of D-penicillamine (25 milligrams/kilogram/dose up to 250 milligrams/dose). Cannot be given to patients allergic to penicillin.
3) Either urine collection showing arsenic excretion greater than 100 micrograms/24 hours is diagnostic and should be followed by a 5 day course of D-penicillamine. 24 hour urine collections to measure arsenic excretion during chelation are recommended. When urine arsenic falls below 50 micrograms/24 hours, chelation may be terminated. Observation for return of symptoms and a repeat of the mobilization test 1 to 2 weeks following initial therapy are strongly recommended.

b) During the mobilization test, the patient should avoid eating seafood. Ingestion of seafood, particularly shellfish, may transiently increase urinary arsenic levels to 200 to 1700 micrograms/liter (Baselt & Cravey, 1989; Baselt, 1988).
c) In epidemiologic studies, blood arsenic, pubic hair arsenic, and nail arsenic may be helpful to define potentially exposed versus unexposed populations, but such results cannot be interpreted in individual patients.

C) DIMERCAPROL

1) EFFICACY - Dimercaprol (BAL) is an effective arsenic chelator, but has the disadvantages of requiring painful intramuscular injections and having numerous side effects. BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948).
2) ADVERSE EFFECTS - Typical side effects which are dose related include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine (Woody & Kometani, 1948).
3) DOSE - Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose used is dependent on the severity of symptoms and urinary arsenic levels.

D) PENICILLAMINE

1) EFFICACY - D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977) Kuravilla et al, 1975; (Watson et al, 1981). It has the advantage of being an oral agent, but the disadvantages of not being able to be given to patients allergic to penicillin, not being retained well if patients are vomiting, and the theoretical problem of enhancing absorption of the arsenic-chelator complex. It does not appear to result in depletion of zinc and copper when given for several weeks (Peterson & Rumack, 1977).
2) ADVERSE EFFECTS - Long term therapy for the treatment of arthritis or Wilson's disease has resulted in fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity; these effects have not been reported when the drug is used for short-term heavy metal chelation (Gilman et al, 1985).
3) DOSE - The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day (Peterson & Rumack, 1977), but larger doses (i.e., up to 2 grams/day) may be required in adults.
4) In an experimental animal model, d-penicillamine was found to lack effectiveness in trivalent arsenic-poisoned mice and guinea pigs (Kreppel et al, 1989).

E) SUCCIMER

1) EFFICACY - 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug which appears to be a very effective arsenic chelator in experimental animals (Graziano et al, 1978) and man (Lenz et al, 1981; Kosnett & Becker, 1987; Fournier et al, 1988). In a patient treated with DMSA (30 milligrams/kilogram/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal arsenic excretion increased 1.5 fold (Fournier et al, 1988). DMSA has the advantage of being an oral agent as well as being relatively non-toxic.
2) In a double-blind, randomized, crossover, placebo-controlled study of patients with chronic environmental arsenical disease in West Bengal, patients were given placebo or DMSA 1400 mg/day for one week followed by 1050 mg/day for two additional weeks. The alternative treatment was then administered following a three week delay. Although both groups reported clinical improvement, treatment was no better than control (Guha Mazumder et al, 1998).

F) ACETYLCYSTEINE

1) EFFICACY - N-acetylcysteine (NAC) has been shown to increase the LD50 of sodium arsenite in mice (Shum et al, 1981). NAC has the advantage of being both an oral and an intravenous agent, but has not been studied for this indication in humans and cannot presently be recommended for the treatment of arsenic poisoning.

G) MONITORING OF PATIENT

1) THERAPEUTIC END-POINT - Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter (Goldfrank et al, 1986; AMA, 1986).

H) NEUROPATHY

1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases (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).

I) 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).

J) HEMODIALYSIS

1) Should be performed in the presence of any degree of renal failure, as the main route of excretion will be inhibited if this occurs. As the serum creatinine falls, urinary arsenic may increase (Giberson et al, 1976). Dialysanse of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980). This may be greater than renal clearance in the presence of oliguria or renal failure.
2) Hemodialysis was instituted 4-hours postadmission in a 30-year-old male who ingested 6 ounces of a rodenticide containing 1.5 percent arsenous oxide (equivalent to 2,150 milligrams metallic arsenic), although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988). Additional studies are needed to evaluate this regimen for safety and efficacy before it can be routinely recommended (Fesmire et al, 1988).

K) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

3) NOREPINEPHRINE

L) 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.

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

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) 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) ALKALINE DIURESIS

1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
2) SODIUM BICARBONATE/INITIAL DOSE

3) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

4) CAUTION

B) CHELATION THERAPY

1) The urine arsenic level which should prompt chelation in an asymptomatic patient has been said to be 200 micrograms/liter (Kersjes et al, 1987).
2) MOBILIZATION TEST

a) Diagnosis for mild or chronic exposure can be aided by the following procedure, although some authorities doubt its usefulness because of the relatively rapid excretion of absorbed arsenic:

C) DIMERCAPROL

D) PENICILLAMINE

E) SUCCIMER

F) ACETYLCYSTEINE

G) MONITORING OF PATIENT

H) NEUROPATHY

I) ACUTE LUNG INJURY

J) HEMODIALYSIS

K) 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.

L) HYPOTENSIVE EPISODE

1) SUMMARY

2) DOPAMINE

3) NOREPINEPHRINE

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

Enhanced Elimination

1) Hemodialysis should be performed in the presence of any degree of renal failure, as the main route of excretion will be inhibited if this occurs. As the serum creatinine falls, urinary arsenic may increase (Giberson et al, 1976).
2) 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). 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.

3) Dialysanse of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980).
4) Additional studies are needed to evaluate the safety and efficacy of hemodialysis in the treatment of arsenic poisoning in the absence of renal insufficiency before it can be routinely recommended.

a) Hemodialysis was instituted 4 hours postadmission in a 30-year-old male 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).

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) One to two mg/kg of ingested arsenic may be lethal in a child (Woody & Kometani, 1948; (HSDB , 2000).
2) As little as 20 mg of arsenic may produce life-threatening toxicity (Zaloga et al, 1970; Schoolmeester & White, 1980) Huttone & Christians, 1983).
3) An oral dose of 120 mg of arsenic trioxide may be fatal (Finkel, 1983).

1) Between 1966 and 1979, 61 cases of accidental sodium arsenite poisoning, including 11 patients who were hospitalized and 24 fatal cases in adults and children, were reported to the EPA's Pesticide Incident Monitoring System (PIMS) (EPA, 1988).

1) Published Values (RTECS, 2000; (EPA, 1985) -

1) LDLo (ORAL) Human-Child 1mg/kg
2) LDLo (ORAL) Human-Child 2mg/kg
3) LDLo (IP) Rat 7mg/kg
4) LDLo (IV) Rat 6mg/kg
5) LDLo (ORAL) Rabbit 12 mg/kg
6) LDLo (ORAL) Rabbit 7.5 mg/kg
7) LDLo (IV) Rabbit 6 mg/kg

Maximum Tolerated Exposure

1) AVERAGE HUMAN ARSENIC INTAKE - 250 to 330 mcg/day (in food and water) (Gilman et al, 1985) Basalt & Cravey, 1989).
2) AVERAGE URINE LEVELS - Persons on non-seafood diets usually excrete 10 to 30 mcg/day (Finkel, 1983). Following a seafood meal, urine arsenic levels may temporarily rise to 200 to 1700 mcg/L, due to the presence of non-toxic organic "fish arsenic" in certain seafood (Baselt & Cravey. 1989; (Baselt, 1988).

a) For persons with a non-seafood diet, twenty-four hour composite urine samples above 100 mcg/d should be repeated and evaluated, and samples above 200 mcg/d should reflect a toxic intake (Morgan, 1989).

1) ARSENIC TRIOXIDE -

a) Arsenic trioxide in a solubilized form becomes sodium arsenite, which is more toxic than in an unsolubilized form.
b) A dose of 200 milligrams of arsenic trioxide ingestion by an adult may be lethal (Basalt & Cravey, 1989; Basalt, 1988).
c) CASE REPORTS

1) Acute ingestion of 9 to 14 milligrams of arsenic trioxide by a 16-month-old child produced classic gastrointestinal signs and symptoms of arsenic poisoning (Watson et al, 1981).
2) A 30-year-old man survived an ingestion of 6 ounces of "Blue Ball Rat Killer" containing 1.5% arsenous oxide (2,150 milligrams metallic arsenic per 6 ounces) with aggressive therapy (fluid resuscitation, chelation and hemodialysis) (Fesmire et al, 1988).

2) TRIVALENT/PENTAVALENT ARSENIC -

a) Trivalent arsenic (arsenite) is more toxic in animals than the pentavalent form (arsenate) (Morgan, 1989).
b) No definite evidence of intoxication was noted in a pharmaceutical plant with an average arsenic air concentration of 0.2 mg/m(3) (ACGIH, 1986).

1) An increased incidence of cancer was reported in factories with airborne arsenic concentrations of 0.002 to 0.65 mg/m(3) in "light exposure areas" and 1.47 to 1.56 mg/m(3) in "medium and high exposure areas" (ACGIH, 1986).
2) Concentrations of arsenic in urine, blood and gastric fluid after admission in a worker buried in arsenic trioxide for about 10 minutes were 1.9, 3.4 and 550 mg/L, respectively (Gerhardsson et al, 1988).

a) Tissue concentration in mcg/g wet weight of arsenic at autopsy were: brain (frontal cortex) 0.3, myocardium (left ventricle) 1.2, kidney (cortex) 1.4, lung (peripheral) 2.9, liver 3.8, and blood 2.3 (Gerhardsson et al, 1988).

3) Chronically exposed workers with urinary arsenic excretions as high as 4.0 mg/L (4000 mcg/L) (average 0.8 mg/L; 800 mcg/L) complained of dermatitis, perforation of the nasal septum, pharyngitis and conjunctivitis (ACGIH, 1986).

a) No systemic toxicity was noted in this group of workers (Finkel, 1983).

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: Sodium arsenite

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: Sodium arsenite

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) References: (RTECS, 2000; EPA, 1985

1) LD50- (INTRAMUSCULAR)MOUSE:

a) 14 mg/kg

2) LD50- (INTRAPERITONEAL)MOUSE:

a) 1170 mcg/kg

3) LD50- (ORAL)RAT:

a) 41 mg/kg

4) LD50- (SKIN)RAT:

a) 150 mg/kg

Pharmacology Toxicology

Physicochemical

Physical Characteristics

1) Commercial: 95%-98% pure (Budavari, 1996)
2) Technical: 90-95% pure (EPA, 1985)
3) Sodium arsenite in solution (94%) is 75% arsenious oxide (Sax & Lewis, 1987)

Molecular Weight

Animal Toxicology

References

General Bibliography

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Classification | Detailed evidence-based information

Therapeutic Toxic Class

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Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

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Monitoring Parameters Levels

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Enhanced Elimination

Summary

Minimum Lethal Exposure

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Workplace Standards

Toxicity Information

Physical Characteristics

Molecular Weight

General Bibliography