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Thallium toxicity
Toxicology Letters 99 (1998) 1 – 13
Mini-review
Thallium toxicity Sonia Galva´n-Arzate *, Abel Santamarı´a Department of Neurochemistry, National Institute of Neurology and Neurosurgery, 14269 S.S. Mexico D.F., Mexico Received 14 April 1998; received in revised form 3 July 1998; accepted 6 July 1998
Abstract Thallium (Tl + ) is a toxic heavy metal which was accidentally discovered by Sir William Crookes in 1861 by burning the dust from a sulfuric acid industrial plant. He observed a bright green spectral band that quickly disappeared. Crookes named the new element ‘Thallium’ (after thallos meaning young shoot). In 1862, Lamy described the same spectral line and studied both the physical and chemical properties of this new element (Prick, J.J.G., 1979. Thallium poisioning. In: Vinkrn, P.J., Bruyn, G.W. (Eds.), Intoxication of the Nervous System, Handbook of Clinical Neurology, vol. 36. North-Holland, New York. pp. 239 – 278). © 1998 Elsevier Science Ireland Ltd. All rights reserved.
1. Chemistry Thallium is classified in the group III A of the periodic chart; the metals of this group are electropositive; as their atomic weights increase, so does their basic character. It forms two kind of compounds: monovalent thallo- and trivalent thalli-compounds. Tl + also tends to form stable complexes with soft ligand donors, such as sulfurcontaining compounds.
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Inorganic Tl (I) compounds are more stable than Tl (III) analogues in aqueous solution at neutral pH. In contrast, covalent organothallium compounds are stable only in the trivalent form (Mulkey and Oehme, 1993). Tl + is particularly toxic in its Tl (I) compounds, such as sulfate (Tl2SO4), acetate (CH3COOTl), and carbonate (Tl2CO3). The sulfide (Tl2S) and iodide (TlI) are both poorly soluble and therefore, much less toxic (Moeschlin, 1980). It has been also reported that organic thallium compounds, such as thallous malonate, show a higher elimination rate constant but are similar in toxicity and distribution pattern compared to the inorganic thallium compounds, such as thallous sulfate (Aoyama, 1989).
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1.1. Ocurrence and distribution Thallium is widely distributed in the environment, although it is generally present in very low concentrations. Tl + is not an ubiquitous trace element. In the earth’s crust, average Tl + concentrations are between 0.3 and 0.5 mg/g. Although it is very toxic (MAC 0.1 mg/m3), it has not been considered a potential environmental pollutant. Thallium occurs in small concentrations in sulfides ores (Fe, Pb, Zn) which are commonly employed for the production of sulfuric acid. In the roasting process, thallium may arrive in the flue dust or in the lead chamber slime or it can remain in the pyrites cinder (0.03 – 0.05% of Tl) which is used in the cement industry (Liem et al., 1984). High levels of thallium can be found in granite, shale and manganese nodules. It has also been detected in volcanic rocks, meteorites and plants. Tl + is concentrated in magmatic potassium minerals such as feldspars and micas. The few Tl + minerals existing contain about 16 – 60% of the metal and they are quite rare: Crookosite ((Cu, Tl, Ag)2Se), Hutchinsonite ((Tl, Ag)2S · Pbs · 2As2S3), Lorandite (Tl2S · AsS3), and Vrbaite (Tl2S3(As,Sb)2S3). Natural thallium concentrations in seawater and freshwater are estimated to be B 0.03 ppb (Mulkey and Oehme, 1993).
used for some medical tests, as well as in research studies.
1.3. Sources of exposure Since its discovery, thallium has been responsible for many occupational and accidental intoxications (Reed et al., 1963). Demonstration of the presence of thallium in urine is the best diagnostic procedure available so far. Any amount of thallium in the body shall be considered abnormal (Reed et al., 1963). According to Mulkey and Oehme (1993), thallium levels in normal human and animals are B 1 ppb in blood and urine, and B 10 ppb in tissues. Few cases of poisoning from industrial exposure are known, probably due to the fact that chronic thallium poisoning mimics many other diseases and thallotoxicosis is not recognized, but accidental poisoning caused by contact with thallium-containing materials or their careless handling occurs more frequently. Thallium has received much more attention as an environmental pollutant since high thallium contents were found in cement powders discharged from stacks and emissions from brickworks, and that had contaminated adjacent farmland (Liem et al., 1984).
2. Mechanisms of toxic action
1.2. Uses Thallium is obtained as a by-product of the refining process of iron, cadmium and zinc. The flue dust of this industry is further processed in order to recover commercial quantities of the metal. Tl + is used as a catalyst in certain alloys, optical lens, jewelry, low temperature thermometers, semiconductors, dyes and pigments and scintillation counters. Tl + has also been employed for clinical purposes as a depilator (Marmo et al., 1987). In addition, thallium salts are still widely used as rodenticides and insecticides in some countries, despite the World Health Organization recommendation against its use in 1973. Thus, although known to be toxic, thallium compounds are still available in many countries around the world (Luckit et al., 1990). At present, Tl201 is
The well-known mechanism of thallium toxicity is related to the interference with the vital potassium-dependent processes, substitution of potassium in the (Na + /K + )-ATPase, as well as a high affinity for sulfhydril groups from proteins and other biomolecules (Aoyama et al., 1988). Since Tl + and K + are both univalent ions with similar ionic radii, thallium is able to interfere with potassium-dependent processes, and then mimics potassium in its movement and intracellular accumulation in mammals (Mulkey and Oehme, 1993). The capability of thallous ions to mimic the biological action of potassium ions has been attributed to the remarkable inability of cell membranes to distinguish between thallium and potassium, possibly due to their similar ionic
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charges and radii. Thus, thallium is expected to interfere competitively with some potassium-dependent biological reactions, as the chemical properties of thallium and potassium are sufficiently alike. Thallium has been shown to replace the physiological ion potassium in the activation of several monovalent cation activated enzymes, e.g. pyruvate kinase, ATPase and aldehyde dehydrogenase. Thallium has also been found to replace potassium in the stabilization of ribosomes, as well as in physiological functions such as muscle contraction (Douglas et al., 1990). On the other hand, Herman and Bensch (1967) demonstrated a variety of changes in the morphology of mitochondria in kidney, liver, intestine, brain, seminal vesicle and pancreas of rats treated with several doses of thallium acetate. Some years later, Spencer et al. (1973) reported cytopathic early effects of thallium with the appearance of considerably enlarged mitochondria in axons of peripheral nerve fibers; with time, the matrix space of these mitochondria were swollen. Other studies have suggested that the biological effects and potential toxicity of specific trace metals, including thallium, are mediated through primary disruption of the structural integrity of subcellular organelle membranes with which impaired biological processes are associated (Woods and Fowler, 1986): thallium may be preferentially sequestered both by mitochondria as well as by other membranous subcellular organelles (Potts and Gonasun, 1980). Woods and Fowler (1986) also suggested that the changes in selective membrane-bound mediated biochemical processes, produced by thallium and other metals, are closely linked both physically and functionally with preliminary disruption of the membranal integrity of mitochondria and endoplasmic reticulum. Although all this evidences suggest some possible specific actions of thallium, its precise mechanism of toxicity still remains unknown. We have to consider that thallium neuropathy could be the consequence of energy deprivation after depletion of tissue flavoproteins (Cavanagh, 1991), as well as the fact that thallium could bind Tl-active sulfhydryl sites of enzymes (Chandler and Scott, 1986).
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3. Clinical toxicity Thallium intoxication appears after its introduction into the body by inhalation, ingestion (via contaminated food and hands), or through the skin. It may rise to acute, subacute or chronic clinical manifestations according to the type of exposure (Rossi et al., 1987), dose and age of the subject (Mulkey and Oehme, 1993). Because of its severe toxicity and the fact that the metal is colorless, odorless and tasteless, thallium has been used for homicidal poisoning purposes (Luckit et al., 1990; Meggs et al., 1994). This highly toxic element is accumulated in the organism, eventually crossing both the blood-brain-barrier and the placenta (Ziskoven et al., 1983). Tl + is generally eliminated by urine, bile, saliva, feces, milk and tears (Rossi et al., 1987). Elimination half-life of thallium is long, due to its large distribution volume (Repetto et al., 1998). The estimated half-life in humans is reported between 1 and 3 days after low doses (Talas et al., 1983) and between 1 and 1.7 days under clinical therapy after ingestion or exposure by a possible lethal dose (Hologgitas et al., 1980; de Groot et al., 1985). Other groups have reported an elimination half-life between 8 and 30 days (Piazolo et al., 1971). Minimum lethal dose (LDL0) of thallium in humans is also highly variable (Repetto et al., 1998). Average lethal dose for thallium sulfate has been reported from 10 to 15 mg/kg (Moeschlin, 1980). Although Gettler and Weiss (1943) reported a minimum lethal dose of 14–15 mg/kg, Moeschlin (1980) reported fatalities with 8 mg/kg. Thallium, as an inhibitor of sweat secretion, was employed in 1861 to counteract the troublesome nocturnal sweating of tuberculosis patients. It occasionally gave good results too, in cases of dysentery with violent or persistent diarrhea. Tl + was also given to patients with syphilis, gonorrhea, gout and mycosis of the scalp (Prick, 1979). Shortly thereafter (1920), thallium was also used as a cosmetic depilatory to remove excessive hair growth. Physicians soon became aware of the toxic effects of thallium. Just few a weeks after its administration, loss of hair would sometimes occur,
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eventually resulting in complete baldness, as well as axillary and pubic hair loss. Misgivings about the use of thallium became stronger when it was found that other symptoms of poisoning could also appear, such as gastrointestinal disturbances (nausea, vomiting, constipation and diarrhea), peripheral and central nervous system disorders as well as pain in the abdomen, back and extremities —particularly in the legs — extreme tenderness of the soles of the feet, ataxia, dyesthesia, motor weakness, paralysis, tremors, chorea, convulsions, periods of confusion, restlessness, sleeplessness, delirium, hallucinations, lethargy, stupor and personality changes alternating with periods of lucity, coma, and also cardiac signs such as tachycardia, irregular pulse and hypotension (Reed et al., 1963; Hasan et al., 1978; Moeschlin, 1980). Recent cases of human thallium poisoning have been reported; most of them showed similar symptomatology. Herrero et al. (1995) described a case of acute poisoning presenting abdominal pain, paraesthesiae, irritability and severe alterations of the peripheral nervous system. Also in 1995, after an intensive international work of diagnosis via Internet, a Chinese student was diagnosed as thallium poisoning when she exhibited abdominal pain, alopecia and a variety of central nervous system complains (Gunby, 1995). McMillan et al. (1997) described some neuropsychological assessments in a patient exposed to acute Tl, showing several neurological signs, including confusion, disorientation and generalized slowing of EEG. Results indicated persistent weakness in verbal abilities consistent with other case reports. Another case of severe Tl intoxication was reported by Malbrain et al. (1997), in which Tl was ingested by a 38-year old woman 2 h before hospitalized; this time an immediate treatment with Prussian blue, enhanced diuresis by intravenous fluids and a prolonged hemodialysis resulted to be successful. Several other report cases are available in the literature and the clinical features observed in them are often similar. Some differences observed in literature on Tl poisoning features mainly depend both on the time and the nature of Tl exposure.
3.1. Skin Alopecia is the best known effect of thallium poisoning. It produces changes in the dermis and its derivatives (hair, nails, sweat and sebaceous glands). One or two days after absorption, a peculiar deposit of a dark pigment can be observed in the hair roots, quite often zebra-like (Prick, 1979). Epilation begins about 10 days after ingestion, complete hair loss is seen in about 1 month. This long latent period coincides with the maturation period of the new epithelial cells of the hair papilla, in which thallium targets (Mulkey and Oehme, 1993). After 2 or 3 months, the hair will be restored to its former condition (Prick, 1979). Other dermic signs may include palmar erythema, acne, anhydrosis and dry scaly skin which is caused by the toxic effect of thallium on sweat and sebaceous glands (Mulkey and Oehme, 1993). The growth of the fingernails is also impaired, and transverse white stripes appear in the nails, they are so-called lunular or Mee’s stripes (Prick, 1979).
3.2. Gastrointestinal tract After oral ingestion of Tl + , the poison causes an inflammatory reaction in the structures that were exposed first, resulting in glossitis, pharyngooesophagitis, gastritis, enteritis and colitis (Prick, 1979). Often, nausea and vomiting occur during the 3–4 day period following intoxication, which may be replaced by severe abdominal pain that is relieved by directed pressure. Depression of the intestinal motility and peristalsis may occur due to possible vagus nerve involvement, resulting in severe constipation (Reed et al., 1963; Mulkey and Oehme, 1993). During the irritative phase of the vagal lesions, patients may have complaints suggestive of a stomach or duodenal ulcer. Persistent, severe vomiting, which is common in acute thallium poisoning, may also play an important role in causing deficiencies that can be exacerbated by inadequate treatment. In such cases, striking emaciation and loss of strength can often be traced to inadequate absorption of fatty acids and deficiency of fat-soluble vitamins (Prick,
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1979). Gastrointestinal symptoms usually follow within hours after acute poisoning. Vomiting, abdominal pain, gastrointestinal hemorrhage and diarrhea are more common, but some patients may only have anorexia or nausea (Smith and Doherty, 1964).
3.3. Ner6ous system Neurological symptoms usually appear between 2 – 5 days after acute exposure cases, which are characterized by a painful, rapidly progressive peripheral neuropathy that dominates clinically in the second or third week. Sensory disturbances include pain and paresthesias of the lower limbs, numbness in the fingers and toes, with the loss of pin-prick and touch sensation. Occasionally, hyperesthesia involving the soles of the feet and tibial region occurs. Motor neuropathy is evident by weakness which are always distal in distribution. The lower body extremities are primarily affected. Upper extremity involvement occurs uncommonly and cranial nerves participation is rare. Insomnia, headache, emotional liability, anxiety, tremor, ataxia, choreoathetosis and signs of cranial nerve involvement may be developed. Psychosis with paranoia, depression, aggressiveness and hallucinations are also common. In chronic poisoning, ataxia and paresthesia may be the outstanding symptoms. In time, the paresthesia may progress to evident peripheral neuropathy with weakness and atrophy of the associated musculature (Prick, 1979; Mulkey and Oehme, 1993). In very serious or even fatal cases, true ‘pseudobulbar paralysis’ due to peripheral neuritis of cranial nerves is observed, with paralysis of the ocular muscles, ptosis, facial paralysis, amblyopia and paralysis of the recurrent nerve. Shortly before death, paralysis of the vagal nerve may supervene, possibly being the direct cause of death. With some cases, in early stages of poisoning, the optic disk reveals the typical picture of neuritis with ill-defined and red papillae, followed by the development of pale or white papillae as a result of atrophy of the optic nerve. In occasional instances, the initial stimulation of the ganglionic cells of the brain may give rise to severe Jacksonian epilectic seizures; also severe epileptiform
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convulsions can be observed (Cavanagh, et al., 1974; Moeschlin, 1980).
3.4. Ner6e findings Limos et al. (1982), reported previous findings from Spencer’s group, in which they used electron microscopy to observe axons of myelinated fibers with markedly dilated myelin sheaths that showed absence, severe alteration or disintegration of axoplasmic organelles in humans exposed to Tl + . Histopathological studies in intoxicated humans and animals have also revealed axonal degeneration of the peripherial nerves (Limos et al., 1982). Cavanagh et al. (1974) described, case by case, some pathological observations in nerve tissue from thallium-poisoned patients. They found ocassional swollen axon with granular fragmented appearance of the sciatic nerve. Similar alterations were found in sural and vagus nerves, also exhibiting degeneration of the associated myelin sheaths; swelling and fragmentation were also seen in cranial nerves. Although no significant abnormalities were found in cerebellum, cerebral cortex, basal ganglia or midbrain from some patients, morphological changes were not discarded in nerve tissue from other patients. Now it is known that some neuropathies induced by Tl + are associated with the pathology of both sensory and motor neurons.
3.5. Kidney Renal excretion of thallium sulfate is slow and may be detected as late as 2 months after ingestion. Toxic injures to the kidney have been indicated by albuminuria and haematuria, however, the renal function is not grossly impaired (Reed et al., 1963). The toxic effects on the kidney, notably resistant to dehydration and decubitus, also strain the body’s resources. In most of cases, the kidney present limited toxic injury. During the first 2 weeks after exposure, there is albuminuria with erythrocytes, leucocytes and cylindrical casts in the urinary sediment, and sometimes porphyria. In this serious phase of the illness, there is a fall in the concentrating ability of the kidneys, often with recovery afterwards. In some cases, there is
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also haemorrhagic damage to the kidneys (Prick, 1979).
3.6. Li6er and lung Additional to some changes observed on the nervous system, Cavanagh et al. (1974) described some pathological findings in several organs — including livers and lungs — of patients intoxicated with thallium. Histopathological findings showed centrilobular necrosis with fatty change present in most liver lobules, as well as the presence of abnormal amounts of porphyrins in the urine. Oedema, moderate congestion, patchy early bronchopneumonia and inflammation were found in lungs. Several other secondary pathological changes were described in the organs of these patients.
3.7. Cardio6ascular system Cardiac signs, such a sinus tachycardia, irregular pulse, hypertension and angina-like pain, have been reported during the second week after the ingestion of thallium sulfate. Some authors suggested that such signs are due to vagus involvement, while others have recorder electrocardiographic evidence of myocardial damage (Reed et al., 1963). The most dreaded effect of bilateral paralysis of the vagus nerve is malfunction of the cardiac muscle evidenced by tachycardia and circulatory disturbances, possibly resulting in left-sided (cardiac asthma) or rightsided decompensation. Under these circumstances, it is quite common for paralyzed patients, often short of breath already, to develop severe dyspnoea and cyanosis, followed by death (Prick, 1979).
3.9. Reproducti6e system Experimental evidence suggests that the reproductive system is highly susceptible to thallium. Decreased libido and impotence in humans, and lower sexual activity in laboratory animals have been both noted after chronic exposure to this metal. In animals and humans, the testes accumulated high levels of thallium (Rı´os et al., 1989). Morphological and biochemical changes in the testes and decreased epididymal sperm motility has been observed in rats exposed to 10 ppm of thallium in drinking water of 2 months. The human fetus may suffer from transplacental exposure, as evidenced by skin and nail dystrophy, alopecia and low body weights in newborns of intoxicated mothers (Mulkey and Oehme, 1993); whereas in animals, thallium also can be detected in fetal tissues after placental transfer of thallium (Ziskoven et al., 1983).
3.10. Eye Thallium acetate is able to induce cataracts in rats within 6 weeks after initiating a daily dose of 0.1 mg, appearing first as radial striations in the anterior cortex between the sutures and the ecuator. While the early phases will remain stationary if thallium administration ceases, development of subcapsular opacities will occur if administration continues. Thallous ion rapidly accumulates into the lens both in vivo and in vitro (Klassen et al., 1986). Retrobulbar neuritis with reduction of vision and central scotoma may occur as a result of thallium intoxication. Iritis, inflammation of the eyelids as well as intraocular hemorrhage have been reported in animals (Mulkey and Oehme, 1993).
3.8. Blood Some reports on acute and chronic poisoning, have mentioned haematological changes such as anaemia, leucocytosis, eosinophilia and limphopenia (Reed et al., 1963; Cavanagh et al., 1974; Moeschlin, 1980; Saddique and Peterson, 1983). Luckit et al. (1990) found lymphopenia, mild neutrophilia and trombocytopenia associated to thallium poisoning.
3.11. Teratogenesis, mutagenesis and carcinogenesis Thallium is teratogenic in chick embryos, causing achondroplasia, leg bone curvature, parrotbeak deformity, microcephaly and decreased fetal size (Mulkey and Oehme, 1993). Rats shown nonossification of the phalanges and vertebral bodies when the mother received thallium while fed (Car-
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son et al., 1987). When puppies are directly exposed to thallium, they showed several alterations in the cartilaginous cells, chrondrine, osteoblasts, osseous tissue and bone marrow (Barroso-Moguel et al., 1992). Rangel-Guerra et al. (1990) reported 50 cases of thallium poisoning — including a newborn exposed through the placenta — exhibiting alopecia and imperforate anus. When intoxication occurs after the first 3 months, only a few newborns presented symptoms which were compatible with thallotoxicosis (Olsen and Jonsen, 1982). Severe intoxications in the mother at the end of pregnancy cause the death of the fetuses (Dimitru and Kalantri, 1990). Thallium salts have produced antimitotic activity on mammalian, avian and plant cells. Thallium (I) is the most active heavy metal found for breaking chromosomes of pea plants. Thallous acetate solutions retarded both mitosis and meiosis in mosquitoes when the larva and nymphs were treated (Smith and Carson, 1977). Chronic oral or cutaneous dosing of mice with thallium salts caused degeneration, papillomas, precancerous lesions and cancer of the female genital tract (Smith and Carson, 1977).
4. Treatment The aim of treatment against thallotoxicosis has been for long time oriented to modify thallium to a less toxic compound, as well as to increase its excretion through the kidneys and gastrointestinal tract (Reed et al., 1963). According to Chamberlain et al. (1958), treatment consists of immediate emphasis on (1) removal of recently ingested thallium sulfate by: (a) gastric lavage; (b) activated charcoal: 0.5 mg/kg orally twice a day during 5 days; and (2) to promote its urinary excretion by: (a) abundant intake of fluids, (b) potassium chloride 3 – 5 mg/day, during 5 – 10 days. The use of antidotal treatment against acute thallium intoxication is stressing because of the severity of the symptoms and the high lethality of the poisoning. Prussian blue is orally administered as antidotal treatment in thallium intoxication cases. It has been demonstrated that accelerating
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tissue elimination of thallium ions from their action sites may represent a useful therapy (Kamerbeek et al., 1971b). Chelating agents have also been tested as antidotes, but their beneficial effects are doubtful since they can cause redistribution of thallium from inactive depots to the target organs, leading to exacerbation of the symptoms (Kamerbeek et al., 1971a). The need of a new therapy against thallium poisoning lead the researchers to investigate the possible protective effects of combined D-penicillamine and Prussian blue treatments; results revealed the positive effects of this combined treatment to antagonize thallium-induced lethality in rats (Rı´os and Monroy-Noyola, 1992), as well as cerebellar lesions (Barroso-Moguel et al., 1994a). Human thallotoxicosis has been treated with different drugs, such as British antilewsite (BAL), potassium chloride, ditizone, EDTA, dithiocarbamate and D-penicillamine, showing diverse and controversial therapeutic results (Kravzov et al., 1993). A very recent alternative for treatment of Tl poisoning was explored by Meggs et al. (1997): N-acetylcysteine (NAC) has been used as an antidote in acetaminophen poisoning because of its positive effects in the treatment for other toxins by its capability to increase the renal excretion of arsenic, gold and methyl mercury. Since Tl is known to bind sulphydryl groups and because NAC contain many sulfhydryl groups, it is likely that NAC could represent an effective new chelation treatment in Tl poisoning (Meggs et al., 1997). However, no improvement, as compared to Prussian blue treatment, was observed on survival after NAC treatment of mice intoxicated with Tl. Further studies on the effects of oral administration of NAC are needed in order to characterize this promising experimental treatment.
5. Distribution and excretion Water-soluble Tl + salts are widely distributed in organs and tissues, including the brain, heart, kidney, skeletal muscle and testis (Rı´os et al., 1989; Mulkey and Oehme, 1993). Renal excretion of thallium sulfate is slow, and may be detected as late as 2 months after ingestion. Toxic injuries to
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the kidney have been indicated by albuminuria and haematuria; however, renal function is not grossly impaired. Using radioactive thallium sulfate in rats, Thyresson found the highest content in the kidneys, intestinal mucosa, thyroid, testes, pancreas, skin, bone and muscle, in that order, whereas fat, liver and all types of nerve tissue were uniformly lower in thallium content (Reed et al., 1963). In studies using field desorption mass spectrometry technique, thallium concentrations were established in stomach, heart, kidney, liver and brain as a time-dependent process. It was also found that, the stomach was the first organ showing the maximal concentration, followed by kidney, heart, liver and brain. After time, the brain was the organ showing the largest Tl + concentrations, whereas the other organs tended to reach excretion levels (Achenbach et al., 1980). Ziskoven et al. (1983) investigated the thallium distribution in both fetal and maternal tissue from mice and rats. They found that Tl + ions are preferentially accumulated in the kidney, whereas the brain concentrations were increased more slowly. No differences between rats and mice were observed. Rı´os et al. (1989) compared the content of thallium in several organs and brain regions of rats at 24 h after the acute administration of increasing doses; they found that thallium content in kidney was higher than in all other organs studied and also that whole brain presented the lowest thallium concentration. However, a differential distribution of thallium was found among brain regions: the highest thallium concentration was found in the hypothalamus and the lowest in the cortex. Such a distribution pattern was similar at the three different doses employed, and the time course of thallium accumulation in brain was found considerably faster in hypothalamus than in others regions— particularly the cortex — suggesting important differences in thallium entry into the brain parenchyma. Galva´n-Arzate and Rı´os (1994) investigated the thallium distribution among body organs and brain regions of developing rats after acute thallium intoxication in order to elucidate a possible participation of the bloodbrain–barrier (BBB) in thallium transport. Differences between weaning and newborn rats were also found in regard to regional distribution of
thallium in the brain as the older animals showed a region-dependent distribution, while newborn rats presented an homogeneous content of thallium among all regions. Results suggested an active participation of the developing BBB on thallium transport into the brain parenchyma, also suggesting a higher susceptibility to the toxic effects of thallium as a function of age. Initial excretion of thallium in urine is high, but after 24–48 h, faecal elimination may be important. Rats may also exhibit a more intense entero-enteral cycling of thallium than humans (Thompson, 1981).
6. Experimental findings
6.1. Neuromyopathy Barroso-Moguel et al. (1996) studied the experimental neuromyopathy induced by thallium in rats, finding a significant reduction of large and medium-sized fibers. Several myelin sheaths showed initial degeneration along the course of the axon. Over time of exposure, large and small myelinated fibers were found to be sinuous, fragmented and scanty. Additionally, muscle fibers had myopathic changes with abnormal central nucleoli and the striated transverse fibers disappeared in many areas. Necrosis and fibrosis were also present.
6.2. Neuromuscular function Thallium induces neuromuscular paralysis in the rat nerve-diaphragm and such an action is irreversible, dependent on temperature and temporarily antagonized by high levels of intracellular Ca2 + in presynaptic nerve terminal preparations (Wiegand et al., 1984a). Spontaneous transmitter release increased during the development of thallium-induced paralysis and disclosed its predominantly presynaptic action on neuromuscular transmission (Wiegand et al., 1984b). Wiegand et al. (1986) recorded both endplate potentials (EPPs) and miniature endplate potentials (MEPPs) after exposure to Tl + ; they found decreased phasic transmitter release until total
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synaptic blockade, whereas spontaneous transmitter release was reversibly enhanced.
6.3. Lipid peroxidation The effect of thallium on lipid peroxidation was first tested by Hasan and Ali (1981) and compared to nickel and cobalt administration. They found that the rate of lipid peroxidation was significantly increased in the cerebrum, cerebellum, and brain stem in all treatments. Thallium caused a maximal lipid peroxidation in cerebellum, in contrast to both nickel and cobalt which produced a maximal effect in brain stem. These authors also found a correlation between lipid peroxidation and lipofuscin-like pigment deposition after thallium intoxication. Aoyama et al. (1988) studied the induction of peroxidative action of Tl in different tissues of hamster. They found an increase in lipid peroxidation — particulary in the kidney— with a marked decrease in NPSH (non-protein sulfhydryls) as an indicator of glutathion levels, as well as a depletion in glutathion peroxidase (GSHpx) activity, suggesting that the tissue damage induced by thallium can be also associated to peroxidative processes.
6.4. Neurochemical alterations Due to the fact that some symptoms of thallotoxicosis are posibly related to catecholamine changes, Hasan et al. (1978) measured the levels of dopamine (DA), norepinephrine (NE) and 5hydroxytryptamine (5-HT) in different rat brain regions after thallium intoxication, showing a decrease in DA concentration in almost all regions; in the case of NE, no important alterations were found, but for 5-HT, they also found decreased levels, mainly in corpus striatum, cerebellum and brain stem. In a previous work conducted by Patterson (1975), levodopa (L-DOPA), a wellknown dopamine precursor, was shown to attenuate the choreiform sequelae of thallotoxicosis, suggesting that Tl + poisoning involves severe alterations in dopamine system and also that LDOPA could be considered of potencial therapeutic value for these specific symptoms. A little later, Marwaha et al. (1980) described the
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effect of chronic administration of thallium on the electrophysiological activity at central noradrenergic synapses. They found that thallium increased the spontaneous discharge rate of cerebellar Purkinje neurons, suggesting that thallium toxicosis in cerebellum involves a disruption of adrenergic mechanisms. Moreover, the results on the use of antipsychotic catecholamine blocking drugs in thallium-treated rats, lead the authors to suggest either an impairment in transmitter release, a reduction in catecholamine stores or a postsynaptic subsensitivity; the hypothesis of noradrenergic deficit during thallium toxicosis was supported by experimental data. Taken together, these reports strongly contribute to understand some neurological symptomatologies produced during Tl + toxicosis. In order to explain whether the observed alterations in catecholamine concentrations after Tl + could be related to the changes in the general metabolism, we recently studied the monoamine oxidase (MAO) activity and the turnover rate of 5-HT and DA in different rat brain regions (Osorio-Rico et al., 1995). Results indicated that thallium induced a significant increase of MAO activity in pons and midbrain and also in serotonin turnover rate as compared to the control animals. DA turnover rate was not significantly modified. All these evidences lead us to suggest that rats intoxicated with thallium, as well as human poisoning, may both develop behavioral and toxic alterations as the result of changes in the brain metabolism.
7. Thallium as a radiactive tracer Radioactive thallium has been used as a myocardial and tumor-scanning agent because of its similarity to potassium (Ando et al., 1988). Thallous has been shown to readily substitute for potassium at the (Na + /K + )-membrane ATPase activation site and does not leak out of tissue as rapidly as potassium. Its potential use for tumor detection was realized when lung carcinoma was revealed by myocardial thallium scans. Its usefulness as a tumor imaging agent was subsequently evaluated and confirmed for neoplasic lesions of the lung, thyroid, liver and brain. Brain tumor
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uptake is a combined function of blood-brain barrier permeability and cell viability in terms of increased cell growth and concomitant enhancement of (Na + /K + )ATPase activity. Human glioma cells have inward rectifying K + channels which are two to five times more permeable to Tl + than K + (Brismar et al., 1989; Rubertone et al., 1993).
8. Antitumoral effect Hart and Adamson (1971) tested the toxicity and antitumoral activity using the four elements of the Group III A against Walker 256 carcinosarcoma (W256) and Leukemia L1210 (L1210) cells in vitro. Thallium exhibited an inhibitory action on the growth of W256, while no inhibitory effect was found on L1210 cells. When compounds of these elements were injected intraperitoneally into the animals carrying the ascitic form of W256 and L1210, the order of the antitumor activity against W256 was identical to that seen in tissue culture: Tl \Al\ Ga\In. None of these compounds produced any activity against L1210. In 1994, our group tested the antitumoral effect of thallium against N-ethyl-N-nitroso-urea-induced brain tumors. Thallium treatment delayed the average time to the onset of the neurological signs of tumor growth, as well as reduced the frequency of some tumor types. The combination of the high cellular toxicity of thallium and its selective action against tumor cells related to the uptake into the cells and may serve to eventually explain its antitumoral effect (Barroso-Moguel et al., 1994b).
9. Analytical procedures for thallium determination Thallium analysis has been performed by differential pulse anodic stripping voltammetry, field desorption mass spectrometry, inductively coupled plasma mass spectrometry and furnace atomic absorption spectrophotometry. Some of the earlier methods for thallium analysis — such
as flame and flameless atomic absorption—require the use of chelation extraction procedure to avoid interference or to preconcentrate the element in order to improve the detection limits (Paschal and Bailey, 1986). However, the chelation extraction procedure in these methods is limited by the organic solvent which autosamplers have difficulty in handling. Direct analysis of thallium has been performed by graphite furnace atomic absorption spectrophotometry and inductively coupled plasma mass spectrometry with sufficient sensitivity. In the case of graphite furnace atomic absorption spectrophotometry, determination is expected to be troublesome since the volatility of the metal restricts the use of high charring temperature for thermal pretreatment with graphite furnace. Important matrix interference are then expected to appear due to incomplete elimination of organic and inorganic background material. Owing to these facts, our group proposed a matrix modifier for the direct determination of thallium using diammonium hydrogenphosphate both in experimental-toxicological studies and in clinical diagnosis of thallium intoxication cases in human patients. This particular technique is also applied for the analysis of both biological fluids and tissue contents (Rı´os and Galva´n-Arzate, 1998).
10. Final comment Thallium poisoning inhibits certain enzymes, coenzymes and structural proteins, and it will causes metabolic disturbances. The latter in turn help to explain the structural and functional changes often seen in cells, tissues and organs, which resulted in physical, neurological and psychiatric abnormalities found in the poisoned patients (Prick, 1979), as well as in animals during experimental procedures. Perspectives on thallium research will bring us new interesting information, not only concerning to its toxic action or as an important environmental pollutant, but also as a possible experimental and clinical tool in several fields of research, as well as a putative therapeutic agent against tumors.
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Acknowledgements The authors wish to thank Dr Camilo Rı´os and Dr Emilo Rojas-Del Castillo for their respective contributions to this manuscript, as well as to Rosa Marı´a Tarrats and Leticia Andre´s-Martı´nez for their technical assistance. This work was partially supported by CONACYT grant 0935-M 9506.
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Monitoring of Metals In Human. Including Feasibility and Need. Lewis, USA, pp. 243 – 254. Cavanagh, J.B., Fuller, N.H., Johnson, H.R.M., Rudge, P., 1974. The effect of thallium salts, with particular reference to the nervous system changes. Quart. J. Med. New Ser. XLIII 170, 293 – 319. Cavanagh, J.B., 1991. What have we learn from Graham Frederick Young? Reflections on the mechanism of thallium neurotoxicity. Neuropathol. Appl. Neurobiol. 17, 3 – 9. Chamberlain, P.H., Stavinoha, W.B., Davis, H., Kniker, W.T., Panos, T.C., 1958. Thallium poisoning. Pediatrics 22, 1170 – 1182. Chandler, H.A., Scott, M., 1986. A review of thallium toxicology. J. R. Nav. Med. Serv. 72, 75 – 79. de Groot, G., van Heijst, A.N.P., van Kesteren, R.G., Maes, R.A.A., 1985. An evaluation of the efficacy of charcoal haemoperfusion in the treatment of three cases of acute thallium poisoning. Arch. Toxicol. 57, 61 – 66. Dimitru, D., Kalantri, A., 1990. Electrophysiologic investigation of thallium poisoning. Muscle Nerve. 13, 433 – 437. Douglas, K.T., Bunni, M.A., Baindur, S.R., 1990. Thallium in biochemistry. Int. J. Biochem. 22 (5), 429 – 438. Galva´n-Arzate, S., Rı´os, C., 1994. Thallium distribution in organs and brain regions of developing rats. Toxicology 90, 63 – 69. Gettler, A., Weiss, L., 1943. Thallium poisoning. III. Clinical toxicology of thallium. Am. J. Clin. Pathol. 13, 422 – 429. Gunby, P., 1995. International electronic link solves medical puzzle. J. Am. Med. Assoc. 13, 1750. Hart, M.M., Adamson, R.M., 1971. Antitumor activity and toxicity of salts of inorganic group IIIa metals: Aluminium, gallium, indium and thallium. Proc. Natl. Acad. Sci. USA 68, 1623 – 1626. Hasan, M., Fatehyab Ali, S., Tariq, M., 1978. Levels of dopamine, norepinephrine and 5-hydroxytryptamine in different regions of the rat brain in thallium toxicosis. Acta Pharmacol. Toxicol. 43, 169 – 173. Hasan, M., Ali, F.S., 1981. Effects of thallium, nickel and cobalt administration on the lipid peroxidation in different regions of the rat brain. Toxicol. Appl. Pharmacol. 57, 8 – 13. Herman, M.M., Bensch, K.G., 1967. Light and electron microscopic studies of acute and chronic thallium intoxication in rats. Toxicol. Appl. Pharmacol. 10, 199 – 222. Herrero, F., Ferna´ndez, E., Go´mez, J., Pretel, L., Canizares, F., Frias, J., Escribano, J.B., 1995. Thallium poisoning presenting with abdominal colic, paresthesia, and irritability. Clin. Toxicol. 33 (3), 261 – 264. Hologgitas, J., Ullicci, P., Driscoll, J., Gauerholz, J., Martin, H., 1980. Thallium elimination kinetics in acute thallotoxicosis. J. Anal. Toxicol. 4, 68 – 73. Kamerbeek, H.H., Rauws, A.G., Ten Ham, M., Van Heijst, A.N.P., 1971a. Dangerous redistribution of thallium by treatment with sodium diethyldithiocarbamate. Acta Med. Scan. 189, 149 – 154.
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Kamerbeek, H.H., Rauws, A.G., Ten Ham, M., Van Heijst, A.N.P., 1971b. Prussian blue in therapy of thallotoxicosis. An experimental and clinical investigation. Acta Med. Scan. 189, 321 – 324. Klassen, C.D., Amdur, M., Doull, J. (Ed.), 1986. In: Cassaret and Doull’s Toxicology. Basic science of poisons. Mac Millan New York, pp. 374, 491, 504, 505, 566, 626. Kravzov, J., Rı´os, C., Altagracia, M., Monroy-Noyola, A., Lo´pez, F., 1993. Relationship between physicochemical properties of prusian blue and its efficacy as antidote against thallium poisoning. J. App. Toxicol. 13 (3), 213– 216. Liem, Y., Kaiser, G., Sager, M., To¨lg, G., 1984. The determination of thallium in rocks and biological materials at ng/g levels by differential-pulse anodic stripping voltammetry and electrothermal atomic absorption spectrometry. Anal. Chim. Acta 158, 179–197. Limos, C.L., Ohnishi, A., Suzuki, N., Kojima, N., Yoshimura, T., Goto, I., Kuroiwa, Y., 1982. Axonal degeneration and focal muscle fiber necrosis in human thallotoxicosis: histopathological studies of nerve and muscle. Muscle Nerve. 5, 598–706. Luckit, J., Mir, N., Hargreaves, M., Costello, C., Gazzard, B., 1990. Thrombocytopenia associated with thallium poisoning. Hum. Exp. Toxicol. 9, 47–48. Malbrain, M.L.N.G., Lambrecht, G.L.Y., Zandijk, E., Demedts, P.A., Neels, H.M., Lambert, W., De Leenheer, A.P., Lins, R.L., Daelemans, R., 1997. Treatment of severe thallium intoxication. Clin. Toxicol. 35 (1), 97–100. Marmo, E., Matera, M.G., Acampora, R., et al., 1987. Prenatal and postanal metal exposure: effect on vasomotor reactivity development of pups: experimental research with antimony trichloride, thallium sulfate and sodium metavanadate. Curr. Ther. Res. 42 (5), 823–838. Marwaha, J., Freedman, R., Hoffer, B., 1980. Electrophysiological changes at a central noradrenergic synapse during thallium toxicosis. Toxicol. Appl. Pharmacol. 56, 345– 352. McMillan, T.M., Jacobson, R.R., Gross, M., 1997. Neuropsychology of thallium poisoning. J. Neurol. Neurosurg. Psychiatry 63, 247 – 250. Meggs, W.J., Hoffman, R.S., Shih, R.D., Weisman, R.S., Goldfrank, L.R., 1994. Thallium poisoning from maliciously contaminated food. Clin. Toxicol. 32 (6), 723–730. Meggs, W.J., Cahill-Morasco, R., Shih, R.D., Goldfrank, L.R., Hoffman, R.S., 1997. Effects of Prussian blue and N-acetylcysteine on thallium toxicity in mice. Clin. Toxicol. 35 (2), 163 – 166. Moeschlin, S., 1980. Thallium poisoning. Clin. Toxicol. 17 (1), 133 – 146. Mulkey, J.P., Oehme, F.W., 1993. A review of thallium toxicity. Vet. Human Toxicol. 35 (5), 445–453. Olsen, I., Jonsen, J., 1982. Whole-body autoradiography of 204 Tl in embryos, fetuses and placentas of mice. Toxicology 23, 353 – 358. Osorio-Rico, L., Galva´n-Arzate, S., Rı´os, C., 1995. Thallium increases monoamine oxidase activity and serotonin
turnover rate in rat brain regions. Neurotoxicol. Teratol. 17, 1 – 5. Paschal, D.C., Bailey, G.G., 1986. Determination of thallium in urine with Zeeman effect graphite furnace atomic absorption. J. Anal. Toxicol. 10, 252 – 254. Patterson, J.F., 1975. Chronic thallitoxicosis. Treatment of the choreiform sequelae. S. Med. J. 68, 923 – 925. Piazolo, P., Franz, H.E., Brech, W., Walb, D., Wilk, G., 1971. Behandlung der thalliumvergiftung mit der hamodialyse. Dtsch. Med. Wschl. 96, 1217 – 1222. Potts, A.M., Gonasun, S.N., 1980. Toxic responses of the eye. In: Doull, J., Klaasen, C.D., Andur, M.O. (Eds.), Toxicology: The Basic Science of Poisons. MacMillan, New York, pp. 275 – 310. Prick, J.J.G., 1979. Thallium poisoning. In: Vinken, P.J., Bruyn, G.W. (Eds.), Handbook of Clinical Neurology. In: Intoxication of the Nervous System, vol. 36. North-Holland, New York, pp. 239 – 278. Rangel-Guerra, R., Martı´nez, H.R., Villareal, H.J., 1990. Intoxicacio´n por talio. Experiencia con 50 pacientes. Gaceta Me´d. Mex. 126 (6), 487 – 495. Reed, D., Crawley, J., Faro, S.N., Pieper, S.J., Kurland, L.T., 1963. Thallotoxicosis: acute manifestations and sequelae. J. Am. Med. Assoc. 183 (7), 516 – 522. Repetto, G., del Peso, A., Repetto, M., 1998. Human thallium toxicity. In: Nriagu, J.O. (Ed.), Thallium in The Environment. Wiley, New York, pp. 167 – 199. Rı´os, C., Galva´n-Arzate, S., Tapia, R., 1989. Brain regional thallium distribution in rats acutely intoxicated with Tl2SO4. Arch. Toxicol. 63, 34 – 37. Rı´os, C., Monroy-Noyola, A., 1992. D-penicillamine and prussian blue as antidotes against thallium intoxication in rats. Toxicology 74, 69 – 76. Rı´os, C., Galva´n-Arzate, S., 1998. Analysis of thallium in biological samples. In: Nriagu, Jerome O. (Ed.), Thallium in the Environment. Wiley, New York, pp. 155 – 166. Rossi, F., Cazzola, M., De Santis, D., Lisa, M., Servodio, R., Guarino, V., Fici, F., Marmo, E., 1987. Cardiovascular effects of thallium sulfate after intracerebroventricular administration in normotensive rats. Curr. Ther. Res. 42 (5), 778 – 789. Rubertone, J.A., Woo, D.V., Emrich, J.G., Brady, L.W., 1993. Brain uptake of thallium-201 from the cerebrospinal fluid compartment. J. Nucl. Med. 34, 99 – 103. Saddique, A., Peterson, C.D., 1983. Thallium poisoning: a review. Vet. Human Toxicol. 25, 16 – 22. Smith, D.H., Doherty, R.A., 1964. Thallotoxicosis: report of three cases in Massachusetts. Pediatrics 34, 480 – 490. Smith, I.C., Carson, B.L., 1977. Trace Metals in The Environment. Ann Arbor Science Publishers, Inc, Ann Arbor, MI, p. 394. Spencer, P.S., Peterson, E.R., Madrid, R.A., Raine, C.S., 1973. Effects of thallium salts on neuronal mitochondria in organotypic cord-ganglia-muscle combination cultures. J. Cell Biol. 58, 79 – 95. Thompson, D.F., 1981. Management of thallium poisoning. Clin. Toxicol. 18 (8), 979 – 990.
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Wiegand, H., Lohman, H., Chandra, S.V., Gotzsch, U., 1986. The action of thallium acetate on phasic transmitter release in the mouse neuromuscular junction. Arch. Toxicol. 58, 265 – 270. Woods, J.S., Fowler, B.A., 1986. Alteration of hepatocellular structure and function by thallium chloride: ultrastructural, morphometric, and biochemical studies. Toxicol. Appl. Pharmacol. 83, 218 – 229. Ziskoven, R., Achenbach, C., Schulten, H.R., Roll, R., 1983. Thallium determinations in fetal tissues and maternal brain and kidney. Toxicol. Lett. 19, 225 – 231.
Mini-review
Thallium toxicity Sonia Galva´n-Arzate *, Abel Santamarı´a Department of Neurochemistry, National Institute of Neurology and Neurosurgery, 14269 S.S. Mexico D.F., Mexico Received 14 April 1998; received in revised form 3 July 1998; accepted 6 July 1998
Abstract Thallium (Tl + ) is a toxic heavy metal which was accidentally discovered by Sir William Crookes in 1861 by burning the dust from a sulfuric acid industrial plant. He observed a bright green spectral band that quickly disappeared. Crookes named the new element ‘Thallium’ (after thallos meaning young shoot). In 1862, Lamy described the same spectral line and studied both the physical and chemical properties of this new element (Prick, J.J.G., 1979. Thallium poisioning. In: Vinkrn, P.J., Bruyn, G.W. (Eds.), Intoxication of the Nervous System, Handbook of Clinical Neurology, vol. 36. North-Holland, New York. pp. 239 – 278). © 1998 Elsevier Science Ireland Ltd. All rights reserved.
1. Chemistry Thallium is classified in the group III A of the periodic chart; the metals of this group are electropositive; as their atomic weights increase, so does their basic character. It forms two kind of compounds: monovalent thallo- and trivalent thalli-compounds. Tl + also tends to form stable complexes with soft ligand donors, such as sulfurcontaining compounds.
* Corresponding author. Tel.: + 52 5 6063822 ext. 2005; fax: + 52 5 5280095; e-mail: [email protected]
Inorganic Tl (I) compounds are more stable than Tl (III) analogues in aqueous solution at neutral pH. In contrast, covalent organothallium compounds are stable only in the trivalent form (Mulkey and Oehme, 1993). Tl + is particularly toxic in its Tl (I) compounds, such as sulfate (Tl2SO4), acetate (CH3COOTl), and carbonate (Tl2CO3). The sulfide (Tl2S) and iodide (TlI) are both poorly soluble and therefore, much less toxic (Moeschlin, 1980). It has been also reported that organic thallium compounds, such as thallous malonate, show a higher elimination rate constant but are similar in toxicity and distribution pattern compared to the inorganic thallium compounds, such as thallous sulfate (Aoyama, 1989).
0378-4274/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-4274(98)00126-X
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1.1. Ocurrence and distribution Thallium is widely distributed in the environment, although it is generally present in very low concentrations. Tl + is not an ubiquitous trace element. In the earth’s crust, average Tl + concentrations are between 0.3 and 0.5 mg/g. Although it is very toxic (MAC 0.1 mg/m3), it has not been considered a potential environmental pollutant. Thallium occurs in small concentrations in sulfides ores (Fe, Pb, Zn) which are commonly employed for the production of sulfuric acid. In the roasting process, thallium may arrive in the flue dust or in the lead chamber slime or it can remain in the pyrites cinder (0.03 – 0.05% of Tl) which is used in the cement industry (Liem et al., 1984). High levels of thallium can be found in granite, shale and manganese nodules. It has also been detected in volcanic rocks, meteorites and plants. Tl + is concentrated in magmatic potassium minerals such as feldspars and micas. The few Tl + minerals existing contain about 16 – 60% of the metal and they are quite rare: Crookosite ((Cu, Tl, Ag)2Se), Hutchinsonite ((Tl, Ag)2S · Pbs · 2As2S3), Lorandite (Tl2S · AsS3), and Vrbaite (Tl2S3(As,Sb)2S3). Natural thallium concentrations in seawater and freshwater are estimated to be B 0.03 ppb (Mulkey and Oehme, 1993).
used for some medical tests, as well as in research studies.
1.3. Sources of exposure Since its discovery, thallium has been responsible for many occupational and accidental intoxications (Reed et al., 1963). Demonstration of the presence of thallium in urine is the best diagnostic procedure available so far. Any amount of thallium in the body shall be considered abnormal (Reed et al., 1963). According to Mulkey and Oehme (1993), thallium levels in normal human and animals are B 1 ppb in blood and urine, and B 10 ppb in tissues. Few cases of poisoning from industrial exposure are known, probably due to the fact that chronic thallium poisoning mimics many other diseases and thallotoxicosis is not recognized, but accidental poisoning caused by contact with thallium-containing materials or their careless handling occurs more frequently. Thallium has received much more attention as an environmental pollutant since high thallium contents were found in cement powders discharged from stacks and emissions from brickworks, and that had contaminated adjacent farmland (Liem et al., 1984).
2. Mechanisms of toxic action
1.2. Uses Thallium is obtained as a by-product of the refining process of iron, cadmium and zinc. The flue dust of this industry is further processed in order to recover commercial quantities of the metal. Tl + is used as a catalyst in certain alloys, optical lens, jewelry, low temperature thermometers, semiconductors, dyes and pigments and scintillation counters. Tl + has also been employed for clinical purposes as a depilator (Marmo et al., 1987). In addition, thallium salts are still widely used as rodenticides and insecticides in some countries, despite the World Health Organization recommendation against its use in 1973. Thus, although known to be toxic, thallium compounds are still available in many countries around the world (Luckit et al., 1990). At present, Tl201 is
The well-known mechanism of thallium toxicity is related to the interference with the vital potassium-dependent processes, substitution of potassium in the (Na + /K + )-ATPase, as well as a high affinity for sulfhydril groups from proteins and other biomolecules (Aoyama et al., 1988). Since Tl + and K + are both univalent ions with similar ionic radii, thallium is able to interfere with potassium-dependent processes, and then mimics potassium in its movement and intracellular accumulation in mammals (Mulkey and Oehme, 1993). The capability of thallous ions to mimic the biological action of potassium ions has been attributed to the remarkable inability of cell membranes to distinguish between thallium and potassium, possibly due to their similar ionic
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charges and radii. Thus, thallium is expected to interfere competitively with some potassium-dependent biological reactions, as the chemical properties of thallium and potassium are sufficiently alike. Thallium has been shown to replace the physiological ion potassium in the activation of several monovalent cation activated enzymes, e.g. pyruvate kinase, ATPase and aldehyde dehydrogenase. Thallium has also been found to replace potassium in the stabilization of ribosomes, as well as in physiological functions such as muscle contraction (Douglas et al., 1990). On the other hand, Herman and Bensch (1967) demonstrated a variety of changes in the morphology of mitochondria in kidney, liver, intestine, brain, seminal vesicle and pancreas of rats treated with several doses of thallium acetate. Some years later, Spencer et al. (1973) reported cytopathic early effects of thallium with the appearance of considerably enlarged mitochondria in axons of peripheral nerve fibers; with time, the matrix space of these mitochondria were swollen. Other studies have suggested that the biological effects and potential toxicity of specific trace metals, including thallium, are mediated through primary disruption of the structural integrity of subcellular organelle membranes with which impaired biological processes are associated (Woods and Fowler, 1986): thallium may be preferentially sequestered both by mitochondria as well as by other membranous subcellular organelles (Potts and Gonasun, 1980). Woods and Fowler (1986) also suggested that the changes in selective membrane-bound mediated biochemical processes, produced by thallium and other metals, are closely linked both physically and functionally with preliminary disruption of the membranal integrity of mitochondria and endoplasmic reticulum. Although all this evidences suggest some possible specific actions of thallium, its precise mechanism of toxicity still remains unknown. We have to consider that thallium neuropathy could be the consequence of energy deprivation after depletion of tissue flavoproteins (Cavanagh, 1991), as well as the fact that thallium could bind Tl-active sulfhydryl sites of enzymes (Chandler and Scott, 1986).
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3. Clinical toxicity Thallium intoxication appears after its introduction into the body by inhalation, ingestion (via contaminated food and hands), or through the skin. It may rise to acute, subacute or chronic clinical manifestations according to the type of exposure (Rossi et al., 1987), dose and age of the subject (Mulkey and Oehme, 1993). Because of its severe toxicity and the fact that the metal is colorless, odorless and tasteless, thallium has been used for homicidal poisoning purposes (Luckit et al., 1990; Meggs et al., 1994). This highly toxic element is accumulated in the organism, eventually crossing both the blood-brain-barrier and the placenta (Ziskoven et al., 1983). Tl + is generally eliminated by urine, bile, saliva, feces, milk and tears (Rossi et al., 1987). Elimination half-life of thallium is long, due to its large distribution volume (Repetto et al., 1998). The estimated half-life in humans is reported between 1 and 3 days after low doses (Talas et al., 1983) and between 1 and 1.7 days under clinical therapy after ingestion or exposure by a possible lethal dose (Hologgitas et al., 1980; de Groot et al., 1985). Other groups have reported an elimination half-life between 8 and 30 days (Piazolo et al., 1971). Minimum lethal dose (LDL0) of thallium in humans is also highly variable (Repetto et al., 1998). Average lethal dose for thallium sulfate has been reported from 10 to 15 mg/kg (Moeschlin, 1980). Although Gettler and Weiss (1943) reported a minimum lethal dose of 14–15 mg/kg, Moeschlin (1980) reported fatalities with 8 mg/kg. Thallium, as an inhibitor of sweat secretion, was employed in 1861 to counteract the troublesome nocturnal sweating of tuberculosis patients. It occasionally gave good results too, in cases of dysentery with violent or persistent diarrhea. Tl + was also given to patients with syphilis, gonorrhea, gout and mycosis of the scalp (Prick, 1979). Shortly thereafter (1920), thallium was also used as a cosmetic depilatory to remove excessive hair growth. Physicians soon became aware of the toxic effects of thallium. Just few a weeks after its administration, loss of hair would sometimes occur,
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eventually resulting in complete baldness, as well as axillary and pubic hair loss. Misgivings about the use of thallium became stronger when it was found that other symptoms of poisoning could also appear, such as gastrointestinal disturbances (nausea, vomiting, constipation and diarrhea), peripheral and central nervous system disorders as well as pain in the abdomen, back and extremities —particularly in the legs — extreme tenderness of the soles of the feet, ataxia, dyesthesia, motor weakness, paralysis, tremors, chorea, convulsions, periods of confusion, restlessness, sleeplessness, delirium, hallucinations, lethargy, stupor and personality changes alternating with periods of lucity, coma, and also cardiac signs such as tachycardia, irregular pulse and hypotension (Reed et al., 1963; Hasan et al., 1978; Moeschlin, 1980). Recent cases of human thallium poisoning have been reported; most of them showed similar symptomatology. Herrero et al. (1995) described a case of acute poisoning presenting abdominal pain, paraesthesiae, irritability and severe alterations of the peripheral nervous system. Also in 1995, after an intensive international work of diagnosis via Internet, a Chinese student was diagnosed as thallium poisoning when she exhibited abdominal pain, alopecia and a variety of central nervous system complains (Gunby, 1995). McMillan et al. (1997) described some neuropsychological assessments in a patient exposed to acute Tl, showing several neurological signs, including confusion, disorientation and generalized slowing of EEG. Results indicated persistent weakness in verbal abilities consistent with other case reports. Another case of severe Tl intoxication was reported by Malbrain et al. (1997), in which Tl was ingested by a 38-year old woman 2 h before hospitalized; this time an immediate treatment with Prussian blue, enhanced diuresis by intravenous fluids and a prolonged hemodialysis resulted to be successful. Several other report cases are available in the literature and the clinical features observed in them are often similar. Some differences observed in literature on Tl poisoning features mainly depend both on the time and the nature of Tl exposure.
3.1. Skin Alopecia is the best known effect of thallium poisoning. It produces changes in the dermis and its derivatives (hair, nails, sweat and sebaceous glands). One or two days after absorption, a peculiar deposit of a dark pigment can be observed in the hair roots, quite often zebra-like (Prick, 1979). Epilation begins about 10 days after ingestion, complete hair loss is seen in about 1 month. This long latent period coincides with the maturation period of the new epithelial cells of the hair papilla, in which thallium targets (Mulkey and Oehme, 1993). After 2 or 3 months, the hair will be restored to its former condition (Prick, 1979). Other dermic signs may include palmar erythema, acne, anhydrosis and dry scaly skin which is caused by the toxic effect of thallium on sweat and sebaceous glands (Mulkey and Oehme, 1993). The growth of the fingernails is also impaired, and transverse white stripes appear in the nails, they are so-called lunular or Mee’s stripes (Prick, 1979).
3.2. Gastrointestinal tract After oral ingestion of Tl + , the poison causes an inflammatory reaction in the structures that were exposed first, resulting in glossitis, pharyngooesophagitis, gastritis, enteritis and colitis (Prick, 1979). Often, nausea and vomiting occur during the 3–4 day period following intoxication, which may be replaced by severe abdominal pain that is relieved by directed pressure. Depression of the intestinal motility and peristalsis may occur due to possible vagus nerve involvement, resulting in severe constipation (Reed et al., 1963; Mulkey and Oehme, 1993). During the irritative phase of the vagal lesions, patients may have complaints suggestive of a stomach or duodenal ulcer. Persistent, severe vomiting, which is common in acute thallium poisoning, may also play an important role in causing deficiencies that can be exacerbated by inadequate treatment. In such cases, striking emaciation and loss of strength can often be traced to inadequate absorption of fatty acids and deficiency of fat-soluble vitamins (Prick,
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1979). Gastrointestinal symptoms usually follow within hours after acute poisoning. Vomiting, abdominal pain, gastrointestinal hemorrhage and diarrhea are more common, but some patients may only have anorexia or nausea (Smith and Doherty, 1964).
3.3. Ner6ous system Neurological symptoms usually appear between 2 – 5 days after acute exposure cases, which are characterized by a painful, rapidly progressive peripheral neuropathy that dominates clinically in the second or third week. Sensory disturbances include pain and paresthesias of the lower limbs, numbness in the fingers and toes, with the loss of pin-prick and touch sensation. Occasionally, hyperesthesia involving the soles of the feet and tibial region occurs. Motor neuropathy is evident by weakness which are always distal in distribution. The lower body extremities are primarily affected. Upper extremity involvement occurs uncommonly and cranial nerves participation is rare. Insomnia, headache, emotional liability, anxiety, tremor, ataxia, choreoathetosis and signs of cranial nerve involvement may be developed. Psychosis with paranoia, depression, aggressiveness and hallucinations are also common. In chronic poisoning, ataxia and paresthesia may be the outstanding symptoms. In time, the paresthesia may progress to evident peripheral neuropathy with weakness and atrophy of the associated musculature (Prick, 1979; Mulkey and Oehme, 1993). In very serious or even fatal cases, true ‘pseudobulbar paralysis’ due to peripheral neuritis of cranial nerves is observed, with paralysis of the ocular muscles, ptosis, facial paralysis, amblyopia and paralysis of the recurrent nerve. Shortly before death, paralysis of the vagal nerve may supervene, possibly being the direct cause of death. With some cases, in early stages of poisoning, the optic disk reveals the typical picture of neuritis with ill-defined and red papillae, followed by the development of pale or white papillae as a result of atrophy of the optic nerve. In occasional instances, the initial stimulation of the ganglionic cells of the brain may give rise to severe Jacksonian epilectic seizures; also severe epileptiform
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convulsions can be observed (Cavanagh, et al., 1974; Moeschlin, 1980).
3.4. Ner6e findings Limos et al. (1982), reported previous findings from Spencer’s group, in which they used electron microscopy to observe axons of myelinated fibers with markedly dilated myelin sheaths that showed absence, severe alteration or disintegration of axoplasmic organelles in humans exposed to Tl + . Histopathological studies in intoxicated humans and animals have also revealed axonal degeneration of the peripherial nerves (Limos et al., 1982). Cavanagh et al. (1974) described, case by case, some pathological observations in nerve tissue from thallium-poisoned patients. They found ocassional swollen axon with granular fragmented appearance of the sciatic nerve. Similar alterations were found in sural and vagus nerves, also exhibiting degeneration of the associated myelin sheaths; swelling and fragmentation were also seen in cranial nerves. Although no significant abnormalities were found in cerebellum, cerebral cortex, basal ganglia or midbrain from some patients, morphological changes were not discarded in nerve tissue from other patients. Now it is known that some neuropathies induced by Tl + are associated with the pathology of both sensory and motor neurons.
3.5. Kidney Renal excretion of thallium sulfate is slow and may be detected as late as 2 months after ingestion. Toxic injures to the kidney have been indicated by albuminuria and haematuria, however, the renal function is not grossly impaired (Reed et al., 1963). The toxic effects on the kidney, notably resistant to dehydration and decubitus, also strain the body’s resources. In most of cases, the kidney present limited toxic injury. During the first 2 weeks after exposure, there is albuminuria with erythrocytes, leucocytes and cylindrical casts in the urinary sediment, and sometimes porphyria. In this serious phase of the illness, there is a fall in the concentrating ability of the kidneys, often with recovery afterwards. In some cases, there is
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also haemorrhagic damage to the kidneys (Prick, 1979).
3.6. Li6er and lung Additional to some changes observed on the nervous system, Cavanagh et al. (1974) described some pathological findings in several organs — including livers and lungs — of patients intoxicated with thallium. Histopathological findings showed centrilobular necrosis with fatty change present in most liver lobules, as well as the presence of abnormal amounts of porphyrins in the urine. Oedema, moderate congestion, patchy early bronchopneumonia and inflammation were found in lungs. Several other secondary pathological changes were described in the organs of these patients.
3.7. Cardio6ascular system Cardiac signs, such a sinus tachycardia, irregular pulse, hypertension and angina-like pain, have been reported during the second week after the ingestion of thallium sulfate. Some authors suggested that such signs are due to vagus involvement, while others have recorder electrocardiographic evidence of myocardial damage (Reed et al., 1963). The most dreaded effect of bilateral paralysis of the vagus nerve is malfunction of the cardiac muscle evidenced by tachycardia and circulatory disturbances, possibly resulting in left-sided (cardiac asthma) or rightsided decompensation. Under these circumstances, it is quite common for paralyzed patients, often short of breath already, to develop severe dyspnoea and cyanosis, followed by death (Prick, 1979).
3.9. Reproducti6e system Experimental evidence suggests that the reproductive system is highly susceptible to thallium. Decreased libido and impotence in humans, and lower sexual activity in laboratory animals have been both noted after chronic exposure to this metal. In animals and humans, the testes accumulated high levels of thallium (Rı´os et al., 1989). Morphological and biochemical changes in the testes and decreased epididymal sperm motility has been observed in rats exposed to 10 ppm of thallium in drinking water of 2 months. The human fetus may suffer from transplacental exposure, as evidenced by skin and nail dystrophy, alopecia and low body weights in newborns of intoxicated mothers (Mulkey and Oehme, 1993); whereas in animals, thallium also can be detected in fetal tissues after placental transfer of thallium (Ziskoven et al., 1983).
3.10. Eye Thallium acetate is able to induce cataracts in rats within 6 weeks after initiating a daily dose of 0.1 mg, appearing first as radial striations in the anterior cortex between the sutures and the ecuator. While the early phases will remain stationary if thallium administration ceases, development of subcapsular opacities will occur if administration continues. Thallous ion rapidly accumulates into the lens both in vivo and in vitro (Klassen et al., 1986). Retrobulbar neuritis with reduction of vision and central scotoma may occur as a result of thallium intoxication. Iritis, inflammation of the eyelids as well as intraocular hemorrhage have been reported in animals (Mulkey and Oehme, 1993).
3.8. Blood Some reports on acute and chronic poisoning, have mentioned haematological changes such as anaemia, leucocytosis, eosinophilia and limphopenia (Reed et al., 1963; Cavanagh et al., 1974; Moeschlin, 1980; Saddique and Peterson, 1983). Luckit et al. (1990) found lymphopenia, mild neutrophilia and trombocytopenia associated to thallium poisoning.
3.11. Teratogenesis, mutagenesis and carcinogenesis Thallium is teratogenic in chick embryos, causing achondroplasia, leg bone curvature, parrotbeak deformity, microcephaly and decreased fetal size (Mulkey and Oehme, 1993). Rats shown nonossification of the phalanges and vertebral bodies when the mother received thallium while fed (Car-
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son et al., 1987). When puppies are directly exposed to thallium, they showed several alterations in the cartilaginous cells, chrondrine, osteoblasts, osseous tissue and bone marrow (Barroso-Moguel et al., 1992). Rangel-Guerra et al. (1990) reported 50 cases of thallium poisoning — including a newborn exposed through the placenta — exhibiting alopecia and imperforate anus. When intoxication occurs after the first 3 months, only a few newborns presented symptoms which were compatible with thallotoxicosis (Olsen and Jonsen, 1982). Severe intoxications in the mother at the end of pregnancy cause the death of the fetuses (Dimitru and Kalantri, 1990). Thallium salts have produced antimitotic activity on mammalian, avian and plant cells. Thallium (I) is the most active heavy metal found for breaking chromosomes of pea plants. Thallous acetate solutions retarded both mitosis and meiosis in mosquitoes when the larva and nymphs were treated (Smith and Carson, 1977). Chronic oral or cutaneous dosing of mice with thallium salts caused degeneration, papillomas, precancerous lesions and cancer of the female genital tract (Smith and Carson, 1977).
4. Treatment The aim of treatment against thallotoxicosis has been for long time oriented to modify thallium to a less toxic compound, as well as to increase its excretion through the kidneys and gastrointestinal tract (Reed et al., 1963). According to Chamberlain et al. (1958), treatment consists of immediate emphasis on (1) removal of recently ingested thallium sulfate by: (a) gastric lavage; (b) activated charcoal: 0.5 mg/kg orally twice a day during 5 days; and (2) to promote its urinary excretion by: (a) abundant intake of fluids, (b) potassium chloride 3 – 5 mg/day, during 5 – 10 days. The use of antidotal treatment against acute thallium intoxication is stressing because of the severity of the symptoms and the high lethality of the poisoning. Prussian blue is orally administered as antidotal treatment in thallium intoxication cases. It has been demonstrated that accelerating
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tissue elimination of thallium ions from their action sites may represent a useful therapy (Kamerbeek et al., 1971b). Chelating agents have also been tested as antidotes, but their beneficial effects are doubtful since they can cause redistribution of thallium from inactive depots to the target organs, leading to exacerbation of the symptoms (Kamerbeek et al., 1971a). The need of a new therapy against thallium poisoning lead the researchers to investigate the possible protective effects of combined D-penicillamine and Prussian blue treatments; results revealed the positive effects of this combined treatment to antagonize thallium-induced lethality in rats (Rı´os and Monroy-Noyola, 1992), as well as cerebellar lesions (Barroso-Moguel et al., 1994a). Human thallotoxicosis has been treated with different drugs, such as British antilewsite (BAL), potassium chloride, ditizone, EDTA, dithiocarbamate and D-penicillamine, showing diverse and controversial therapeutic results (Kravzov et al., 1993). A very recent alternative for treatment of Tl poisoning was explored by Meggs et al. (1997): N-acetylcysteine (NAC) has been used as an antidote in acetaminophen poisoning because of its positive effects in the treatment for other toxins by its capability to increase the renal excretion of arsenic, gold and methyl mercury. Since Tl is known to bind sulphydryl groups and because NAC contain many sulfhydryl groups, it is likely that NAC could represent an effective new chelation treatment in Tl poisoning (Meggs et al., 1997). However, no improvement, as compared to Prussian blue treatment, was observed on survival after NAC treatment of mice intoxicated with Tl. Further studies on the effects of oral administration of NAC are needed in order to characterize this promising experimental treatment.
5. Distribution and excretion Water-soluble Tl + salts are widely distributed in organs and tissues, including the brain, heart, kidney, skeletal muscle and testis (Rı´os et al., 1989; Mulkey and Oehme, 1993). Renal excretion of thallium sulfate is slow, and may be detected as late as 2 months after ingestion. Toxic injuries to
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the kidney have been indicated by albuminuria and haematuria; however, renal function is not grossly impaired. Using radioactive thallium sulfate in rats, Thyresson found the highest content in the kidneys, intestinal mucosa, thyroid, testes, pancreas, skin, bone and muscle, in that order, whereas fat, liver and all types of nerve tissue were uniformly lower in thallium content (Reed et al., 1963). In studies using field desorption mass spectrometry technique, thallium concentrations were established in stomach, heart, kidney, liver and brain as a time-dependent process. It was also found that, the stomach was the first organ showing the maximal concentration, followed by kidney, heart, liver and brain. After time, the brain was the organ showing the largest Tl + concentrations, whereas the other organs tended to reach excretion levels (Achenbach et al., 1980). Ziskoven et al. (1983) investigated the thallium distribution in both fetal and maternal tissue from mice and rats. They found that Tl + ions are preferentially accumulated in the kidney, whereas the brain concentrations were increased more slowly. No differences between rats and mice were observed. Rı´os et al. (1989) compared the content of thallium in several organs and brain regions of rats at 24 h after the acute administration of increasing doses; they found that thallium content in kidney was higher than in all other organs studied and also that whole brain presented the lowest thallium concentration. However, a differential distribution of thallium was found among brain regions: the highest thallium concentration was found in the hypothalamus and the lowest in the cortex. Such a distribution pattern was similar at the three different doses employed, and the time course of thallium accumulation in brain was found considerably faster in hypothalamus than in others regions— particularly the cortex — suggesting important differences in thallium entry into the brain parenchyma. Galva´n-Arzate and Rı´os (1994) investigated the thallium distribution among body organs and brain regions of developing rats after acute thallium intoxication in order to elucidate a possible participation of the bloodbrain–barrier (BBB) in thallium transport. Differences between weaning and newborn rats were also found in regard to regional distribution of
thallium in the brain as the older animals showed a region-dependent distribution, while newborn rats presented an homogeneous content of thallium among all regions. Results suggested an active participation of the developing BBB on thallium transport into the brain parenchyma, also suggesting a higher susceptibility to the toxic effects of thallium as a function of age. Initial excretion of thallium in urine is high, but after 24–48 h, faecal elimination may be important. Rats may also exhibit a more intense entero-enteral cycling of thallium than humans (Thompson, 1981).
6. Experimental findings
6.1. Neuromyopathy Barroso-Moguel et al. (1996) studied the experimental neuromyopathy induced by thallium in rats, finding a significant reduction of large and medium-sized fibers. Several myelin sheaths showed initial degeneration along the course of the axon. Over time of exposure, large and small myelinated fibers were found to be sinuous, fragmented and scanty. Additionally, muscle fibers had myopathic changes with abnormal central nucleoli and the striated transverse fibers disappeared in many areas. Necrosis and fibrosis were also present.
6.2. Neuromuscular function Thallium induces neuromuscular paralysis in the rat nerve-diaphragm and such an action is irreversible, dependent on temperature and temporarily antagonized by high levels of intracellular Ca2 + in presynaptic nerve terminal preparations (Wiegand et al., 1984a). Spontaneous transmitter release increased during the development of thallium-induced paralysis and disclosed its predominantly presynaptic action on neuromuscular transmission (Wiegand et al., 1984b). Wiegand et al. (1986) recorded both endplate potentials (EPPs) and miniature endplate potentials (MEPPs) after exposure to Tl + ; they found decreased phasic transmitter release until total
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synaptic blockade, whereas spontaneous transmitter release was reversibly enhanced.
6.3. Lipid peroxidation The effect of thallium on lipid peroxidation was first tested by Hasan and Ali (1981) and compared to nickel and cobalt administration. They found that the rate of lipid peroxidation was significantly increased in the cerebrum, cerebellum, and brain stem in all treatments. Thallium caused a maximal lipid peroxidation in cerebellum, in contrast to both nickel and cobalt which produced a maximal effect in brain stem. These authors also found a correlation between lipid peroxidation and lipofuscin-like pigment deposition after thallium intoxication. Aoyama et al. (1988) studied the induction of peroxidative action of Tl in different tissues of hamster. They found an increase in lipid peroxidation — particulary in the kidney— with a marked decrease in NPSH (non-protein sulfhydryls) as an indicator of glutathion levels, as well as a depletion in glutathion peroxidase (GSHpx) activity, suggesting that the tissue damage induced by thallium can be also associated to peroxidative processes.
6.4. Neurochemical alterations Due to the fact that some symptoms of thallotoxicosis are posibly related to catecholamine changes, Hasan et al. (1978) measured the levels of dopamine (DA), norepinephrine (NE) and 5hydroxytryptamine (5-HT) in different rat brain regions after thallium intoxication, showing a decrease in DA concentration in almost all regions; in the case of NE, no important alterations were found, but for 5-HT, they also found decreased levels, mainly in corpus striatum, cerebellum and brain stem. In a previous work conducted by Patterson (1975), levodopa (L-DOPA), a wellknown dopamine precursor, was shown to attenuate the choreiform sequelae of thallotoxicosis, suggesting that Tl + poisoning involves severe alterations in dopamine system and also that LDOPA could be considered of potencial therapeutic value for these specific symptoms. A little later, Marwaha et al. (1980) described the
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effect of chronic administration of thallium on the electrophysiological activity at central noradrenergic synapses. They found that thallium increased the spontaneous discharge rate of cerebellar Purkinje neurons, suggesting that thallium toxicosis in cerebellum involves a disruption of adrenergic mechanisms. Moreover, the results on the use of antipsychotic catecholamine blocking drugs in thallium-treated rats, lead the authors to suggest either an impairment in transmitter release, a reduction in catecholamine stores or a postsynaptic subsensitivity; the hypothesis of noradrenergic deficit during thallium toxicosis was supported by experimental data. Taken together, these reports strongly contribute to understand some neurological symptomatologies produced during Tl + toxicosis. In order to explain whether the observed alterations in catecholamine concentrations after Tl + could be related to the changes in the general metabolism, we recently studied the monoamine oxidase (MAO) activity and the turnover rate of 5-HT and DA in different rat brain regions (Osorio-Rico et al., 1995). Results indicated that thallium induced a significant increase of MAO activity in pons and midbrain and also in serotonin turnover rate as compared to the control animals. DA turnover rate was not significantly modified. All these evidences lead us to suggest that rats intoxicated with thallium, as well as human poisoning, may both develop behavioral and toxic alterations as the result of changes in the brain metabolism.
7. Thallium as a radiactive tracer Radioactive thallium has been used as a myocardial and tumor-scanning agent because of its similarity to potassium (Ando et al., 1988). Thallous has been shown to readily substitute for potassium at the (Na + /K + )-membrane ATPase activation site and does not leak out of tissue as rapidly as potassium. Its potential use for tumor detection was realized when lung carcinoma was revealed by myocardial thallium scans. Its usefulness as a tumor imaging agent was subsequently evaluated and confirmed for neoplasic lesions of the lung, thyroid, liver and brain. Brain tumor
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uptake is a combined function of blood-brain barrier permeability and cell viability in terms of increased cell growth and concomitant enhancement of (Na + /K + )ATPase activity. Human glioma cells have inward rectifying K + channels which are two to five times more permeable to Tl + than K + (Brismar et al., 1989; Rubertone et al., 1993).
8. Antitumoral effect Hart and Adamson (1971) tested the toxicity and antitumoral activity using the four elements of the Group III A against Walker 256 carcinosarcoma (W256) and Leukemia L1210 (L1210) cells in vitro. Thallium exhibited an inhibitory action on the growth of W256, while no inhibitory effect was found on L1210 cells. When compounds of these elements were injected intraperitoneally into the animals carrying the ascitic form of W256 and L1210, the order of the antitumor activity against W256 was identical to that seen in tissue culture: Tl \Al\ Ga\In. None of these compounds produced any activity against L1210. In 1994, our group tested the antitumoral effect of thallium against N-ethyl-N-nitroso-urea-induced brain tumors. Thallium treatment delayed the average time to the onset of the neurological signs of tumor growth, as well as reduced the frequency of some tumor types. The combination of the high cellular toxicity of thallium and its selective action against tumor cells related to the uptake into the cells and may serve to eventually explain its antitumoral effect (Barroso-Moguel et al., 1994b).
9. Analytical procedures for thallium determination Thallium analysis has been performed by differential pulse anodic stripping voltammetry, field desorption mass spectrometry, inductively coupled plasma mass spectrometry and furnace atomic absorption spectrophotometry. Some of the earlier methods for thallium analysis — such
as flame and flameless atomic absorption—require the use of chelation extraction procedure to avoid interference or to preconcentrate the element in order to improve the detection limits (Paschal and Bailey, 1986). However, the chelation extraction procedure in these methods is limited by the organic solvent which autosamplers have difficulty in handling. Direct analysis of thallium has been performed by graphite furnace atomic absorption spectrophotometry and inductively coupled plasma mass spectrometry with sufficient sensitivity. In the case of graphite furnace atomic absorption spectrophotometry, determination is expected to be troublesome since the volatility of the metal restricts the use of high charring temperature for thermal pretreatment with graphite furnace. Important matrix interference are then expected to appear due to incomplete elimination of organic and inorganic background material. Owing to these facts, our group proposed a matrix modifier for the direct determination of thallium using diammonium hydrogenphosphate both in experimental-toxicological studies and in clinical diagnosis of thallium intoxication cases in human patients. This particular technique is also applied for the analysis of both biological fluids and tissue contents (Rı´os and Galva´n-Arzate, 1998).
10. Final comment Thallium poisoning inhibits certain enzymes, coenzymes and structural proteins, and it will causes metabolic disturbances. The latter in turn help to explain the structural and functional changes often seen in cells, tissues and organs, which resulted in physical, neurological and psychiatric abnormalities found in the poisoned patients (Prick, 1979), as well as in animals during experimental procedures. Perspectives on thallium research will bring us new interesting information, not only concerning to its toxic action or as an important environmental pollutant, but also as a possible experimental and clinical tool in several fields of research, as well as a putative therapeutic agent against tumors.
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Acknowledgements The authors wish to thank Dr Camilo Rı´os and Dr Emilo Rojas-Del Castillo for their respective contributions to this manuscript, as well as to Rosa Marı´a Tarrats and Leticia Andre´s-Martı´nez for their technical assistance. This work was partially supported by CONACYT grant 0935-M 9506.
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