Thallium Toxicity 

Thallium is a heavy metal that was serendipitously discovered by Sir William Crookes in 1861 while trying to extract selenium from the by-products of sulfuric acid production. Crookes named the new element "thallium" from the Greek thallos, meaning "green shoot or twig" after the bright green spectral emission lines that identified the element. In 1862, Claude-Auguste Lamy independently isolated thallium, studying both its chemical and physical properties.^[1]

In the past, thallium was used as a therapeutic agent to treat syphilis, gonorrhea, tuberculosis, and ringworm, and it was also used as a depilatory for excess hair. In the early part of the last century, a product known as Koremlu was marketed in the United States for the treatment of ringworm as well as a depilatory agent. By 1934, 692 cases of thallium poisoning were reported with at least 31 deaths.^{[2, 3]} Thallium was also widely used as a rodenticide. Its use as a household rodenticide was banned in the United States in 1965 after multiple unintentional poisonings.^[4] Commercial use was banned a decade later. Unfortunately, unintentional poisonings are still reported in other countries where thallium is used as a rodenticide and ant killer.

Currently, thallium is used in the manufacture of electronic components, optical lenses, semiconductor materials, alloys, gamma radiation detection equipment, imitation jewelry, artist's paints, low temperature thermometers, and green fireworks.^[5] Trace amounts of thallium are used as a contrast agent in the visualization of cardiac function and tumors. Thallium exposure may occur at smelters in the maintenance and cleaning of ducts and flues and through contamination of cocaine, heroin, and herbal products. Criminal and unintentional thallium poisonings are still reported, some leading to death.^{[2, 3]}

Thallium is a soft and pliable metal. It melts at 303.5°C and boils at 1482°C. It is colorless, odorless, and tasteless. Thallium has a similar ionic radii to potassium (Tl 0.147 nm vs K 0.133 nm), which is one principle behind its toxicity.^[1]

The biochemical research on the cellular effects of thallium is extensive, but little data exist in humans. Thallium demonstrates at least 5 major toxicologic effects:^[6]

• Disruption of potassium-dependent processes
• Riboflavin sequestration
• Interference with cysteine residues
• Ribosomal inhibition
• Myelin sheath injury

Thallium accumulates in tissues with high potassium concentrations such as muscle, heart, and central and peripheral nerve tissue. Thallium’s similar size to potassium results in early stimulation then inhibition of potassium-dependent processes. Key enzymes involved in thallium toxicity include pyruvate kinase and succinate dehydrogenase. Their inhibition leads to impaired glucose metabolism and disrupts the Kreb’s cycle leading to decreased ATP production. In addition, sodium-potassium ATPase is affected, resulting in cell membrane injury. This enzymatic injury results in swelling and vacuolization of mitochondrial and cell death. Within the mitochondria, thallium also causes sequestration of riboflavin resulting in the inhibition of flavin coenzyme flavin adenine dinucleotide (FAD), impairing the electron transport chain, and further reduction of ATP.

Similar to other metals, thallium has a high affinity of disulfide bonds. This interferes with cysteine residue cross-linking reducing keratin formation. This results in alopecia and the formation of Mees lines. Decreased cysteine cross-linking also leads to decreased glutathione resulting in accumulation of lipid peroxides in the brain, which are most prominent in the cerebellum, often seen as dark pigmented lipofuscinlike areas.^[7]

Thallium interferes with protein synthesis by damaging ribosomes, particularly the 60s ribosome, further leading to cellular injury and death.^[8]

Although the exact mechanism of myelin injury by thallium is unknown, there are consistent findings of fragmentation and degeneration of myelin in both the central and peripheral nervous systems. A Wallerian degeneration pattern first develops in long peripheral axons (lower then upper extremities) with sensory then motor impairment.

The lethal dose of thallium is approximately 15-20 mg/kg; however, significant toxicity and death may occur with smaller amounts. Severe poisoning is expected with oral exposures greater than 200 mg. Thallium poisoning more commonly occurs after oral ingestion. Thallium is rapidly distributed intracellularly throughout all body tissues. Little information is known about the volume of distribution in humans but is estimated to be 3.6-5.6 L/kg.

Thallium follows a 3-phase toxicokinetics: first intravascular distribution, then CNS distribution, and finally elimination. In the first 4 hours following exposure, thallium is rapidly distributed to the blood and to well-perfused organs such as the kidney, liver, and muscle. Over the next 4-48 hours, thallium is distributed into the CNS. The elimination phase begins about 24 hours after ingestion. Thallium is primarily eliminated through excretion into the feces (51.4%) and the urine (26.4%). The high concentrations of thallium found in the kidney (>5.5 times more than other tissues) result from renal filtration with approximately 50% reabsorbed in the kidney tubules. Elimination is slow with an elimination half-life of 3-30 days, varying with the dose and chronicity of the exposure. Because of this prolonged elimination phase, thallium may act as a cumulative poison.

Frequency

United States

Between 2003 and 2006, 82 cases if thallium exposures were reported to poison centers. No deaths were reported, and only one major outcome was reported. There is likely an overlap of reports from patients with concerns of the radioactive contrast agent (thallium-201) following noninvasive cardiac studies rather than true thallium poisonings. Although several deaths have been reported in the literature following suicidal or homicidal poisonings over the past few years, few data exist related to actual thallium intoxication cases in the United States.^[9]

International

Thallium toxicity is likely more common in developing countries where thallium rodenticides are still in use, but few data exist as to the incidence of thallium poisoning outside the United States.^{[10, 9]}

Mortality/Morbidity

The mortality rate for acute thallium toxicity has been reported as 6-15%; among survivors, 33-50% have neurologic or ocular sequelae.

Thallium is lethal to humans. The lethal dose for humans is 15-20 mg/kg (around 1 g for a 70-kg person). Nonfatal effects occur below this dose. However, it is conceivable that even smaller doses can still cause fatality (minimal reported dose was 8 mg/kg). In addition, some treated patients have survived exposure up to 28 mg/kg.

Race

No scientific data substantiate any differences in thallium toxicity that are attributable to race.

Sex

No scientific data substantiate any differences in thallium toxicity that are attributable to sex.

Age

No scientific data substantiate any differences in thallium toxicity that are attributable to age.