Dimercaprol (Systemic)

VA CLASSIFICATION
Primary: AD300

Commonly used brand name(s): BAL in Oil.

Other commonly used names are
British Anti-Lewisite and dimercaptopropanol .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Chelating agent—

Indications

Accepted

Toxicity, arsenic (treatment) ^{{02} {05} {11} {12} {13} {16} {17} {26} {27} {36}{38}{39}{40}{41}{42}{43}}
Toxicity, gold (treatment) ^{{02} {11} {13} {26} {27}} or
Toxicity, mercury (treatment) ^{{02} {05} {09} {11} {13} {26} {27} {34}{38}{44}{45}{46}{47}{48}{49}{50}{51}{52}{53}}—Dimercaprol is indicated as a chelating agent in arsenic, gold, and mercury (soluble inorganic compounds) poisoning following ingestion, inhalation, or absorption through the skin of these metals or their salts, or following overdose of therapeutic agents containing the metals. ^{03}
—In arsenic (except for arsine gas) ^{{11} {25}} toxicity, early administration of dimercaprol may help reverse the acute and some of the chronic manifestations of poisoning, although polyneuropathy may be refractory. ^{16} Chelation therapy is recommended if urine arsenic levels are consistently above 200 mcg per liter. ^{11}
—In gold toxicity resulting from therapeutic uses of gold compounds for arthritis, dimercaprol may be effective in enhancing the excretion of accumulated gold salts. In patients with severe renal, hematologic, pulmonary, or enterocolitic complications who do not improve with high-dose corticosteroid treatment or who develop steroid-related adverse reactions, dimercaprol may be considered and has been used successfully. However, patients must be carefully monitored because of the adverse reactions that accompany its use. ^{10}
—In acute inorganic ^{19} and aryl organic ^{{11} {32}} mercury toxicity, dimercaprol therapy is most effective when begun within 1 or 2 hours after ingestion, ^{{02} {03} {26} {27}} and ceases to be effective after about 6 hours. ^{02} Dimercaprol is of questionable efficacy in elemental mercury poisoning. ^{11}

Toxicity, lead (treatment adjunct) ^{{02} {05} {11} {13} {26} {27} {35}}—Dimercaprol is indicated for treatment of acute and chronic ^{19} lead poisoning when administered in conjunction with edetate calcium disodium (calcium EDTA). When administered promptly, dimercaprol complements edetate calcium disodium by more rapidly removing lead from red blood cells and the central nervous system (CNS) ^{{11} {32}} than does edetate calcium disodium alone, and by assisting in mobilization of lead from skeletal stores. ^{04} This combination is less toxic than edetate calcium disodium alone because lower doses of each can be used. The rate of lead excretion is doubled ^{04} when the combination is used, thus decreasing the mortality rate and the likelihood of permanent neurologic deficits from lead poisoning. ^{03}
—Signs and symptoms of severe, symptomatic lead poisoning include anemia, ^{35} gastrointestinal complaints (abdominal pain and vomiting), ^{{11} {35}} nephropathy, and encephalopathy. ^{01} Signs and symptoms of lead encephalopathy include headache and insomnia; persistent vomiting, sometimes projectile; visual disturbances; irritability, restlessness, delirium, hallucinations; ataxia; ^{11} convulsions and coma; and characteristically high intracranial pressure. Recovery is slow and often incomplete, with residual neurological deficits. ^{01}
—Clinical signs suggesting lead poisoning in children and adults ^{28} that should be treated with the dimercaprol, edetate calcium disodium combination include the following:    • Patient is severely symptomatic (with or without encephalopathy). ^{{01} {05} {35}}
   • Blood lead concentrations are greater than or equal to 70 mcg per deciliter. ^{{01} {35}}


Unaccepted
Dimercaprol should not be used in iron, ^{{02} {26} {27}} cadmium, ^{{02} {11} {26} {27}} selenium, ^{{02} {11} {26} {27}} silver, or uranium poisoning because the dimercaprol-metal complexes are more toxic, especially to the kidneys, than the metal alone. ^{{01} {02} {07}}

In methylmercury or other short-chain alkyl organic mercury intoxication, dimercaprol enhances the distribution of mercury into the brain, and is contraindicated. ^{{05} {07} {15}}

Dimercaprol is of questionable value in poisoning by the heavy metals antimony and bismuth. ^{{02} {26} {27}}

Dimercaprol is contraindicated ^{25} in poisoning from arsine gas (AsH ₃). ^{{03} {05}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    124.22 ^{26}

Mechanism of action/Effect:


Chelating agent:

Certain heavy metals, especially arsenic, gold, lead, and mercury, form ligands in the body with the sulfhydryl (-SH) groups of the pyruvate-oxidase enzyme system, and inhibit the normal functioning of the enzymes ^{{11} {34} {35} {36}} that are dependent on free sulfhydryl groups for their activity. Dimercaprol, having a greater affinity for the metal than does the protein, reverses the enzyme inhibition by chelating the metal and preventing or reversing its toxic effects ^{26} by regeneration of free sulfhydryl groups. The resulting dimercaprol-metal complex is relatively stable and rapidly excreted. ^{{04} {05} {06}}

In addition, in lead toxicity, dimercaprol causes a fast but short-lived reduction in lead concentrations in red blood cells and CNS, ^{{11} {32}} and effects a greater total lead excretion (urinary and fecal) than edetate calcium disodium because of its high fecal lead output. ^{04} The addition of equimolar amounts of dimercaprol to edetate calcium disodium doubles the ratio of chelants to lead, thus providing the molar excess of chelating agent that is necessary for significant heavy metal excretion. ^{04}


Distribution:

All tissues, including the brain, but mainly in the intracellular space. ^{03} The highest concentrations are in the liver and kidneys. ^{03}

Biotransformation:

About 50% rapidly metabolized to inactive metabolites. ^{08}

Onset of action:

30 minutes. ^{11}

Time to peak concentration:

30 to 60 minutes after intramuscular administration. ^{{02} {05}}

Duration of action:

About 4 hours. ^{{04} {05}} Frequent doses at 3- to 4-hour intervals over prolonged periods are necessary to maintain therapeutic effect. ^{04}

Elimination:
    50% as the dimercaprol-metal complex, via the renal and biliary tracts; as metabolites, in the urine; metabolism and excretion are usually complete within 6 to 24 hours. ^{{02} {04} {05}}


Precautions to Consider

Cross-sensitivity and/or related problems

Dimercaprol injection should not be used in patients who are allergic to peanuts or peanut products. ^{01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies have not been done in humans. ^{{01} {26}}

Studies have not been done in animals. ^{26}

FDA Pregnancy Category C. ^{{26} {27}}

Breast-feeding

It is not known whether dimercaprol is distributed into breast milk. ^{{26} {27}}

Pediatrics

Fever, ^{{02} {05} {11}} which appears after the second or third dose of dimercaprol, persists throughout therapy, and disappears upon withdrawal of therapy, is more likely to occur in children than in adults. ^{02} A transient reduction of polymorphonuclear leukocytes may also be seen. ^{05}


Geriatrics


No information is available on the relationship of age to the effects of dimercaprol in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Iron salts^{02}    (concurrent administration of medicinal iron with dimercaprol results in the formation of a toxic complex; ^{{01} {11} {27}} if iron deficiency is present, its treatment should be postponed until therapy with dimercaprol has been discontinued for at least twenty-four hours; ^{03} however, severe iron deficiency anemia occurring during dimercaprol therapy should be managed with blood transfusion ^{{04} {14}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Thyroid tests    (when test is done during or immediately after dimercaprol therapy, iodine I 131 thyroidal uptake values may be decreased because of dimercaprol interference with normal accumulation of iodine in the thyroid gland ^{03})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (values may be temporarily elevated ^{{02} {14}})


Polymorphonuclear leukocyte count    (a transient reduction may be seen in children ^{05})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Arsine gas poisoning    (chelation with dimercaprol is not useful in acute poisoning because it does not prevent hemolysis ^{{05} {11}})


» Hepatic function impairment^{{02}{05}{11}{26}{27}}    (except in postarsenical jaundice, which may only require a reduction in dosage, metabolism may be reduced)


» Iron, cadmium, selenium, silver, or uranium poisoning    (dimercaprol-metal complexes of these metals are more toxic than the metal alone, and may cause nephrotoxicity ^{{07} {27}})


» Organic (short-chain alkyl) mercury poisoning    (distribution of mercury to the brain is enhanced by dimercaprol ^{15})


Risk-benefit should be considered when the following medical problems exist
Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (dimercaprol may induce hemolysis and should be used only in life-threatening situations in patients with this deficiency ^{{01} {02} {05} {11}})


Hypertension    (may be exacerbated ^{{11} {27}})


Renal function impairment^{11} or
» Renal insufficiency, acute^{26}    (dimercaprol should be used cautiously if acute renal insufficiency develops during therapy because accumulation of dimercaprol may result in toxic serum concentrations; ^{{02} {27}} if oliguria is present, dimercaprol should be used with caution and/or in reduced dosage ^{03})


Sensitivity to dimercaprol

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alkaline phosphatase concentrations, serum^{04} and
Blood urea nitrogen (BUN) concentrations^{09} and
Calcium concentrations, serum^{04} and
Creatinine concentrations, serum^{09} and
Electrolyte concentrations, serum^{04}{34} and
Phosphorus concentrations, serum^{04}    (determinations recommended to detect evidence of renal function impairment; hemodialysis may be necessary ^{16})


Blood pressure^{11}{35} and
Heart rate    (recommended periodically during therapy, since both may be increased ^{07})


Fluid balance^{05}{34}    (recommended for determination of dehydration or impending renal insufficiency; ^{22} parenteral fluids should be administered, at least during the first 2 or 3 days of dimercaprol therapy, to replace oral feedings that may not be tolerated or to minimize nausea and vomiting caused by either dimercaprol or the toxic agent or both ^{19})


Heavy metal concentration in blood^{19}{34} and
24-hour urine excretion^{05}{07}    (recommended to determine dosage and duration of therapy ^{21})


Hemoglobin    (recommended periodically in mercury toxicity)


Urinary pH    (recommended periodically; maintenance of an alkaline pH decreases the risk of nephrotoxicity, which may occur because of dissociation of the dimercaprol-metal complex in acidic urine ^{{02} {03}})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Fast heartbeat ^{{02}{05}{11}{26}{27}{34}{36}}
    
fever —especially in children^{{02}{05}{11}{26}{34}{36}}
    
increased blood pressure —both systolic and diastolic, roughly dose related^{{02}{05}{11}{26}{27}{36}}

Incidence less frequent
    
Abscesses, usually sterile, at injection site (painful, red, and pus-containing sores)^{{02}{05}{26}{27}}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Burning feeling in lips, mouth, throat, and penis ^{{02}{05}{11}{26}{36}}
    
conjunctivitis ^{{02}{05}{11}{26}{36}}
    
eyelid twitching
    
^{05}{26}{34} feeling of constriction or pain in throat, chest, or hands ^{02}{05}{26}
    
headache ^{{01}{02}{05}{11}{26}{34}}
    
nausea and sometimes vomiting ^{{01}{02}{05}{09}{11}{26}}
    
pain at injection site ^{26}{27}
    
runny nose ^{{01}{02}{05}{26}}
    
sweating of forehead and hands ^{02}{05}
    
tingling of hands ^{05}{26}{35}
    
unpleasant breath odor ^{02}
    
watery eyes and mouth ^{{01}{02}{05}{11}{34}{35}}

Note: All of the effects listed above, except pain at injection site and unpleasant breath odor, may occur with doses above the recommended dose, may be mild and temporary, and are often accompanied by feelings of anxiety, weakness, and unrest. ^{05}


Incidence less frequent
    
Abdominal pain ^{02}{05}{26}
    
lower back pain ^{08}
    
tremors ^{08}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Convulsions ^{11}{26}

severe drowsiness

severe vomiting^{01}{26}

Note: These symptoms may be seen at doses above 5 mg per kg of body weight (mg/kg), beginning within 30 minutes and usually subsiding within 6 hours following injection. ^{01}



General Dosing Information
In any heavy metal poisoning, supportive therapy is as important to survival as chelation therapy. Removal of patient from exposure is the primary therapy for exposed patients. ^{{05} {32} {34} {36}} Depending on the metal, supportive treatment may include removal of the residual metal from the body with emesis or gastric lavage; intravenous fluids to correct dehydration and electrolyte deficiencies; bed rest; preservation of body heat; exchange transfusions; abdominal radiographs; and analgesics. ^{{04} {36}}

Since dimercaprol is better able to prevent inhibition of sulfhydryl enzymes than to reactivate them, dimercaprol therapy is most effective when begun immediately after exposure. The toxic metal ion is inactivated and its incorporation into binding sites in blood and tissue is prevented. If reactivation of enzymes is necessary, prolonged therapy may be required. ^{{02} {05}}

Dimercaprol is always administered by deep intramuscular injection, ^{{11} {26}} never by intravenous or subcutaneous injection. ^{02} Rotating injection sites may minimize development of abscesses. ^{{02} {29}}

The dosage of dimercaprol must be repeated frequently for several days. This maintains a plasma concentration of free dimercaprol in the body fluids that enhances the continuous formation of a rapidly excreted stable complex of 2:1 (dimercaprol:metal) until a significant portion of the metal is eliminated from the body. ^{{05} {08}}

Because the dimercaprol-metal chelation is reversible and can rapidly dissociate in an acid medium, alkalinization of the urine is necessary to prevent dissociation into the toxic metal and potentially nephrotoxic dimercaprol. ^{{02} {05} {11} {26}} After assuring adequate urine volume, a less acid urine may be achieved by oral administration of sodium bicarbonate, with the dosage and frequency being determined by monitoring urinary pH. If patients are placed on parenteral fluids, adjustment of the composition of the solutions may provide a neutral urine, or alkalization of the urine may be achieved by intravenous infusion of sodium bicarbonate over 4 to 8 hours. Such patients may be advanced cautiously to clear oral liquids or oral rehydration solutions. ^{{20} {22}}

For acute lead encephalopathy
Dimercaprol is combined with edetate calcium disodium because the maximum safe dose of edetate calcium disodium alone may cause a shift of lead into the central nervous system (CNS). ^{{11} {32}} The preferred route of administration for edetate calcium disodium is intravenous, and dimercaprol is given by deep intramuscular injection, ^{35} in divided doses every 4 hours for 5 days. If both medications are given by intramuscular injection, they must be given at separate sites. Dimercaprol is given alone for the first dose 4 hours before the combination is begun. ^{05} In asymptomatic or mildly symptomatic patients, dimercaprol may be discontinued after 72 hours, ^{20} with edetate calcium disodium being continued for an additional 48 to 72 hours at reduced dosage. ^{{09} {18}}

Oral penicillamine is used for long-term chelation therapy after initial therapy with edetate calcium disodium or combined dimercaprol and edetate calcium disodium, especially if long-bone radiographs show lead lines. ^{18} The oral chelating agent succimer is used for treatment of children with blood lead concentrations greater than 45 micrograms per deciliter. ^{37} Although use to date has been limited, toxicity with succimer appears to be less than with other agents. ^{{01} {31}}

For prevention or treatment of adverse effects
   • For histaminic effects, mild and temporary—Recommended treatment may include administration of diphenhydramine in doses up to ^{30} 1.5 mg per kg intramuscularly or orally every 6 hours. ^{11}
   • For nausea or vomiting—May be prevented by giving patient nothing orally and hydrating initially with parenteral fluids. ^{18} After clinical improvement occurs, clear liquids may be administered orally as parenteral fluids are phased out. ^{19}
   • For sterile abscesses—May be prevented by rotating sites of injection and always administering deep intramuscular injections. ^{{18} {20}} If existing abscess does not subside spontaneously, aspiration and drainage may be necessary. ^{{20} {21} {22} {24}}


Parenteral Dosage Forms

DIMERCAPROL INJECTION USP

Usual adult and adolescent dose
Arsenic or gold toxicity
Severe: Intramuscular (deep), 3 mg per kg of body weight every four hours for two days, four times on the third day, then twice a day for ten days; ^{{26} {27}} or 3 mg per kg of body weight every four hours on the first day, 2 mg per kg of body weight every four hours on the second day, 3 mg per kg of body weight every six hours on the third day, and 3 mg per kg of body weight every twelve hours on each of the following ten days or until recovery. ^{08}

Mild: Intramuscular (deep), 2.5 mg per kg of body weight every six hours for two days, every twelve hours on the third day, and once a day on each of the following ten days or until recovery. ^{{26} {27}}

Mercury toxicity
Intramuscular (deep), 3 to 5 mg per kg of body weight every four hours for two days, then 2.5 to 3 mg per kg of body weight every six hours for two days, then 2.5 to 3 mg per kg of body weight every twelve hours for seven days. ^{23}

Lead toxicity
Severe (encephalopathy): Intramuscular, 4 mg per kg of body weight for the first dose, repeated at four-hour intervals in conjunction with edetate calcium disodium (calcium EDTA) injection, which is usually administered intravenously, but may be administered intramuscularly at a separate site. This treatment is maintained for two ^{{05} {27}} to seven days. ^{27} If the blood lead concentration after this first course of therapy exceeds 100 mcg per deciliter, treatment may be resumed for an additional five days, following an interval of at least two days without treatment. ^{{25} {32}}

Mild: Intramuscular, 4 mg per kg of body weight for the first dose, the dose then being reduced to 3 mg per kg of body weight and administered at four-hour intervals in conjunction with edetate calcium disodium injection, which is administered at a separate site.


Usual adult prescribing limits
5 mg per kg of body weight. ^{{02} {26}}

Usual pediatric dose
Arsenic toxicity
Severe: Intramuscular (deep), 3 mg per kg of body weight every four hours for two days, four times on the third day, then twice a day for ten days.^{38}

Mild: Intramuscular (deep), 2.5 mg per kg of body weight every six hours for two days, every twelve hours on the third day, and once a day on each of the following ten days or until recovery.^{38}

Mercury toxicity
Intramuscular (deep), 5 mg per kg of body weight initially, followed by 2.5 mg per kg of body weight one or two times a day for ten days.^{38}

Lead toxicity


Symptomatic children:
Acute (with or without encephalopathy) ^{11}—Intramuscular (deep), 75 mg per square meter of body surface area every four hours (up to 450 mg per square meter per twenty-four hours). After four hours, calcium EDTA injection, 1500 mg per square meter of body surface area per twenty-four hours, should be administered on a four-hour schedule, intravenously or intramuscularly at a separate site. This treatment is maintained for five days. If the blood lead concentration after this first course of therapy exceeds 70 mcg per deciliter, treatment may be resumed for an additional five days, following an interval of at least two days without treatment. ^{32} The cycle may be repeated, depending on the clinical response. ^{{01} {11} {14}}



Asymptomatic children:
Intramuscular (deep), 50 mg per square meter of body surface area every four hours. After four hours, calcium EDTA injection, 1000 mg per square meter of body surface area per twenty-four hours, should be administered on a four-hour schedule simultaneously intravenously or intramuscularly at a separate site. This treatment is maintained for five days. Dimercaprol may be discontinued after three days if blood lead concentrations are less than 50 mcg per deciliter. If the blood lead concentration after this first course of therapy exceeds 70 mcg per deciliter, treatment may be resumed for an additional five days, following an interval of at least two days without treatment. ^{32} Calcium EDTA injection should be continued for five more days. The cycle may be repeated depending on the clinical response. ^{{11} {14} {33}}



Strength(s) usually available
U.S.—


100 mg per mL (Rx) [BAL in Oil (benzyl benzoate 200 mg) (peanut oil 700 mg)]

Canada—


100 mg per mL (Rx) [BAL in Oil (benzyl benzoate 200 mg) (peanut oil 700 mg)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), ^{26} unless otherwise specified by manufacturer.

Revised: 11/11/1994

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