102: Thallium

Thallium (Tl^o), a metal with atomic number 81, is located between mercury and lead on the periodic table. Thallium is a soft, pliable metal that melts at 572°F (300°C), boils at 2699.6°F (1482°C), and is essentially nontoxic. Thallium forms univalent thallous (Tl⁺¹) and trivalent thallic (Tl⁺³) salts, which are highly toxic. Thallium is a commonly found constituent of granite, shale, volcanic rock, and pyrites used to make sulfuric acid and is also recovered as flue dust from iron, lead, cadmium, and copper smelters.²⁵

In the early 1900s, thallium salts were used medicinally to treat syphilis, gonorrhea, tuberculosis, and as a depilatory for ringworm of the scalp.^8,68 Although the usual oral dose given for ringworm was 7 to 8 mg/kg, fatal doses ranged from 6 to 40 mg/kg.^15,57 Many cases of severe thallium poi­soning (thallotoxicosis) resulted from this treatment for ringworm, with one author summarizing nearly 700 cases and 46 deaths.⁷¹

Because thallium sulfate is odorless and tasteless, it was also successfully used as a rodenticide. Commercially available as Thalgrain, Echol’s Roach Powder, Mo-Go, Martin’s Rat Stop liquid, and Senco Corn Mix, thallium sulfate was a very efficient rodenticide. As a consequence of numerous case reports of unintentional poisonings,^71,72,83 the use of thallium salts as a household rodenticide was restricted in the United States in 1965. Ultimately, even the commercial use of thallium salts as a rodenticide was banned in the United States in 1972 because of continued reports of human toxicity.

Life-threatening unintentional poisoning continues to occur in other countries, especially where thallium salts are still commonly used as rodenticides.^{2,14,81,89,97,106} Additional cases of thallium poisoning are reported in the United States and other countries as a result of the use of thallium for homicide^{21,62,67,75,77,86,94} and through contamination of herbal products⁹¹ and illicit drugs such as heroin^1,80 and cocaine.⁴⁴ Although occupational exposures to consequential amounts of thallium salts are uncommon, occupational toxicity is well described.³⁸

The following discussion of thallium toxicity refers to toxicity resulting from exposure to inorganic thallium salts, which represents virtually the entire literature on thallium poisoning. Although exceedingly rare, cases of poisoning with organic thallium compounds are reported⁴ and should be assessed and managed in a fashion similar to that used for patients with inorganic exposures. Although small amounts of thallium salts are used as radioactive contrast to image tumors and to permit the visualization of cardiac function, the doses used are insignificant without potential for thallium toxicity.⁶⁸

Exposures usually occur via one of three routes: inhalation of dust, ingestion, and absorption through intact skin. Thallium is rapidly absorbed ­following all routes of exposure. Bioavailability is greatest after ingestion and exceeds 90%.⁴⁰ Distribution follows three-compartment toxicokinetics⁸² (Chap. 9) into a final volume of distribution that is estimated to be about 3.6 L/kg.¹⁹ Thallium can be found in all organs, but it is distributed unevenly, with the highest concentrations found in the large and small intestine, liver, kidney, heart, brain, and muscles.^8,52 In animals, the highest concentrations of thallium are found in the kidneys.^3,52

The toxicokinetics of thallium can be described in the following three-phase model. The first phase occurs within the first 4 hours after oral exposure during which thallium is distributed to a central compartment and to well-perfused peripheral organs such as the kidney, liver, and muscle. In the second phase, which may last between 4 and 48 hours, thallium is distributed into the central nervous system (CNS).⁸² Whereas some literature suggests that this distribution phase is generally completed within 24 hours of ingestion,⁸² one human case suggests slower distribution into the CNS as evidenced by increasing cerebrospinal fluid (CSF) concentrations in the days after exposure when blood concentrations were declining, which thereby excludes ongoing absorption.⁹⁴ The third or elimination phase usually begins within 24 hours after ingestion. The primary mechanism of thallium elimination is secretion into the intestine, but enteral reabsorption of thallium that is present in the bile subsequently reduces the fecal elimination.^19,67 Thallium is excreted primarily via the feces (51.4%) and the urine (26.4%).⁵⁶ It is filtered by the glomerulus, with approximately 50% being reabsorbed in the tubules. Thallium is also secreted into the tubular lumen in a manner similar to potassium.⁷ The duration of the elimination phase depends on the route of exposure, dose, and treatment. Unlike many other metals, thallium does not have a major anatomic reservoir. For this reason, reported elimination half-lives are as short as 1.7 days in humans with thallium poisoning.⁴²

The mechanism of thallium toxicity is not well established. Thallium behaves biologically in a manner similar to potassium because both have similar ionic radii (1. 47 Å for thallium and 1.33 Å for potassium). Because cell membranes cannot differentiate between thallous (Tl⁺¹) and potassium (K⁺) ions, thallous ions accumulate in areas with high potassium concentrations, such as the central and peripheral nervous system and hepatic and muscle tissue.^63,106 This accumulation is the fundamental principle that governs the use of radioactive thallium in cardiac imaging studies. Thallium replaces potassium in the activation of potassium-dependent enzymes.⁶³ In low concentrations, thallium stimulates these enzyme systems, but in high concentrations, it inhibits them.^9,65 Pyruvate kinase, a magnesium-dependent glycolytic enzyme that requires potassium to achieve maximum activity, has 50 times greater affinity for thallous ions than potassium ions.⁴⁸ Succinate dehydrogenase, an essential enzyme in the Krebs cycle, is inhibited by small doses of thallium in rats.³⁷ Sodium-potassium adenosine triphosphatase (ATPase), which is responsible for active transport of monovalent ions across cell membranes, can use thallous ions at extremely low concentrations because of an affinity that is 10-fold greater than that of potassium ions^10,30 but is inhibited by thallium at higher concentrations.⁴⁵

Thallium also impairs depolarization of muscle fibers.⁶⁸ Mitochondrial energy is decreased as a result of the inhibition of pyruvate kinase and succinate dehydrogenase, resulting in a decrease of adenosine triphosphate (ATP) generation via oxidative phosphorylation. Enzymatic destruction results in swelling and vacuolization of the mitochondria after exposure to thallium.⁹⁵ At low concentrations, thallium can activate other potassium-dependent enzymes such as phosphatase, homoserine dehydrogenase, vitamin B₁₂–dependent diol dehydrogenase, l-threonine dehydrogenase, and adenosine monophosphate (AMP) deaminase.⁶⁸ The net result of these processes is a failure of energy production.

Thallous ions have been used to isolate riboflavin from milk in the form of a reversible precipitate. Thallous ions may also form insoluble complexes and cause intracellular sequestration of riboflavin in vivo.¹³ Riboflavin is the vitamin precursor of the flavin coenzyme flavin adenine dinucleotide (FAD). Because of a decrease in riboflavin, metabolic reactions dependent on flavoproteins decrease, causing disruption of the electron transport chain and a subsequent further decrease or impairment in the generation of cellular energy.¹³ This decrease in cellular energy may lead to a decrease in mitotic activity and cessation of hair follicle formation, resulting in the clinical sign of alopecia. Subsequent hair loss is the result of combined arrested formation and local destruction of hair shaft cells in the hair bulb^13,83 (Chap. 18). Unfortunately, riboflavin supplementation was not beneficial in one animal model of thallium poisoning.⁶ Data also demonstrate that the dermatologic, neurologic, and cardiovascular effects of thallium toxicity mirror the manifestations of thiamine deficiency (beriberi), highlighting the inhibitory effect of thallium on glycolytic enzymes.^13,68 It is unclear whether thiamine administration has any beneficial effect in patients with thallium poisoning.

Thallium has a high affinity for the sulfhydryl groups present in many other enzymes and proteins. Keratin, a structural protein, consists of many cysteine residues that cross-link and form disulfide bonds. These disulfide bonds add strength to keratin. Thallium interferes with the formation of disulfide bonds, which may lead to the development of alopecia and defects in nail growth, resulting in Mees lines.^{33,68,75,88,89} Additionally, the complexation of sulfhydryl groups with thallium results in a decrease in both the production of glutathione and the reduction of oxidized glutathione.^35,107 This results in oxidative damage²⁸ and the accumulation of lipid peroxides in the brain (which is most prominent in the cerebellum) and appears as dark, pigmented, lipofuscinlike areas.³⁶ The complexity and presumable multifactorial nature of thallium poisoning are again highlighted by the inability of N-acetylcysteine (NAC)–induced augmentation of glutathione stores to protect against toxicity in an animal model.⁶

Thallium also adversely affects protein synthesis in animals by damaging ribosomes, particularly the 60S subunit.⁴³ Although ribosomes are primarily dependent on potassium and magnesium, thallium will be used if present. In an experimental model, low concentrations of thallium are protective against hypokalemia-induced ribosomal inactivation. As thallium concentrations increase, the protective effects diminish, resulting in progressive destabilization and destruction of the ribosomes. Ribosomal destruction can also be produced by exposure to high potassium concentrations, but usually on the order of 4.5 to 20 times higher than the thallium concentrations necessary to achieve the same effect.⁴³

Pathologic studies of the CNS in patients with thallium poisoning reveal localized areas of edema in the cerebral hemispheres and brainstem. Chromatolytic changes are prominent in neurons of the motor cortex, third nerve nuclei, substantia nigra, and pyramidal cells of the globus pallidus. In chronic exposures, there are signs of edema of the pial and arachnoidal membranes and chromatolysis, swelling, and fatty degeneration in the ganglion cells of the ventral and dorsal horns of the spinal cord.^8,83

The peripheral nervous system, which is usually clinically affected before the CNS, develops a diffuse axonopathy in a classic dying back or Wallerian degeneration pattern^7,8,17,23,64 (Chap. 24). Fragmentation and degeneration of associated myelin sheaths are accompanied by activation of Schwann cells.^8,12,13 Because thallium affects the longer peripheral fibers—first sensory, then motor, and finally the shorter fibers—toxic effects occur initially in the lower extremities.^55,74,111

Many of the effects of thallium poisoning are nonspecific and occur over a variable time course.⁵³ When combined, however, a clear toxic syndrome can be defined (Table 102–1). Alopecia and a painful ascending peripheral neuropathy are the most characteristic findings.^7,27,67,74 Because of the delayed development of alopecia, the diagnosis of thallotoxicosis is often delayed. In fact, with acute exposures, a dose-dependent latent period of hours to days may precede initial symptoms.^53,68 When death occurs, it is usually the result of coma with loss of airway protective reflexes, respiratory paralysis, and cardiac arrest.

Unlike most other metal salt poisonings, diarrhea is often modest or even absent in thallium toxicity.¹⁵ The most common symptom is abdominal pain, which may be accompanied by vomiting and either diarrhea or constipation.^{21,50,53,65,88,108,109} Constipation may be a result of decreased intestinal motility and peristalsis caused by direct involvement of the vagus nerve.^15,68 Rarely, severe symptoms occur, such as hematemesis, bloody diarrhea, or ulceration of the mucosal lining.

Pleuritic chest pain was described in a small series of poisoned patients.⁶² Another patient was reported to have developed “chest tightness” shortly after drinking thallium-poisoned tea.⁶⁷ The etiology for this finding is uncertain, although it may also relate to involvement of the vagus nerve.

Tachycardia and hypertension frequently occur in patients with thallotoxicosis and usually develop during the first or second week after acute ingestion. A poor prognosis may be associated with a persistent and pronounced tachycardia. No exact mechanism has been determined for these cardiovascular effects of thallium toxicity. Some authors theorize that they result from autonomic neuropathic dysfunction directly related to involvement of the vagus nerve,⁷⁴ but others have noted early electrocardiographic (ECG) changes, such as prolongation of the QT interval, T wave flattening or inversion, and nonspecific ST segment abnormalities, which might suggest direct myocardial injury.^{8,12,65,68,85} Another theory suggests that the direct stimulation of ATPase in the chromaffin cells by thallium may lead to increased output of catecholamines, resulting in sinus tachycardia.^5,67

Neurologic symptoms usually appear 2 to 5 days after exposure. Patients may develop severely painful, rapidly progressive, ascending peripheral neuropathies.^7,8,23,62 Pain and paresthesias are present in the lower extremities (especially the soles of the feet), and although numbness is present in the fingers and toes, there is also decreased sensation to pinprick, touch, temperature, vibration, and proprioception.^7,91 The weight of bedsheets on the lower extremities may be sufficient to cause excruciating pain.^62,64 Motor weakness is always distal in distribution, with the lower limbs more affected than the upper limbs.^12,68

Symptoms of confusion, delirium, psychosis, hallucinations, seizures, headache, insomnia, anxiety, tremor, ataxia, and choreoathetosis are common. The onset of these symptoms is variable and most likely dependent on dose. Ataxia may develop within 48 hours after ingestion. Insomnia occurs in most patients and may progress to total reversal of sleep rhythms. Coma may occur, especially with larger exposures.^12,53,68,88 All cranial nerves can probably be affected by thallium, although abnormalities of cranial nerves I, V, and VIII have not been reported. Cranial nerve III involvement, as evidenced by ptosis, is common and may be asymmetric.¹² Nystagmus, another common finding, demonstrates involvement of cranial nerves IV and VI.¹² Cognitive abnormalities may persist for months after exposure.⁵⁹

Thallium is toxic to both the retinal fibers and the neural retina.⁹² In cases of a large, single ingestion of thallium, approximately 25% of patients may develop severe lesions of the optic nerve.^68,88 Optic neuropathy may lead to optic atrophy and a permanent decrease in visual acuity. In the early stages, the optic disk shows signs of neuritis, which is red and poorly defined, and later develops pallor from resultant optic nerve atrophy. In patients exposed to multiple small doses, nearly 100% suffer optic nerve injury.⁶⁵ Visual complaints may be delayed in comparison to other neurologic findings⁹² and may include decreased acuity and central scotomata. Other described ophthalmic effects are noninflammatory keratitis, cataracts, and the color vision defect of tritanomaly (blue color defect).^99,100

Kidney function may remain normal in mild cases of thallium poisoning, even though the kidney has greater bioaccumulation than any other organ. Changes in kidney function in patients with severe thallotoxicosis include oliguria, diminished creatinine clearance, elevated blood urea nitrogen, and albuminuria.^5,62,65,68 These findings correlate with morphologic studies in thallium poisoned rats, demonstrating abnormalities in the renal medulla, mainly in the thick ascending limb of the loop of Henle, that occur by the second day after exposure and resolve by the tenth day.⁵

Alopecia is the most common and classic manifestation of thallium toxicity.^67,103 Typically occurring as the presenting symptom in patients with chronic exposures after an acute exposure, hair loss begins in approximately 10 days and is maximal within 1 month.^27,67,71 Facial and axillary hair, especially the inner third of the eyebrows, may be spared, but in some cases, full beards, as well as all scalp hair, are lost.⁸³ Microscopic inspection of the hair reveals a diagnostic pattern of black pigmentation of the hair roots of the scalp in approximately 95% of poisoned patients,^11,67,88,103 which can be found within 3 to 5 days of initial exposure^11,65 (Fig. 102–1). In patients with recurrent exposures, several bands may be noted on the hair shaft, demonstrating multiple exposures. Initial hair regrowth is very fine and unpigmented but usually returns to normal after mild exposure.⁶⁵ In patients with severe exposures, alopecia may be permanent. Other dermatologic effects that are observed include acne, palmar erythema, and dry scaly skin that results from sebaceous gland damage.¹⁰³ Mees lines appear within 2 to 4 weeks after exposure^67,75,88 (Fig. 89–4).

Other less common findings include hepatotoxicity,⁴⁴ hypochloremic metabolic acidosis,⁸⁸ anemia, and thrombocytopenia.^54,88

Teratogenicity

In animal models, thallium is teratogenic.^32,34 In humans, one study evaluated 297 children born in a region in which the population’s urine thallium concentrations were higher than normal because of industrial contamination of their environment.²² Urine thallium concentrations in the exposed children were as high as 76.5 μg/L. Although these children had a slightly higher than expected incidence of congenital abnormalities, no causal relationship could be established with regard to thallium exposure.²²

There are few human reports of acute thallium poisoning during pregnancy. A comprehensive literature review demonstrated 25 cases, which included acute and chronic exposures that occurred during all trimesters.³⁹ Thallium slowly traverses the placenta and is able to cause characteristic fetal toxicity,^24,73 which manifests initially as decreased fetal movement, possibly as a consequence of fetal paralysis. The classic clinical signs and symptoms of thallium poisoning are described both in the fetus after abortion and in neonate after viable delivery.^24,65,73,81 However, the outcome of the pregnancy may be normal despite significant maternal toxicity.^24,46 The only consistent finding is a trend toward prematurity and low birth weight, especially in children exposed during the first trimester.³⁹ One author recommends continuing the pregnancy as long as the mother is clinically improving.²⁴ It is reasonable to conclude that a fetus exposed to thallium during organogenesis has the potential for permanent injury. Those exposed later in pregnancy may recover without deficit if their exposures are limited and the mother recovers. If the exposure occurs closer to term, the child may be born with overt toxicity such as alopecia, dermatitis, nail growth disturbances, and permanent CNS injury.⁶⁵

These few case reports and animal studies provide confusing and sometimes contradictory results. It seems that fetal outcome is determined by both the trimester of pregnancy and the extent of maternal toxicity. However, because there are insufficient data to predict the outcome of pregnancy complicated by maternal thallium poisoning, no specific course of action can be recommended other than extensive fetal monitoring and aggressive treatment for the mother. When a viable child is delivered, it is important to note that thallium is eliminated in breast milk, and that ongoing evaluation of maternal toxicity is essential because nursing may result in continued exposure for the child.³⁷

Most patients with acute thallium toxicity seek health care soon after exposure because of either alterations in their GI, cardiovascular, and neurologic function. Establishing the correct diagnosis at this early stage is essential to assure a satisfactory outcome. Unfortunately, many patients with either smaller acute exposures or chronic thallium poisoning first present days to weeks after their initial exposure and diagnosis is often further delayed. In these instances, many valuable epidemiologic aspects of the exposure history may be difficult to obtain. GI symptoms may not have occurred or their consequence or etiology may have gone unrecognized because of their nonspecific, mild, and transient nature. Many patients with small acute or chronic exposures usually seek care because of alopecia or neuropathy.

The differential diagnosis of the neuropathy includes poisoning by arsenic, colchicine, vinca alkaloids, and disorders such as botulism, thiamine deficiency, and Guillain-Barré syndrome. Both the sensory neuropathy and the preservation of reflexes help differentiate thallium-induced neuropathy from Guillain-Barré syndrome and most other causes of acute neuropathy.¹² When GI symptoms are present in addition to a neuropathy and other end-organ effects, poisoning with metal salts such as arsenic and mercury should be considered (Chaps. 89 and 98). The differential diagnosis of rapid onset alopecia is more restricted and includes arsenic, selenium, colchicine, and vinca alkaloid poisoning (Chap. 18). When present, Mees lines indicate past exposure to metals, mitotic inhibitors, or antimetabolites and as such are nonspecific for thallium poisoning (Chaps. 18, 89, and 98).

Diagnostic Testing

Radiographs of tampered food products⁶² or of the abdomen³³ can document the presence of a metal such as thallium, which is radiopaque. Although abdominal radiography may be useful shortly after a suspected exposure, the sensitivity and specificity of this test is unknown. Similarly, the yield from other routine studies, such as the complete blood count, electrolytes, urinalysis, and ECG, is limited in that these other studies are often normal or at most, merely demonstrate nonspecific abnormalities. Although microscopic inspection of the hair is intriguing, this test is unlikely to be conclusive for inexperienced observers.

The definitive clinical diagnosis of thallium poisoning can only be established by demonstrating elevated thallium concentrations in various body fluids or organs. Thallium can be recovered in the hair, nails, feces, saliva, CSF, blood, and urine, and standard assays and normal concentrations for most of these sources can be found.⁶⁸ Qualitative point of care urine spot tests notoriously give false negative results and require the use of dangerous chemicals that are not routinely available (20% nitric acid) and therefore should be avoided.⁸⁸ The standard toxicologic testing method is to assay a 24 hour urine sample for thallium by atomic absorption spectroscopy.^16,110 Normal urine concentrations are below 5 μg/L. Some authors suggest a potassium mobilization test to enhance urinary elimination, similar to the ethylenediaminetetraacetic acid (EDTA) mobilization test, to assist in the diagnosis of thallium exposure.^11,44,88 We advise against this practice because of its lack of proven usefulness and its potential to exacerbate neurologic toxicity (see Potassium below).

The treatment goals for a patient with thallium poisoning are initial stabilization, prevention of absorption, and enhanced elimination. After the initial assessment and stabilization of the patient’s airway, breathing, and circulatory status, GI decontamination should be instituted in all patients with suspected thallium ingestions because of the morbidity and mortality associated with a significant exposure.

Decontamination

Patients who present within 1 to 2 hours after ingestion should be considered candidates for orogastric lavage (Chap. 8). If the patient presents more than 2 hours after ingestion or has had considerable spontaneous emesis, gastric emptying is unnecessary.

Thallium salts are substantially adsorbed to activated charcoal (AC) in vitro.^41,50 Additionally, because thallium undergoes enterohepatic recirculation, AC may be useful both to prevent absorption after a recent ingestion and to enhance elimination of thallium in patients who present in the post-absorptive phase.¹⁰¹ In fact, a rat model of thallium poisoning demonstrated that multiple-dose AC (given as 0.5 g/kg twice daily for 5 days) increased the fecal elimination of thallium by 82% and substantially improved survival.⁵⁶ Other data demonstrate that AC alone is superior to either forced diuresis or potassium chloride therapy.⁵¹

In patients with severe thallium toxicity, constipation is common, so the addition of oral mannitol^58,96,108 or another cathartic to the first dose of AC is appropriate. Although no studies address the efficacy of whole-bowel irrigation with polyethylene glycol electrolyte lavage solution, this technique may prove useful, especially when radiopaque material is demonstrated in the GI tract (Antidotes in Depth: A2).

Potassium

The similarities between the cellular handling of potassium ions and thallium ions led to the investigation of a possible role for potassium in the treatment of thallium poisoning. In humans, potassium administration is associated with an increase in urinary thallium elimination.^15,29,76 The magnitude of this increase is reported to be on the order of two- to threefold.⁷⁶ This is supported by animal models that demonstrate some benefit in terms of either enhanced thallium elimination or animal survival.^30,51,56 Potassium administration is believed to both block tubular reabsorption of thallium and mobilize thallium from tissue stores, thereby increasing thallium concentrations available for glomerular filtration.^70,88 However, the mobilization of the thallium is of concern. Many authors report either the development of acute neurologic toxicity or the significant exacerbation of neurologic symptoms during potassium administration.^{7,29,62,76,85,104} Others cite data demonstrating that the augmentation of thallium elimination by potassium administration in humans is quite limited.⁴⁹ Additionally, animal models demonstrate that potassium loading enhances lethality⁶¹ and permits thallium redistribution into the CNS.³⁶ For these reasons, the routine use of potassium should be considered potentially dangerous. Some authors recommend forced diuresis, especially in conjunction with potassium chloride.^20,101 However, no convincing experimental or clinical evidence can support the use of forced diuresis with or without potassium at this time.

Likewise, the similarities between thallium and potassium might suggest a role for administration of sodium polystyrene sulfonate (SPS) as a sodium–thallium exchange resin. Although in vitro binding between thallium and SPS is excellent, it is unlikely to be clinically useful because of preferential binding between potassium and SPS.⁴¹ Consequently, neither the use of potassium nor of SPS is recommended.

Prussian Blue

Prussian blue is approved by the Food and Drug Administration for thallium toxicity (Antidotes in Depth: A28).¹⁰² When given orally, Prussian blue acts as an ion exchanger for univalent cations, with its affinity increasing as the ionic radius of the cation increases. As such, Prussian blue interferes with the enterohepatic circulation of thallium by exchanging potassium ions from its lattice for thallium ions in the GI tract. This results in the formation of a concentration gradient, causing an increased movement of thallium into the GI tract.

Humans with thallium poisoning are routinely given Prussian blue, which appears to result in clinical benefits, enhanced fecal elimination, and decreasing thallium concentrations.^{16,18,62,79,96,104,105,108,109} One series of 11 thallium poisoned patients demonstrated both the safety of Prussian blue and its ability to substantially increase fecal thallium elimination.⁹⁶ Unfortunately, because there have been no controlled trials in humans that compare Prussian blue with other drugs and because many of the patients reported above received multiple therapies, the actual efficacy of Prussian blue is unknown.

The dose of Prussian blue is 250 mg/kg/d orally via a nasogastric tube in two to four divided doses.⁹⁶ For patients who are constipated, the Prussian blue may have greater benefit if dissolved in 50 mL of 15% mannitol.¹⁰¹ Although any cathartic may be useful, most authors have used mannitol, possibly because of concerns regarding repeated use of magnesium containing cathartics in patients with neurologic findings and the use of sorbitol in patients with poor GI mobility. (Other dosing regimens are discussed in Antidotes in Depth: A28.)

Extracorporeal Drug Removal

Extracorporeal drug removal may have a limited beneficial role in patients with thallium toxicity, especially if it is begun shortly after the initial exposure while serum concentrations remain high before effective tissue distribution. Because a frequently quoted review attests to the benefits of hemodialysis,⁶⁵ many patients still receive this therapy.⁶⁴ The actual data, however, show that hemodialysis, at various stages of poisoning, is no better than forced diuresis.^18,78 Reported thallium removal rates by hemodialysis are trivial: 143 mg of thallium was removed by 120 hours,⁷⁹ 222.8 mg was removed by 121 hours,¹⁸ and 128 mg was removed by 54 hours of hemodialysis.¹⁸ These quantities can be placed in perspective knowing that the minimum lethal adult dose of thallium is estimated to be on the order of 1 g,⁶⁸ and that many reported cases exceed that by a factor of 10. Data from a more recent hemodialysis experience suggest that by using high blood flow rates (300 mL/min), clearances as high as 90 to 150 mL/min could be obtained.⁵⁸ Although these clearances seem encouraging, they should be interpreted with an appreciation of the large volume of distribution that thallium achieves in the post absorptive phase. With lower blood flow rates, charcoal hemoperfusion may be two to three times more efficient than hemodialysis, providing clearance rates as high as 139 mL/min.¹⁸ Combined hemoperfusion and hemodialysis were used in several cases^4,18,19 and were reported to remove as much as 93 mg of thallium within 3 hours of therapy.⁴ Although extracorporeal therapy alone is probably insufficient for patients with significant poisoning and unnecessary in those with small exposures, it may have some benefit when used in combination with other therapies, especially in patients with either underlying chronic kidney disease or acute kidney injury from thallium poisoning, and those with early massive, and presumed lethal, exposures. As is the case with other xenobiotics, thallium is probably not effectively removed by peritoneal dialysis.⁴⁹ A multidisciplinary consensus work group recently supported extracorporeal therapy in patients with acute poisoning when blood thallium concentrations are greater than 400 μg/L (if rapidly available), or, if in the absence of laboratory support severe signs and symptoms are present and treatment can be initiated within 24 to 48 hours of ingestion.³¹ Table 102–2 summarizes the suggested therapy for thallium poisoned patients.

Chelation

Patients with thallium toxicity do not respond to traditional chelation therapy. Studies demonstrate that the use of EDTA and diethylenetriamine pentaacetic acid are without benefit.^68,88 Dimercaprol (British anti-Lewisite {BAL}) and d-penicillamine also fail to enhance thallium excretion in experimental models.^68,88 In one model in which d-penicillamine was able to enhance thallium elimination, the resultant substantial thallium redistribution into vital organs was a significant disadvantage.⁸⁴ More recently, a rodent model of combined use of Prussian blue with dl-penicillamine not only suggested a survival advantage for combined therapy but demonstrated reduced thallium concentrations in vital organs, including the brain.⁶⁶ Sulfur-containing compounds such as cysteine and NAC are not beneficial.^56,60 Another chelator, diphenylthiocarbazone (dithizone), forms a minimally toxic complex with thallium, resulting in a 33% increase in fecal elimination of thallium in rats.⁹³ Unfortunately, dithizone is goitrogenic and diabetogenic in animal studies.^56,69,101 Dithiocarb (sodium diethyldithiocarbamate), an intermediate metabolite of tetraethylthiuram disulfide (disulfiram, or Antabuse) (Chap. 79), also increases the urinary excretion of thallium.^93,98 Before thallium elimination, however, the formation of a lipophilic thallium–diethyldithiocarbamate complex may result in the redistribution of thallium into the CNS.^47,98 After decomposition of the chelate complex, thallium may remain in the CNS, potentially exacerbating neurologic symptoms.^47,86 Because of the significant adverse effects of dithizone and the redistribution of thallium after Dithiocarb use, neither chelator is recommended in the treatment of patients with thallium poisoning.

Currently, there is renewed interest in the water-soluble analogs of BAL (DMPS and succimer). However, in an animal model, DMPS failed to decrease tissue concentrations of thallium.⁶⁹ Similarly, in another ­animal model, although succimer improved survival over control subjects, the benefit was less than that achieved for Prussian blue and was at the cost of an increase in brain thallium concentrations.⁸⁷ Preliminary animal investigations demonstrate reduction in serum thallium concentrations after administration of the iron chelators deferoxamine and deferasirox.^26,90 Although worthy of additional study, these results are too preliminary to recommend either antidote in thallium-poisoned patients.

• Thallium is a multisystem toxin whose effects result from cellular mimicry for potassium and avid binding to sulfhydryl groups.

• The elimination of thallium salts from depilatories and rodenticides has substantially reduced the incidence of both intentional and unintentional thallium toxicity in the United States.

• Cases of significant poisoning still occur in countries where thallium-containing rodenticides remain in use, as well as in this country, from attempted homicide and by personal injury from contamination of foods and illicit xenobiotics.

• Early recognition of the characteristic signs and symptoms of thallium poisoning, such as a painful ascending neuropathy and alopecia, followed by prompt initiation of safe and appropriate therapy will substantially improve the prognosis.

• Patients with acute oral poisonings should receive at least one dose of oral AC followed by either multiple dose activated charcoal (MDAC) or Prussian blue, if available. Oral mannitol can be added to either MDAC or Prussian blue when constipation is present.

• In severe acute poisoning, the addition of hemodialysis or combined hemodialysis and hemoperfusion in series may be beneficial.

References