Thallium Toxicity

Etiology

Thallium was banned from United States households in 1965, then commercially in 1975. Thallium intoxication often mimics other diseases. Thus, the condition is frequently overlooked in diagnoses. More recently, thallium has been used in the semiconductor and optical industries. Previously used as an insecticide and rodenticide, the element's lack of odor and taste properties has led to accidental poisonings and, in some cases, criminal use. 

Although thallium is no longer used as a pesticide in the United States, it is still occasionally employed for this purpose in other countries. Contamination of Chinese herbal medications with thallium has also been reported. Intoxication can result from cumulative exposure through the skin, respiratory system, or gastrointestinal tract. Accidental insufflation or injection in individuals using cocaine or intravenous opioids, as well as skin absorption through protective gloves, has also been documented.[7][8][9] The causes of thallium toxicity include occupational exposure, accidental ingestion, contaminated drug use, eating contaminated foods like fish, exposure to hazardous waste sites, and criminal poisoning.[10]

Epidemiology

Within the United States, 49 single exposures, with only one major outcome and no deaths, were reported in 2019 through the National Poison Data Center.[11] Internationally, thallium toxicity is common in developing countries. However, little data is available.

Mortality and Morbidity

Mortality rates approximate 6% to 15% for acute thallium toxicity. Between 10 and 15 mg/kg is the lethal dose for humans. Death can still occur at lower doses.

Demographics

No data regarding age, sex, or race is available.

Pathophysiology

Thallium is structurally similar to potassium and is treated as such at the cellular level. Five major toxicologic effects are seen with thallium toxicity.

First, tissues with high potassium concentrations also accumulate large thallium concentrations, causing early stimulation, followed by inhibition of potassium-dependent processes. Inhibiting pyruvate kinase and succinate dehydrogenase disrupts the Krebs cycle and glucose metabolism. This interference reduces adenosine triphosphate (ATP) production and impairs the sodium-potassium ATPase channel, causing cellular swelling and vacuolization. Second, riboflavin sequestration due to thallium and inhibition of flavin adenine dinucleotide disrupts the electron transport chain and decreases ATP production.

Third, thallium’s high affinity for sulfur in disulfide bonds disrupts cysteine residue cross-linking, reducing keratin formation. Fourth, ribosomes are damaged by thallium’s effects on protein synthesis, especially the 60S ribosome. Fifth, thallium causes myelin degeneration in the central and peripheral divisions of the nervous system, though the mechanism remains unknown.

Toxicokinetics

The 3 toxicokinetic phases of thallium are as follows:

• Intravascular distribution phase: During the first 4 hours postexposure, thallium is distributed to organs via the blood.
• CNS distribution phase: During the next 4 to 48 hours, thallium reaches the central nervous system.
• Elimination phase: This phase begins around 24 hours postexposure and is mainly achieved through renal excretion and feces. This slow phase may take up to 30 days.

History and Physical

Acute versus Chronic Exposure

Initial symptoms include gastrointestinal, neurological, and dermatological manifestations. Delayed alopecia is a hallmark of acute thallium poisoning. After prolonged exposure, acute poisoning symptoms persist, with neurological effects continuing even as blood thallium levels decrease.

Manifestations of Thallium Toxicity

Early gastrointestinal symptoms, presenting within 3 to 4 hours, include abdominal pain, nausea, vomiting, diarrhea or constipation, and, rarely, blood in vomitus or stool. Neurologic symptoms, typically presenting 2 to 5 days after exposure, include ascending and often severely painful peripheral neuropathies, distal motor weakness, ataxia, tremor, and cranial nerve palsies.

Dermatologic symptoms initially include nonspecific findings, such as scaling and acneiform or pustular eruptions. After 2 to 3 weeks, alopecia develops due to the disruption of cysteine disulfide bonds. Mees lines appear on the nails a month after poisoning. Other dermatological manifestations include hypohidrosis or anhidrosis and painful glossitis.

Ocular symptoms include diplopia, ptosis, 7th cranial nerve palsy, nystagmus, optic neuropathy, and lens opacities. Patients may experience tachycardia and hypertension. Other manifestations include headache, seizures, insomnia, and, in severe cases, coma. Death may occur in some cases.

Physical Examination

While the examination should focus on the affected areas, a comprehensive assessment, including neurologic, ophthalmologic, and gastrointestinal evaluations, is crucial. For the gastrointestinal assessment, a rectal examination and stool guaiac test should be performed alongside an abdominal examination. The neurological exam should assess all cranial nerves and check for nystagmus and ptosis. Lower extremity strength and decreased sensation to pinprick, touch, temperature, vibration, and proprioception should be evaluated. Severely painful peripheral neuropathy is a classic presentation of thallium poisoning. For the ophthalmologic evaluation, slit lamp and funduscopic examinations should be conducted, and visual acuity and color vision should be assessed.

Evaluation

Laboratory Tests

Elevated thallium levels in hair, nails, blood, urine, feces, and saliva can aid in establishing a diagnosis. The standard method for measuring thallium concentration is a 24-hour urine test, analyzed by inductively coupled plasma mass spectroscopy (ICP-MS). Although hair, saliva, and feces testing have been used, urine is preferred for clinical use. Atomic absorption spectroscopy, while less accurate than ICP-MS, may still be employed. A urine spot test provides quicker results but has a high false-positive rate, and blood thallium levels may be falsely negative. Additional tests to consider include a complete blood count with differential, electrolyte levels, glucose, blood urea nitrogen, liver function tests, and calcium.

Radiography

Thallium is radiopaque. Radiographs may reveal the presence of this heavy metal in the body after ingestion.

Ancillary Tests

Arrhythmias are rare complications and should be evaluated through electrocardiography. An electroencephalogram is recommended for any seizure-like activity, and a nerve conduction study should be performed for patients experiencing neurological symptoms.

Treatment / Management

Much like many other toxic exposures, care starts with stabilization, airway, breathing, and circulation, as well as removal of contaminated clothing. Activated charcoal, Prussian blue, or both can be used for internal decontamination after ingestion and should be administered as early as possible. [12][10][13](B3)

If the patient is dermally exposed, their skin should be washed with soap and water. For eye exposure, the eyes should be irrigated with room-temperature water or saline. Activated charcoal and Prussian blue may be used for gastrointestinal ingestion.

Prussian blue is the treatment of choice for thallium poisoning and results in reduced enterohepatic recirculation of thallium, enhancing its elimination. The typical dose is 250 mg/kg per day in 2 or 4 divided doses. A definitive end point of therapy has not been established. Prussian blue can be mixed in 15% mannitol or administered with polyethylene glycol for patients with constipation. 

Compared to activated charcoal, Prussian blue is more effective and has been approved by the United States Food and Drug Administration.[14] Multidose activated charcoal should be used in cases where Prussian blue is not available.(B3)

Hemodialysis can also enhance the elimination of thallium. The use of this method is typically isolated to cases where gastrointestinal decontamination with either Prussian blue or activated charcoal is not feasible. Consultation with a medical toxicologist and nephrologist should be obtained if extracorporeal elimination procedures, such as hemodialysis, are considered.

Differential Diagnosis

The presentation of thallium toxicity is similar to other toxicities and also mimics other diseases. The following alternative diagnoses should be considered in patients with thallium toxicity:

• Carbon monoxide
• Arsenic 
• Isoniazid
• Mercury
• Organophosphates
• Thiamine deficiency
• Diabetic polyneuritis
• Acute and chronic demyelinating disease
• Botulism
• Vasculitis
• Poliomyelitis

Thallium poisoning can be challenging to diagnose, given its similarity to other toxicities and diseases. A thorough clinical evaluation and diagnostic workup, considering the above alternative conditions, help ensure accurate diagnosis and appropriate treatment.

Prognosis

The prognosis for patients with thallium toxicity depends on the dose ingested and the presence of neurological symptoms. Patients with minimal symptoms can fully recover with treatment, but individuals with severe toxicity may have persistent alopecia, neuropathy, and psychiatric effects.

Early diagnosis and treatment portend a better prognosis.[15] Neurologic damage may persist if gastrointestinal decontamination therapy is delayed. Patients can have signs and symptoms of peripheral neuropathy for many years after poisoning. Reports of persistent findings most commonly involve painful neuropathy of the lower extremities.

Complications

Neurological damage may be persistent. Involvement of the lower extremities has been reported to be the most likely to remain. Alopecia is common. Psychiatric symptoms that have also been reported include agitation, aggression, depression, and personality changes.