Background

Enormous achievements and incredible misfortune mark arsenic’s history. Dating back to 400 BC, Greek and Roman physicians included arsenic in their medical armamentarium.¹ Today, arsenic continues to be found in treatments offered by practitioners of Indian folk medicine and traditional Chinese medicine.^2,3 In addition, in Western medicine, arsenic trioxide (Trisenox) and melarsoprol are used to treat promyelocytic leukemia⁴ and late-stage African trypanosomiasis.⁵

Arsenic’s therapeutic usefulness is based on its ability to poison cells, and it is best known as a poison. While arsenic has been noted to produce a garlic odor and possess a characteristically sweet flavor, most arsenical compounds have no perceptible smell or taste.⁶ This has made the detection of arsenic difficult when employed as a homicidal agent. Historically, this has afforded arsenic the illustrious title of “Poison of Kings and the King of Poisons.”⁷

Toxicity

Environmental arsenic comes from both natural (volcanic eruption, water runoff) and manmade sources (mining, smelting, combustion of fossil fuels, and pesticide use).^7,8 Food, predominantly seafood, represents the principal route for human exposure; however, rice, mushrooms, and poultry also contribute to exposure.⁶ Alternative sources include air and water, particularly in Bangladesh where tube-wells supply millions with arsenic-contaminated drinking water.⁹ In the United States, the average person consumes 50 µg of arsenic daily, with inorganic arsenic accounting for 3.5 µg of this total. Certain occupations such as metal working, electronics manufacturing, and glass manufacturing also increase arsenic exposure.⁶

Arsenic is found in nature in several different forms: combined with carbon and other elements in organic compounds, in inorganic compounds, in gaseous compounds, and in the nontoxic elemental form. Arsenobetaine, an organic arsenic compound found in fish and shellfish, possesses a low risk for human toxicity.⁶ Inorganic arsenicals, found as trivalent (As³⁺, arsenite, more toxic) or pentavalent (As⁵⁺, arsenate, less toxic) compounds, account for the majority of human toxicity. Arsenite compounds exhibit high affinity for binding to proteins, whereas the majority of arsenate compounds remain unbound. Weak protein binding allows arsenate compounds to be freely excreted. Protein-bound arsenite functions as both a storage depot and a target action site.¹⁰ Alternating hepatic reduction and methylation reactions convert inorganic arsenic to an organic form. This transformation detoxifies the parent compound but also increases arsenic’s carcinogenicity.^7,10,11

The mechanism accounting for arsenic’s ability to disrupt cellular function, and that which results in acute toxicity, differs depending on the form of arsenic responsible for the exposure. By disrupting the activity of key enzymes by binding to critical sulfhydryl groups, arsenite impairs both oxidative phosphorylation and gluconeogenesis. Especially important in this regard is arsenite’s ability to inhibit the enzyme, pyruvate dehydrogenase (PDH), which catalyzes the first and rate-limiting step in the tricarboxylic acid (TCA) cycle. Inhibition of PDH hinders the production of acetyl-CoA from pyruvate, limiting cellular ATP production. In addition, arsenate can substitute for phosphate and become incorporated into arsenate analogs of glucose-6-phosphate, 6-phosphogluconate, and adenosine triphosphate (ATP).^6,12,13 These arsenate analogs are less stable than their phosphate-containing counterparts, and their formation can lead to uncoupling of oxidative phosphorylation.^6,13–16

Arsine gas (AsH₃) is released when many arsenic-containing compounds come in contact with an acid or when metallic arsenic comes into contact with water. Workers involved with lead plating, soldering, etching, smelting, and galvanizing are at risk for exposure to arsine gas.¹⁷ Being colorless and nonirritating, arsine gas is particularly difficult to detect following industrial exposure. As with arsenic, arsine gas has been noted to possess a slight garlic odor; also like arsenic, however, arsine’s odor is not always detectable.¹⁸

Exposure to arsine causes acute hemolysis. The exact mechanism for this hemolysis is not completely understood and is likely multifactorial, involving both binding of arsine to hemoglobin and perhaps inhibition of sulfhydryl-containing enzymes.^19–22 One complication of arsine exposure is acute renal failure. Arsine-induced renal failure most likely is secondary to direct nephrotoxic effects of arsine as well as the renal toxicity caused by the release of hemoglobin from lysed red blood cells.²³ Although chronic renal dysfunction has been described after arsine exposure, recovery is possible.^22,24

Clinical Presentation

A patient’s clinical presentation after arsenic exposure is influenced by four factors: the arsenic species, the amount, the route, and the duration of exposure. In addition, the symptoms of acute arsenic toxicity differ depending on whether exposure was oral or inhalational. Gastrointestinal symptoms are a reliable finding in cases of acute arsenic poisoning. Shortly after exposure, patients typically experience abdominal discomfort, nausea, emesis, and profuse diarrhea.^7,25,26 Severe gastroenteritis and hemorrhage may develop. Furthermore, arsenic induces capillary dilation, third-spacing of fluid, ventricular arrhythmias, and cardiomyopathy. Collectively these changes can result in pulmonary edema, hypotension, congestive heart failure, and shock.^7,20 Cardiac abnormalities following arsenic exposure can include QTc prolongation, T-wave abnormalities, second-degree heart block, QRS widening, nonconducted P-waves, nonsustained ventricular tachycardia, torsades de pointes, complete heart block, asystole, pericardial effusion, and serositis.^27–31 Cardiac conduction abnormalities have been described following therapeutic use of arsenic trioxide. These conduction abnormalities may be a consequence of arsenic trioxide–induced electrolyte abnormalities (hypokalemia or hypomagnesemia).²⁹ Alternatively, these changes in cardiac conduction might reflect the cardiotoxic effects of other cancer chemotherapeutic agents. Additionally, arsenic-induced blockade of I_Kr and I_Ks channels with activation of I_K-ATP channels has been demonstrated.³² The variability seen in arsenic-induced QTc prolongation likely occurs secondary to the combined effects of this activation and blockade.

Neurologic symptoms are also associated with arsenic toxicity and typically include altered mental status and confusion.^20,25 Seizures have been linked to arsenic-induced arrhythmias,^27,33 and if related to hypoxemia may signal a terminal stage in cases of arsenic poisoning. While typically delayed 2 to 8 weeks after exposure, peripheral neuropathy from large arsenic exposures sometimes can become apparent within a few hours.^7,34 Patients describe pain, numbness, and paresthesias in a “stocking/glove” sort of distribution.^20,25,35 The symmetric sensorimotor neuropathy seen following arsenic exposure can be misdiagnosed as Guillain-Barré.^7,35 Marked abnormalities in sensory and mixed nerve conduction in conjunction with moderate motor conduction abnormalities can be seen on electrophysiologic testing. These results are consistent with axonal degeneration, which is also apparent histologically in nerve biopsies.³⁶

Symptoms of chronic arsenic toxicity differ from those of acute toxicity. Patients demonstrate hematologic abnormalities including pancytopenia, anemia, and macrocytosis. Dermal manifestations include Mees lines (transverse white striae on the fingernails), hyperkeratotic extremity lesions, and hyperpigmented melanosis. Gastrointestinal symptoms as well as liver disease are also described.^7,26,37,38 Additionally, patients may note a metallic taste.^7,38,39

Inhalational exposure to arsenic in the form of arsine gas produces symptoms that differ from those seen with oral arsenic exposure. Classically, exposure is characterized by the development of a triad of symptoms: abdominal pain, hematuria, and jaundice. Within 2 to 24 hours of exposure, patients develop headache, malaise, abdominal discomfort, nausea, and emesis. The variability in the onset of symptoms is influenced by the duration of exposure and the concentration of the gas.¹⁷ Hemolysis with subsequent gross hematuria and renal failure often follow. Additionally, patients may develop scleral icterus and a bronze skin discoloration.^17,24 As with exposure to other arsenic compounds, exposure to arsine gas can lead to development of peripheral neuropathy.⁴⁰

Diagnosis

The potential for arsenic toxicity can be determined by combining the patient’s clinical presentation with the likelihood of exposure. Blood and urine testing can confirm the diagnosis. Blood arsenic clearance occurs in three phases: Phase 1 takes place 2 to 3 hours following intravenous (IV) administration and is associated with a half-life (t_1/2) of about 2 hours; phase 2 occurs 3 hours to 7 days following administration and is associated with a t_1/2 of about 27 hours; and phase 3 occurs 10 or more days following administration and is associated with a t_1/2 of about 230 hours.⁴¹ Arsenic is rapidly cleared from the blood during phases 1 and 2; thus, the reliability of blood arsenic testing is limited to the early stages of acute toxicity.³³ Following IV administration of radioactive arsenic, urinary recovery has been demonstrated at 18% to 30% after 1 hour, 36% to 56% at 4 hours, 57% to 90% by 9 days, and 96.6% by 18 days.⁴¹ A positive urine arsenic level should be followed up by arsenic speciation to distinguish nontoxic organic arsenic (commonly found in seafood) from the toxic inorganic form. A random urine arsenic level greater than 50 µg/L, or a 24-hour urine sample demonstrating more than 100 µg of arsenic, can confirm the diagnosis of acute arsenic toxicity. However, this diagnosis should be questioned if there is a history of recent seafood ingestion or the sample was not collected in a metal-free container. Hair and nail samples may be used to confirm exposure when chronic toxicity is suspected.⁷ Hair testing can also be performed to estimate an approximate exposure date based on the rate of hair growth (0.4 mm/d) and the distance of the root from the arsenic peak.⁴² Additionally, an electrocardiogram (ECG) should be obtained in cases of potential arsenic toxicity; T-wave abnormalities, QTc prolongation, and torsades de pointes have been described following arsenic exposure.^27,31

Following possible exposure to arsine gas, laboratory evaluation should include complete blood count, measurement of circulating lactate dehydrogenase and other liver enzyme concentrations, measurement of serum bilirubin concentration, Coombs testing, and monitoring of serum electrolyte levels and renal function. Patients will demonstrate a Coombs-negative hemolytic anemia with elevated circulating lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and bilirubin levels, renal dysfunction, and subsequent hyperkalemia. Hemoglobinuria, albuminuria, and occasional erythrocyte and hemoglobin tubular casts are commonly seen on urinalysis. A peripheral blood smear can show signs of red blood cell damage including erythrocyte fragments, basophilic stippling, anisocytosis, poikilocytosis, and Heinz bodies.^17,18,22,43 Methemoglobinemia also has been described.⁴³

Treatment

Initial treatment of arsenic toxicity must include prevention of further exposure to the poison, careful monitoring of the cardiovascular system, and judicious repletion of intravascular fluid deficits. Hyperkalemia, which can be clinically significant, should be treated. Despite a lack of supporting data, gastric lavage and administration of activated charcoal should be considered following oral exposure to a large of dose of arsenic in an attempt to limit absorption of the toxic compound(s).⁷ Patients presenting with renal failure following arsenic exposure may need renal replacement therapy until renal function recovers.⁴⁴ Additionally, patients demonstrating ECG abnormalities, particularly QTc prolongation, should have close monitoring of their electrolytes, with replacement as indicated. Antiarrhythmic therapy should be instituted as needed.

Chelators are an additional treatment to be considered. Dimercaprol, a parenteral chelating agent which functions intracellularly as well as extracellularly, is the first line of therapy for patients experiencing abdominal symptoms following acute arsenic exposure.³³ Dimercaprol should be administered intramuscularly (IM) at doses of 3 to 4 mg/kg every 4 to 12 hours.²⁰ In cases of subacute or chronic exposure when the patient can take oral medications, succimer (DMSA or 2,3-dimercaptosuccinic acid) is the chelator of choice. Succimer should be administered orally (10 mg/kg every 8 hours for 5 days). Following the initial 5 days of administration, succimer dosing is adjusted to every 12 hours.³³ Clinical course determines the duration of chelator therapy.²⁰ Urinary arsenic levels can be used to calibrate duration of treatment, with therapy being discontinued when 24-hour urinary arsenic levels are below 50 µg/L.³³ Despite its recommended use, succimer has not consistently demonstrated increased urinary arsenic excretion following administration, and neuropathy can progress despite therapy.^25,42 Succimer is not currently approved by the U.S. Food and Drug Administration (FDA) for treatment of arsenic toxicity.⁴⁵

Treatment of arsine gas exposure represents a special circumstance. As with other forms of arsenic exposure, initial therapy requires elimination of the source. Caution should be taken to prevent additional casualties as first responders enter the exposure site. Since arsine toxicity is associated with hemolysis, exchange transfusion can be used to replenish red blood cell mass and remove both the toxic complexes formed from the arsine/hemoglobin interaction as well as the released hemoglobin pigment.^40,46 Patients with renal failure should receive renal replacement therapy as indicated by clinical findings.^17,18 The use of chelation therapy to treat patients acutely poisoned by arsine is controversial and may not affect the clinical course.¹⁸

Background

Mercury is a naturally occurring metal found in elemental, inorganic salt, and organic forms. The use of mercury dates back to before 1500 BC. Throughout history, mercury has been employed as a cosmetic component, decoration, and even medicine. Mercury is also a natural part of our atmosphere, with 30,000 to 50,000 tons degassing from the earth’s surface annually; human activity adds another 20,000 tons each year.⁴⁷ Toxicity from mercury can occur as a result of occupational, environmental, or medical exposure. Each year, mercury exposure accounts for over 6000 cases of toxicity reported to U.S. poison centers.⁴⁸ The dose, length of exposure, and form of mercury can cause wide variation in the clinical presentation and ultimate outcome.^49–52

Toxicity

Elemental mercury can be found in barometers, dental amalgams, electronics, thermostats, thermometers, and batteries. It is also found in some folk remedies. Elemental mercury is a liquid at room temperature. Even without heating, elemental mercury releases sufficient mercury in the gas phase to cause toxicity. Most problems from elemental mercury are the result of vapor inhalation, with nearly 80% of inhaled vapor being absorbed by the alveoli and transferred into circulating red blood cells. Most absorbed mercury is converted to its divalent (mercuric) form, thus decreasing its lipid solubility. If the patient is exposed to a very high dose of mercury vapor, a small amount of gaseous mercury can remain in the bloodstream, leading to penetration of the blood-brain barrier and central nervous system (CNS) injury.⁸ By comparison, the gastrointestinal tract takes up less than 2% of ingested elemental mercury⁵³; however, in patients with mucosal disruption, transmucosal absorption of mercury can be markedly increased.⁵⁴ Absorption of mercury across intact skin is minimal,⁵⁵ but subcutaneous injection can cause an increase in urinary mercury concentrations. Intravenous injection of mercury can cause both mercury toxicity and mechanical obstruction of pulmonary blood flow.^56,57 Elimination of inhaled vapor is via the urinary tract, and the elimination t_1/2 of absorbed elemental mercury is about 60 days.⁵⁶ Elemental mercury when orally ingested is typically nontoxic owing to minimal absorption across intact gastric and intestinal mucosa.⁵⁸

Elemental mercury primarily targets the lungs and brain, but the poison also can cause renal and gastrointestinal injury.^5,14,15 By forming complexes with sulfhydryl groups, mercury interferes with protein and nucleic acid synthesis, protein phosphorylation, and calcium homeostasis. It can also cause oxidant stress via this mechanism.^59,60 Inhaled mercury vapor has a corrosive effect on the lungs and is capable of producing acute inflammation of the bronchi and bronchioles. This may result in a fatal interstitial pneumonitis.⁶⁰

Depending upon the dose and length of exposure, symptoms of poisoning caused by elemental mercury can vary widely. Onset of chills, gastrointestinal distress, cough, weakness, and dyspnea can occur within hours of an acute exposure, and in severe cases can result in adult respiratory distress syndrome and renal failure. On the other hand, it can take weeks or months before symptoms become apparent in some cases of chronic elemental mercury exposure. Commonly attributed to a viral illness, symptoms from chronic elemental mercury exposure are nonspecific and include gastrointestinal upset, anorexia, abdominal pain, headache, dry mouth, and myalgia. Chronic exposure to either elemental or inorganic mercury, however, also can result in a recognizable syndrome called acrodynia. Also known as pink disease, Feer syndrome, or Feer-Swift disease, acrodynia is a complex of symptoms including the following:

Elemental mercury poisoning can be misdiagnosed as pheochromocytoma. This can occur as mercury inactivates the coenzyme, S-adenosylmethionine, which inhibits catechol-O-methyltransferase (COMT). As a result, catecholamine breakdown decreases and adrenergic symptoms such as hypertension and diaphoresis develop.^18–20 A constellation of personality changes in affected individuals has come to be known as erethism. The symptoms include the following⁶¹:

There has been a reported association between mercury exposure, erethism, and the development of parkinsonism^61–63; however, the evidence for this association comes from only two studies^64,65 and two case reports.^21,22

Inorganic mercury is most commonly found in nature as cinnabar (mercury [II] sulfide). In humans, however, exposure to inorganic mercury compounds comes from germicides, pesticides, and mercury-containing antiseptics.⁶¹ Of interest, there have been several recent reports of inorganic mercury intoxication due to the use of skin-lightening beauty creams.^66,67 Inorganic mercury can be absorbed through the skin, via the lungs, and via the gastrointestinal tract. In blood, inorganic mercury has a t_1/2 of about 24 to 40 hours, and clearance of mercury by the kidneys is responsible for the toxic effects on the distal portion of the proximal convoluted tubules.^68,69

More corrosive to the gut than elemental mercury,^61,70 ingestion of mercury salts commonly causes nausea, vomiting, abdominal pain, and hematemesis. Ingestion of relatively large doses of mercury salts can lead to colitis with necrosis and mucosal sloughing, resulting in massive fluid losses.^14,29,30

Along with gastrointestinal symptoms, the other notable acute effect of inorganic mercury is development of acute renal failure. Potentially reversible, renal injury can occur within hours to days of an acute exposure.^71,72 Membranous glomerulonephritis and nephrotic syndrome also may occur after chronic exposure. Termination of exposure may lead to resolution of nephrotic syndrome.^50,73

With prolonged skin exposure, gray-brown hyperpigmentation of skin folds of the neck and face can occur. Used as an analgesic for teething in the 19th century, dental application of calomel (mercuric chloride) can cause loose teeth, blue discoloration of the gingiva, and systemic toxicity.^14,31 As with elemental mercury, acrodynia and erethism have been reported with inorganic mercury exposure.^50,61

Organic mercury compounds are found in fungicides, antiseptics such as merthiolate and mercurochrome, preservatives including thimerosal, and as a contaminant of predatory fish including tuna and swordfish. As much as 90% of ingested organic mercury is absorbed by the gastrointestinal tract.⁷⁴ Pulmonary absorption of organic compounds such as methylmercury vapor, approaches 80%, depending on particle size. Absorption across intact skin also can occur.⁴⁷ Methylmercury readily crosses the blood-brain barrier, achieving CNS levels that are three to six times those in blood.⁷⁵

Perhaps the best-known mass poisonings of mercury involved methylmercury. During the 1950s and 1960s, a chemical company in the Japanese fishing village of Minamata dumped wastewater containing mercury into Hyakken Harbor on Minamata Bay. Aquatic organisms converted the inorganic waste to an organic form (methylmercury) that was then passed up the food chain. The mercury eventually was concentrated in larger fish, which were then consumed by residents of the area.⁷⁶ Over time, more than 2265 patients developed ataxia, sensory disturbances, constriction of visual fields, dysarthria, auditory disturbances, and tremor. Children exposed in utero developed congenital Minamata disease, which was characterized by seizures, spasticity, deafness, and severe mental deficiency.⁷⁷ All these children had mental retardation, cerebellar ataxia, limb deformities, primitive reflexes, and dysarthria. Hypersalivation and chorea were seen in 95% and microcephaly in 60% of affected children.^77–79

In a second event in 1971, 6500 Iraqis suffered symptoms similar to the Minamata patients after eating bread baked with flour made from grain intended for use as seed. The grain had been treated with a fungicide containing methylmercury.⁸⁰

These two events demonstrated that organic mercury targets the CNS and that fetal brain tissue is more susceptible than the adult brain to the toxic effects of organic mercury. Postmortem findings have shown damage to gray matter of the cerebral and cerebellar cortex. The temporal cortex and calcarine region of the occipital lobe are most affected.^81,82 Pathologic changes in adults and children include cortical atrophy, hypoplasia of the corpus callosum, hypoplasia of the granular cell layer of the cerebellum, and demyelination of the pyramidal tracts.⁷⁸

Diagnostic Tests

Following exposure to elemental or inorganic mercury, whole-blood mercury concentrations are elevated for only 2 or 3 days and then rapidly decrease. Mercury detection beyond that point is better done by 24-hour urine testing. Reference ranges for whole blood can vary somewhat among laboratories but usually fall between 0 and 10 ng/mL. As is the case for testing for other metals, care should be taken to follow the instructions for sample collection provided by the reference laboratory. Such information is usually available online. Heparin-containing collection tubes should be avoided unless otherwise specified. Measurement of mercury is usually performed by atomic absorption spectroscopy (AAS) or inductively coupled plasma mass spectroscopy (ICP-MS).

Urine testing (24-hour collection) is most useful for confirming exposure/toxicity to either elemental or inorganic mercury. Collection containers are frequently washed with nitric acid, but laboratory practices may vary. Specimens should be refrigerated to decrease bacterial reduction of mercury to volatile elemental mercury.⁸³ Samples should not be collected within 48 hours of gadolinium administration (as with magnetic resonance imaging) or within 72 hours of consuming predatory fish (e.g., tuna or swordfish).

Urine concentrations in excess of 50 ng/mL are considered elevated, although reference ranges vary, and there is no exact threshold for determination of toxicity. Some laboratories also report the concentration in µg/gm creatinine along with a reference range. Treatment with chelating agents frequently increases mercury excretion. Results of such tests should not be applied to reference ranges for nonchelated specimens.

Because approximately 90% of methylmercury is bound to red blood cells⁷⁴ and very little is excreted via the kidneys, the preferred test to determine organic mercury is a whole-blood mercury level. While most persons have whole-blood mercury concentrations of less than 6 ng/mL, diets rich in predatory fish can elevate levels to 200 ng/mL or higher.⁸⁴ For that reason, patients should avoid consumption of fish for at least 72 hours prior to blood testing.

Caution is advised in the use of either blood or urine concentrations of mercury as the sole determinant of toxicity. The diagnosis of mercury poisoning should be based upon history and physical findings in conjunction with blood and/or urine testing.

Treatment

The first and most important step in treatment of mercury toxicity is to avoid further exposure of the patient to the toxin.^50,61,85,86 Whereas removal of clothing and decontamination of skin may be helpful, gastrointestinal and pulmonary decontamination are of little use. Chelation is often considered the cornerstone of therapy, although the benefit remains somewhat controversial. Chelating agents bind metal ions to form a complex that can be excreted, thereby reducing the body burden of the offending metal. Dimercaptosuccinic acid (DMSA, Chemet, Succimer) is currently the favored agent. Because DMSA is available only in an oral form, dimercaprol (British antilewisite [BAL]) is used in patients unable to take oral medications. D-penicillamine is an alternate but less effective choice. Chelation therapy may take several months to eliminate the body burden of heavy metal, and clear evidence for long-term benefit is lacking.^86,87 Patients with renal failure may require renal replacement therapy. Aggressive fluid replacement may be necessary to correct large losses of fluid from the gastrointestinal tract, particularly in cases of inorganic mercury exposure.