By Cyrus Rangan, MD
Thallium was accidentally discovered in 1861 by Sir William Crookes, who noted an unexpected green banding on colorimetric spectroscopy, while researching tellurium ore (Greek, thallos: “green young shoot”). Thallium is a metal with a storied history of medicinal and commercial applications as a depilatory, syphilis remedy, rodenticide, ant killer, and in the manufacturing of photocells and semiconductors. Today, medicinal use is limited to trace amounts of radioactive thallium for nuclear imaging. Thallium is a tasteless, odorless, and extremely potent poison – acute ingestions of as little as one gram of thallium salt may kill an adult. Thallium is a well-known poison cited in numerous works of fictional literature, but is also a popular real-life agent of murder with worldwide homicidal usage documented since the 1800s.
A 26-year-old man developed nausea, abdominal cramping, and mildly bloody diarrhea, 9 hours after a suicidal ingestion of illegally imported rat poison. He had clinical signs of dehydration and laboratory evidence of fluid depletion and was admitted overnight for treatment of dehydration. The next day, he developed a feeling of “pins and needles” in the lower extremities, followed by pain, burning sensations, and weakness in both upper and lower distal extremities over the next 12 hours. During this time, he had over 10 episodes of diarrhea, and became slightly confused, and moderately diaphoretic. Electrocardiogram revealed intermittent runs of supraventricular tachycardia. Urinalysis revealed trace urine protein and specific gravity of 1.020. Complete blood count and serum electrolytes were found to be within normal limits.
On Day 2, the patient continued with severe pain, discomfort, weakness, waxing-and-waning lethargy, and confusion. During a period of lucidity, he disclosed that he ingested a large amount of illegal rat poison from the “Old Soviet Union.” Thallium toxicity was suspected and he was prepared for hemodialysis. He was started on an oral antidote every six hours, and underwent two 4-hour runs of hemodialysis. Urine thallium level was noted to be 1285 mcg/L. The patient’s mental status began to normalize and other symptoms improved very slowly each day as he continued on the oral antidote. By day 10, the patient was able to walk without assistance. When he walked to the bathroom to brush his hair, his noted several clumps of hair in his hairbrush.
- Why did hair loss take so long to occur after acute exposure to thallium?
- What was the oral antidote? How does it work?
Commercial and consumer use of thallium as a rodenticide or insecticide was banned in the United States and most other countries by 1975. A few countries, such as Russia and China, continue to use thallium commercially as a rat poison. Thallium enters the environment primarily from coal-burning power plants, smelters, and cement factories. Plants, fish, and shellfish harvested near thallium-producing facilities may accumulate thallium from the soil and from runoff. Such exposures may result in chronic thallium poisonings. Most unintentional exposures in the United States are environmental through inhalation of workplace air in industries that use thallium, smoking cigarettes, and living near hazardous waste sites containing thallium. However, the majority of environmental exposures are unlikely to lead to thallium toxicity. In 1987, the CDC conducted an epidemiologic investigation of a striking increase in the number of reported cases of presumed acute and chronic thallium intoxication in Georgetown, Guyana. The Government Laboratory of Guyana had been confirming thallium poisonings with a qualitative, colorimetric atomic absorption spectrometer because the laboratory’s quantitative atomic absorption equipment was inoperable. Confirmatory samples of blood and urine were analyzed for thallium content at the CDC’s laboratories, and were considered by CDC to be within normal limits for thallium (0-5 mcg/L). The CDC concluded that numerous common substances, such as detergents, might give rise to false-positive results on qualitative colorimetric atomic spectroscopy.
Although ingestion is the most common route of exposure thallium may also be absorbed by inhalation or skin penetration. Thallium and its salts are corrosive to the gastrointestinal mucosa, leading to abdominal pain, intestinal fluid secretion, diarrhea, and vomiting. After absorption, thallium distributes widely to multiple organs with a distribution pattern similar to that of potassium ions, which have a similar atomic radius to thallium. Thallium deposition therefore occurs primarily in tissues with high potassium concentrations such as neuronal, myocardial, hepatic, renal, and dermal tissues. In contrast to more common heavy metal exposures such as lead, mercury, or arsenic, long-term, low-level exposure to thallium does not typically lead to accumulation in body tissues for an extended duration. Thallium replaces potassium in numerous potassium-dependent enzyme systems usually with superior affinity over potassium. Affected enzyme systems include pyruvate kinase, succinic dehydrogenase, sodium-potassium-ATPase, hemoserine dehydrogenase, vitamin B12-dependent diol dehydrogenase, guanine deamiase, L-threonine dehydrogenase, monoamine oxidase, acid phosphatase, and cathepsin. In addition, thallium damages the 60s subunit of ribosomes, resulting in impaired protein synthesis. The combined effect of these acute cellular dysfunctions is the failure of aerobic respiration and poor cellular energy production. In the peripheral nervous system, thallium causes a “dying-back” or Wallerian degenerative sensory neuropathy due to acute myelin fragmentation and axonal degeneration. This process is mediated by mitochondrial dysfunction, swelling, and vacuolization from inhibition of pyruvate kinase and succinicdehydrogenase and subsequent decrease in ATP production. Motor neuropathy may occur with severe acute exposures, as high thallium concentrations impair depolarization of muscle fibers. Central nervous system findings are mediated by multi-focal edematous changes and chromatolysis, particularly in the frontal lobe, motor cortex, basal ganglia, and pyramidal cells. Similar changes are noted in the ganglia of the spinal cord in chronic poisoning. Inhaled or ingested thallium induces pulmonary inflammation and hyaline membrane formation. High doses of thallium directly damage the myocardium with myocardial thinning, lipid droplet infiltration, necrosis, and inflammatory changes. Thallium damages kidney tissue, most likely via infarction. Hepatic findings in severe cases may include centrilobular necrosis with fatty infiltration; however, most cases of thallium poisoning result in mild hepatic inflammation. Hair loss is caused by stunted mitosis of hair follicle epithelial cells, and by destruction of hair shaft cells.
Signs and symptoms of thallium ingestion often begin with a non-febrile gastroenteritis, severe abdominal pain, cramping, vomiting, and diarrhea during the first 6 hours after exposure. Gastrointestinal symptoms last for 12-96 hours. Constipation often occurs for several days after diarrhea has resolved. Patients with chronic poisoning may have few or no gastrointestinal findings. Thallium inhalation leads initially to non-febrile cough and pleuritic chest pain, persisting for several days. After 1-5 days, systemic symptoms begin to develop. Neurological symptoms usually predominate secondary to the predilection of thallium for nerve tissue. Findings include painful, rapidly ascending, sensory neuropathy. Motor neuropathy may accompany sensory neuropathy, but rarely occurs alone. Patients commonly complain of severe pain and burning in the feet, difficulty walking, skeletal muscle cramps, and “stocking-glove” numbness and tingling. Both oral and inhalational exposures may lead to pneumonitis, ARDS, and pulmonary edema. Respiratory depression may occur from neurological dysfunction of the respiratory muscles. Dysfunction of cranial nerves II, III, IV, and VI which govern oculomotor and visual function are most common. Nystagmus, confusion, anxiety, tremor, ataxia, optic neuritis, altered mental status, seizures, and coma may also occur. Peripheral and cranial nerve findings may persist for several weeks-to-months after exposure, and may be permanent in severe cases. Some patients may endure persistent short-term memory and cognitive deficits. Cardiac effects include sinus bradycardia or tachycardia, and ventricular dysrhythmias in severe cases. Rapidly fatal cases of thallium poisoning are likely to result from acute myocardial injury. Renal findings occur within the first several days after exposure and include proteinuria, diminished creatinine clearance, elevated blood urea nitrogen, and acute tubular necrosis. Urine may have a slight green discoloration. Hepatic failure or jaundice occurs in extreme cases. Alopecia, a hallmark of thallium poisoning, occurs 7-12 days after other symptoms begin. Hair loss commonly involves the scalp, often involves body hair, and is generally not permanent. Complete hair loss usually occurs by one month post-exposure. Mees lines, horizontal white depositions in the nails, may be observed up to 4 weeks after exposure, but are not specific. Alopecia and neuropathy may be the only presenting symptoms in cases of chronic thallium poisoning.
Thallium poisoning should be suspected in any patient with neurological symptoms and hair loss. Gastrointestinal findings may be mild or nonexistent, especially in chronic poisoning. Thallium blood levels may be elevated after recent exposures, but it is cleared from the blood relatively quickly. Cases of known thallium exposure may be confirmed easily by early blood testing with quantitative atomic absorption. The diagnosis of thallium poisoning may not be considered until several days after exposure – typically when hair loss begins – by which time blood levels may have decreased significantly. Measurable urine concentrations of thallium tend to persist for several days after exposure, and may be used to monitor treatment. A 24-hour urine thallium concentration is the most accurate way to assess thallium toxicity; however, a “spot” urine level provides more rapid confirmation. Acute toxicity will produce a thallium concentration many times higher than the reference range of 0-5 mcg/L. Injection of large boluses of potassium to enhance urinary thallium excretion before urine sampling, also known as “potassium mobilization” (described below) is not advised, as this practice may precipitate cardiac and neurological toxicity. Both blood and urine levels should be obtained in cases of known or suspected thallium poisoning. Hair testing for thallium may provide additional confirmation of thallium exposure in the presence of strongly positive urine and blood results; however, hair testing is a highly unreliable method of diagnosing acute or chronic thallium poisoning, and is generally not recommended. Experienced pathologists may detect a characteristic pattern of black pigmentation at the roots of scalp hair in thallium-poisoned patients. Electrocardiography may demonstrate prolongation of the QTc interval, non-specific T-wave changes, and dysrhythmias. Serum transaminases and alkaline phosphatase may be elevated. Complete blood count may reveal anemia from gastrointestinal hemorrhage. Plain abdominal radiography may show opacities due to heavy metal retention in the gastrointestinal tract; however, absence of radiographic findings may be misleading and does not exclude retained metal. Electromyelography may reveal diminished neuromuscular transmission, and electroretinography may demonstrate delayed visual evoked response. These findings may precede clinical symptoms. The differential diagnosis of thallium poisoning includes arsenic poisoning, selenium poisoning, colchicine poisoning, Guillain-Barre Syndrome (GBS), and botulism. Serum or urine determinations of arsenic, selenium, or colchicine may rule out these poisonings, but may be difficult to obtain rapidly. Hair loss following neurological symptoms is a useful clue to exclude GBS and botulism.
Patients with very recent ingestions of thallium should be treated with activated charcoal. Although most metals bind poorly to activated charcoal, thallium is an exception and binds well. Patients with radiographic evidence of retained thallium in the gastrointestinal tract may benefit from whole bowel irrigation with polyethylene glycol solution. Extracorporeal removal of thallium using hemodialysis or hemoperfusion should take place as early as possible during the course of poisoning. Hemodialysis is most beneficial when blood levels are high, before tissue distribution has taken place. After systemic signs develop, dialysis reveals inconsistent results. Although excretion of thallium is nominally enhanced with dialysis, this procedure may accelerate the redistribution of thallium out of tissues such as the central nervous system. Therefore, hemodialysis should be performed in most symptomatic patients with acute thallium poisoning in conjunction with other treatments. Prussian Blue, an FDA-approved antidote for cesium and thallium poisonings, is a potassium-rich oral cation exchange resin. Potassium is exchanged preferentially for thallium entering the enterohepatic circulation. As Prussian Blue sequesters thallium, a concentration gradient is established for the continued movement of thallium into the gut. Dosing of Prussian Blue is 250 mg/kg/day, divided every 6-12 hours. Constipation may complicate Prussian Blue administration, and may be attenuated by the addition of a cathartic such as mannitol. Duration of treatment with Prussian Blue is not well-studied. Case reports have suggested this therapy can be safely discontinued when spot urine thallium levels are <100 mcg/L. Patients with persistent neurological findings may require physical or occupational therapy for several weeks-to-months after acute toxicity is treated. Hair growth spontaneously returns to normal over days or weeks. Multiple-dose activated charcoal (MDAC) may enhance thallium excretion by interruption of enterohepatic circulation; however, human models of toxicity have not demonstrated clinical benefit to MDAC. Forced diuresis provides no clinical benefit in the treatment of thallium poisoning. Some proposed treatments attempt to take advantage of the similarities between cellular handling of potassium and thallium. For example, the administration of potassium blocks renal tubular reabsorption of thallium, thus enhancing excretion up to 300%; however, potassium administration also mobilizes thallium from tissue depots, thus making more thallium available to the central nervous system. Therefore, “potassium mobilization” is not advised as either a diagnostic challenge nor as a treatment modality. Sodium polystyrene sulfonate(Kayexelate®) is a proposed treatment, demonstrating excellent in vitro binding to thallium. However, polystyrene binds preferentially to potassium, not thallium, in vivo, and is not recommended because of its potential to cause hypokalemia. Thallium binds poorly to medicinal chelators, such as Ca-Na-EDTA, British anti-Lewisite (BAL), and DMPS. D-penicillamine may worsen thallium toxicity. Other proposed pharmaceutical treatments, such as N-acetylcyesteine,diphenylthiocarbazone, and dithiocarb may increase thallium excretion, but are not recommended, because they are ineffective or may worsen neurological toxicity.
Discussion of case questions
- Alopecia is a very common characteristic of thallium poisoning; however, hair loss is often delayed by 7-12 days after symptoms begin, and this delay may be inversely dependent on dose.
- The oral antidote for thallium poisoning is Prussian Blue. In combination with hemodialysis and supportive care, Prussian Blue enhances thallium excretion, and may speed recovery by exchanging potassium for thallium in the gastrointestinal tract.