Thallium 
A Review and Summary of 
Medical Literature 
By 
Francis F. Heyroth, M.D. 
SUPPLEMENT No. 197 
to the 
PUBLIC HEALTH REPORTS jf ihLUhtiAL SECURITY AGENCY 
United States Public Health Service 
Thomas Parran, Surgeon General 
DIVISION OF PUBLIC HEALTH METHODS 
G. St. J. Pebbott, Chief of Division 
This manuscript was prepared during the war at the request of the 
Committee on Insect and Rodent control of the Office of Scientific Research 
and Development. Thallium is used as a rodenticide. Information on its 
toxicity and potential dangers, including methods of treatment, were abso- 
lutely necessary for its use for general rodenticide purposes. This manu- 
script was used by the Army, the Navy, and the United States Public 
Health Service during the war. Since the end of the war, several cases of 
thallium poisoning with deaths have occurred from the use of thallium as a 
rodenticide. Requests from official agencies, such as State Health Depart- 
ments, and private practitioners, for the information in this manuscript have 
been received repeatedly during the past year. 
UNITED STATES GOVERNMENT PRINTING OFFICE, WASHINGTON : 1947 
For sale by the Superintendent of Documents, U. S. Government Printing Office 
Washington 25, D. C. - Price 10 cents A REVIEW AND SUMMARY OF MEDICAL LITERATURE 
THALLIUM 
Francis F. Heyroth, M.D. 
From the Kettering Laboratory of Applied Physiology, College of Medicine, 
University of Cincinnati 
HISTORY 
In 1861, in the course of the spectroscopic examination of deposits on 
the flues from an oven in which sulfur-containing ores had been roasted, 
Crookes (70) observed a previously-unknown green line (535.0 m mu) 
which he attributed to a new element. Because the color of the line sug- 
gested that of young vegetation, he gave the element the name “thallium” 
from a Greek word thallus for a budding twig. During the following 
year, its chemical properties were investigated by Crookes (71, 72, 73, 74), 
and by Lamy {l6O, 161, 162), who found it in the sludge in the lead 
chambers of a Belgian factory producing sulfuric acid. During the course 
of his work, Lamy {160) experienced weakness and felt pain in his legs, 
symptoms which led him to test the toxicity of the sulfate of the new ele- 
ment by feeding it to dogs, ducks and hens. All died within a few days, 
after having given evidence of intestinal and respiratory embarrassment, 
peripheral paralyses and general weakness {161). Although Crookes 
(74) doubted the toxicity of thallium and is said to have taken several 
grains of a thallium compound without suffering ill effects, both Paulet 
{211) and Grandeau {124, 125), after further experimentation, expressed 
the opinion that it is more toxic than lead. 
SOURCE, PROPERTIES AND USES 
Although thallium occurs in small amounts in minerals such as crooke- 
site, lorandite, hutchinsonite and urbaite, its chief source is pyrites, in 
which it occurs as an impurity {190). During the roasting of the ore for 
the production of sulfur dioxide, it passes into the dust which settles on 
the flues or accumulates in the sludge in the lead chambers. After ex- 
traction from the dust or sludge by means of dilute sulfuric acid, the 
element is precipitated as the relatively insoluble chloride by the addition 
of concentrated hydrochloric acid. After conversion into the soluble sul- 
fate, the element may be liberated by electrolysis or by the action of zinc. 
Smaller quantities of thallium compounds are obtained by similar methods 
from zinc sulfate prepared from zinc-bearing pyrites which contain thal- 
lium as an impurity. 
In appearance, thallium resembles tin, but is soft and malleable like 
lead. It melts at about 300° C.? snd bpils at about 1482° C, (758). It forms 
1 2 
univalent thallous salts and trivalent thallic salts; the latter are more or 
less readily hydrolyzable by water and on boiling tend to be reduced to 
thallous compounds. Thallous acetate, a light yellow to white powder, is 
soluble in cold water, but thallous chloride, thallous iodide and thallous 
hydroxide are insoluble. 
Compounds of thallium have been used to impart a high refractive in- 
dex to glass intended for lenses and for imitations of precious stones. 
They are of some use in pyrotechnics, in the preparation of catalysts, in 
the analytical laboratory, and in extending the life of the tungsten fila- 
ments of lamps. The metal has been added to the mercury employed in 
thermometers intended for use at low temperatures. 
Thallium sulfate was found effective as a rodenticide in Germany about 
1920 (138), and was marketed in the form of Zelio paste and Zelio 
granules, preparations which contained it to the extent of about 2 percent. 
Investigations by the Division of Predatory Animal and Rodent Control, 
United States Bureau of Biological Survey {201) confirmed its effective- 
ness in the eradication of rats. It has been used in the control of prairie 
dogs and ground squirrels that had resisted strychnine baits. In California 
“Thallgrain,” prepared to contain 1 percent of thallium sulfate, was at 
one time distributed over certain areas of 10 counties in a program for 
the control of ground squirrels {153). Pastes and syrups containing 
thallium also have been used for the eradication of certain species of ants 
in the Southwest {215). 
DETECTION AND DETERMINATION 
Thallium can be detected readily by means of the spectroscope. Methods 
for its determination in biological material have been reviewed by Gettler 
and Weiss (111). Among the earlier methods were those of Bodnar and 
Terenyi (18), Schee (239), Stich (255) and Schwarzacher (244). Although 
various precipitants, as mercaptobenzothiazole (252) and dithizone (9) 
have been suggested for the gravimetric determination of thallium, the 
more recent volumetric methods are based upon the ability of the thallic 
ion, formed by the use of an oxidizing agent, to liberate iodine from 
potassium iodide {lOB, 111, 237). 
TOXICOLOGIC PROPERTIES 
Thallium compounds, which are extremely toxic to higher forms of life, 
do not precipitate proteins in vitro, according to Dixon {B6). The salts 
are not markedly bactericidal {223 a), but the metal in the presence of 
air is said to have a strong oligodynamic action upon certain bacteria 
{4l). 
Deaths have occurred among toads, mice, rats, rabbits, dogs, ducks, 
geese and quail as the result of the oral administration of one or another 3 
soluble compound of thallium in amounts equivalent to from 6 to 40 mg. 
of the metal per kilogram of body weight {32, 61, 112, 144, 157, 
176, 196, 201, 204, 209, 247, 259, 263, 279). For dogs, Gettler and 
Weiss {112) estimate the lethal dose as 12 to 15 mg. per kilogram, while 
Munch and Silver {201) give the following percentages of deaths occur- 
ring among rats given various doses of the sulfate: 
Dose Mortality 
Milligrams/Kilogram percentage 
10 0 
15 12 
20 37 
25 73 
greater than 35 100 
The available data indicate that results are not greatly different when the 
subcutaneous or intravenous route of administration is employed, but 
precise values cannot be given. Buschke and Peiser (57) found that or- 
ganic compounds of trivalent thallium, such as thallium dimethyl bromide, 
are only one-tenth as toxic as thallous acetate when administered to mice. 
They assume from this that the organometallic radical does not break 
down in the body to yield the toxic thallous ion. Other investigators state 
that certain trivalent thallium compounds are among the most toxic 
compounds of that metal {144). 
Marme {186) as well as Swain and Bateman {259) offered some evidence 
that the action of the metal is cumulative. The latter investigators found 
that the effects of administering 200 mg. of a thallium compound to a 
dog in divided doses over a period of 13 days were as marked as those 
resulting from the giving of a similar amount within 4 days. Severe intoxi- 
cation occurred in rats as a result of the oral administration of 0.2 mg. of 
the acetate per rat daily for several weeks (47). The statement that a 
tolerance for small amounts of the metal can be developed has been 
attributed to Marme {186), whose paper is inaccessible. No other infor- 
mation in regard to this feature of the toxicity of thallium is available. 
THE NATURE OF THE TOXICOLOGIC RESPONSE 
The feature of the toxic response to thallium that has aroused the greatest 
interest—its ability to cause a loss of hair—was apparently discovered by 
Combemale {62, 63) in 1898. In accordance with the belief then that 
thallium was useful in treating colitis and in lessening the night sweats 
of phthisis, he instructed a patient to take a pill containing 0.1 gm. of a 
salt of thallium on each of 4 days. Several days later there was a complete 
and rapid loss of the hair, an observation that was soon confirmed by 
Huchard {140), Dubreuille {93, 94), Jeanselme {146, 147) and Guinard 
{129) on patients, and by others (44) on rabbits and guinea pigs. The on- 
set of alopecia is always delayed for a week or more and it does not occur 4 
in animals that die within a few days of the administration of a large dose. 
Hallopeau (131) found that guinea pigs died without any loss of hair 
within 48 hours after a cutaneous application of an ointment containing 
50 percent of a thallium salt. 
The signs of severe intoxication of animals by thallium—restlessness, 
tremors (29), ataxic gait, convulsive movements of the legs followed by 
partial paralysis, anorexia, loss of weight, constipation or bloody diarrhea, 
and dyspnea—are indicative of widespread damage to the nervous system 
and digestive tract and, to a lesser extent, the circulatory apparatus. At 
necropsy, lesions are encountered in the digestive tract, nervous system and 
kidneys. 
Toads die in asphyxia following loss of control of their hind legs, after 
having been given doses of 1 to 30 mg. of thallium (259). In frogs, after 
a period during which there are convulsions, paralysis ensues, the respira- 
tions weaken and the heart stops in diastole (75, 157). When a solution of 
a salt of thallium is perfused through the isolated heart of the frog, its 
contractions decrease in height and it finally stops in diastole (40). The 
action is diminished by the presence of calcium in the solution. 
The appearance of signs of intoxication in mammals is usually delayed, 
rats dying from respiratory failure on the second or third day following 
the administration of a lethal dose (19). Cardiac depression has been 
mentioned by only a few investigators (176, 259) and does not appear to 
be a usual feature of the response, although Mauro (188) found histologic 
changes in the myocardium. Curci (75) states that the blood pressure is 
increased. Dyspnea has been frequently observed, and several investigators 
have found bronchitis or broncho-pneumonia at necropsy. 
Symptoms of nervous dysfunction are commonly encountered (98). 
Dogs become restless, and after a time exhibit an arching of the back and 
convulsive movements, especially of the hind legs, which later became 
partially paralyzed (61, 176). Fishes swim in queer positions (259). 
In rabbits, an ataxic gait, tremors of the head, trismus and tonic-clonic 
convulsions and paralyses (247) have been described (128, 240, 241, 265). 
Dixon (86) states that such signs are always delayed, the immediate action 
being limited to a relaxation of the smooth muscle of the bronchioles, 
intestine and uterus. He holds that the later signs result not so much from 
an action upon the medulla and spinal cord, as from a state of increased 
sensitivity of the autonomic system. A degree of faradic stimulation of 
the cervical sympathetic, insufficient to affect the pupil of a normal cat, 
caused strong mydriasis in a cat that had been given a small but unstated 
dose of a thallium compound. Dixon indicated, however, that the cranio- 
sacral nerves may be affected in a similar manner but to a lesser degree, 
and that the time required for a reflex to pass through the cord is lessened 5 
by thallium, which he thought acted directly upon the neurones. Unfor- 
tunately, Dixon published only a brief discussion of this work, and made 
no allusion to the origin of the paralyses which are a late feature of the 
poisoning. 
Histologic examinations by Greving and Gagel (128) showed changes 
typical of polyneuritis in the peripheral nerves, but no lesions in the 
vegetative nervous system. In the brain there were degenerative changes, 
in the Purkinje cells, the medial geniculate body and the nuclei of the 
oculomotor nerves. In the peripheral nerves and in certain tracts of the 
brain and cord of rats, Cortella (65, 66, 67) found the neurilemma thinned, 
swollen or ruptured at places, and noted varicose swellings of the axis 
cylinders. The ganglion cells were spherical in form, with their nuclei 
deformed and displaced toward the periphery. The cortical cells were 
pale, vacuolated and lacking in Nissl granules. The meninges were con- 
gested, the pia being thickened. Schneider (240, 241, 242), on the other 
hand, found that the brain was only slightly damaged. Ma and Mu (179, 
180) found an almost complete absence of Nissl substance from the cells 
of the ganglia of the spinal cords of rats removed during the fourth week 
after the administration of a dose of the acetate equivalent to 8 mg. per 
kilogram of body weight. 
Richet (223) and Rabuteau (218) noted that after the symptoms of 
nervous origin had been present for a time, there resulted an atrophy of 
the muscles, especially those of the jaw and spine. Muscular atrophy also 
has been described in human poisoning. Bacq suggested (7), from the 
results of experiments with the rectus abdominis of amphibia, that thallium, 
like the iodoacetates, may inhibit some enzymatic process concerned in 
muscular contraction. 
Gastroenteric disturbances, including stomatitis, bloody diarrhea and 
loss of weight (176, 247), have been observed after the subcutaneous ad- 
ministration of thallium compounds. The repeated administration of small 
doses of thallium acetate to young rats caused an inhibition of growth (47, 
132) and alterations of the bones (44, 184, 185), which were soft, curved, 
poorly calcified and had fusiform deposits of osteoid tissue. The marrow 
became fibrous, and Buschke and his co-workers (31, 37, 48) likened the 
in histologic appearance to that seen in ostetis fibrosa. Bony lesions ap- 
peared within 4 to 6 weeks in 68 percent of the rats given 0.2 mg. of 
thallium acetate daily (50), and were especially evident in the ribs and less 
so in the vertebrae and extremities. 
Urabe (271) found thallium caused decreased amounts of ash in the 
teeth of rats and that small doses increased and large ones decreased the 
proportion of calcium in the ash. The content of phosphorus was not 
markedly affected. Rominger, Meyer and Bomskov (227) believe the re- 
tention of phosphorus is impaired in the first stage of intoxication, while 6 
the calcium stores remain normal for a longer period, but decrease grad- 
ually as the poisoning advances. At one time Buschke and Peiser (48) 
asserted, without publishing the analyses, that the calcium content of the 
blood increases, but that the bones were unable to utilize it. Buschke (44) 
also asserted there may be hypochlorhydria and alkalosis. 
A noninflammatory keratitis with progressive opacification of the cornea 
was observed by Richet {223). Several reports deal with the formation 
of cataracts in the eyes of chronically poisoned animals {33, 47, 55, 115, 
253). No relation has been found between these and either the bony lesions 
or the degree of alopecia {lB4, 185). Other lesions of the eye, as inflam- 
mations of the lids, intraocular hemorrhage, retrobulbar neuritis and par- 
tial atrophy of the optic nerve have been described {43. 
In the forestomach of rats with chronic poisoning, inflammatory-pro- 
liferative lesions, including hyperkeratosis, papillomas and epithelial cysts 
and tufts extending into the muscularis mucosa have been described (44, 
135, 166, 260). They were limited to the areas lined by flat epithelial 
cells, and were not seen beyond the point of transition to the main stomach, 
nor on other organs covered with flat epithelium (49). 
Polydipsia and polyuria have been noted by some investigators, while 
others state that in severe poisoning the damage to the kidney may be 
sufficient to cause complete anuria (259). In the kidney, Dal Collo (77, 
78) found parenchymal and vascular lesions, and Buschke, Loewenstein 
and Joel {43) mentioned changes in the cells of the tubules suggestive of 
those induced by chromium. 
Hyperglycemia has been observed following the intravenous administra- 
tion of a thallium salt {156), but in the development of chronic poisoning 
of rats transitory hyperglycemia is later followed by a decrease in the 
amount of sugar in the blood (784). Repeated subcutaneous injections of 
thallium compounds are said to increase the potassium and cholesterol of 
the blood and decrease the calcium (755, 756). Testoni (262, 264) failed 
to find hematoporphyrin in the urine of rabbits or dogs poisoned by 
thallium. 
Buschke, in many papers asserted that endocrine disturbances of various 
types are common in chronic intoxication and may serve to explain many 
of the manifestations of the action of thallium. He noted that sexual 
activity was lessened {139), and observed apathy and somnolence in 
chronic poisoning (46), but Swain and Bateman (259) believed they had 
detected an aphrodisiac effect in an acutely poisoned dog. Various ob- 
servers (282, 55, 87) have claimed that thallium inhibits the production of 
ovarian hormones in rats and less readily in mice. Doses so small as to 
induce no other effects were said to have produced this result, the cycle 
being resumed a few weeks after the regular feeding of thallium com- 
pounds had been stopped, Buschke and Bickel (76) asserted that even 7 
(luring the continued administration of thallium, the cycle could be re- 
stored temporarily by the administration of ovarian or pituitary extracts. 
In contrast, Cox and Rodgerson {6B) were unable to demonstrate any 
selective effect of thallium upon either the function or the histological ap- 
pearance of the ovaries of rats. Buschke {46), however, stated that the 
testes may be completely atrophied and free from sperm. Baumann {JO) 
and Maraoli {184) also reported some lesions in the sex glands. 
Although it has been suggested that the convulsive response and the 
bony changes may be the result of interference with the action of the para- 
thyroids, histologic examination of these glands by Mamoli {184) revealed 
few if any lesions. Lansbury {164), however, found the parathyroid 
gland markedly degenerated in the only rat he examined. The cells showed 
vacuolation and hyperchromatic, pyknotic and fragmented nuclear changes. 
Similar changes were observed in the pancreas, although the islands of 
Langerhans were but slightly affected. 
Buschke and Reiser {4B) asserted that thallium retards the growth and 
metamorphosis of tadpoles, and Mu and Hu {194) observed a transitory 
and slight diminution in the basal metabolic rate of rats 2 to 11 weeks 
following the subcutaneous administration of the acetate in doses of 8 to 12 
mg. per kilogram of body weight. On the other hand, Julian Huxley and 
Curtis {142) were unable to demonstrate any antagonism between thallium 
and either iodine or thyroid extract upon the metamorphosis of tadpoles. 
They concluded that if thallium had any effect at all, it consisted in a very 
slight acceleration of the rate of metamorphosis. Balbi (8) also did not 
believe there is a specific action upon the thyroid. Histological changes in 
the thyroid were noted by Dal Collo (77, 78) and by Mamoli {184), but 
were not seen by Baumann {10), Lansbury {164), or Buschke, Loewen- 
stein and Joel {43). Ma and Mu {179, 180) examined the thyroid of rats 
at various intervals following the subcutaneous administration of a dose of 
8 mg. of the acetate per kilogram. During the first week, the Golgi appara- 
tus in some of the thyroid cells changed from a network at the side of the 
nucleus into droplets, the mitochondria changed from filaments into seg- 
mented granules and the colloid assumed an acidophilic reaction. During 
the second week the droplets and granules of the Golgi apparatus and the 
mitochondria became much finer and were dispersed in the distal portion 
of the cells. By the third week the thyroid cells had become flattened, and 
their nuclei were poorly stained, while many vacuoles were present in the 
acidophilic colloid. Recovery then began and was complete in about 6 
weeks. 
It has been asserted by Buschke and Reiser {46) that the adrenals either 
became devoid of adrenaline or contained less than the normal amount. 
The lipoid of the adrenals and skin of rats was also said to be reversibly 
diminished in chronic thallium poisoning (45). The reticulo-endothelial 8 
apparatus of the liver and the sinuses of the splenic veins were also 
swollen {43). 
Contrary to the belief of Buschke (35) that the toxic response is the 
result of a functional deficiency on the part of the endocrines, the evidence 
indicates that in those instances in which some measure of dysfunction of 
any of the glands of internal secretion has been demonstrated, this has 
not exceeded that which might be found in any animal under the influence 
of a general cellular poison. 
Alterations in the cellular composition of the blood of animals, 
detected after the administration of thallium, are neither characteristic nor 
regularly reproducible. Some observers believed that alterations similar 
to those due to lead could be produced (158). Seitz (247), however, 
found no stippled red cells after four injections of 0.2 c.c. of a 1 percent 
solution of the acetate into rabbits, but mentioned polychromasia and a 
definite increase of lymphocytes. Others have found only occasional 
erythropenia and leucocytosis {lB4, 100, 166). 
Landauer {163) described experiments which suggest the progeny of 
chronically poisoned male animals are adversely affected. The chicks of 
hens fertilized by poisoned cocks had a significantly higher mortality 
within the first 3 weeks after hatching than did those fertilized by normal 
cocks. 
THE EPILATING ACTION OF THALLIUM ON ANIMALS AND ITS MECHANISM 
Thallium is unique among the metals in its ability to produce epilation. 
This phenomenon occurs but rarely in acute poisoning either of man or 
animals {172, 145), although other types of cutaneous dysfunction, as a 
scaly erythema, have occasionally been observed. Following the adminis- 
tration of smaller doses, diffuse depilation occurs after a period of several 
days to 2 weeks {26, 30, 15, 85). This is said to be brought about more 
readily in the rat than in the guinea pig {266, 267). In the instance of the 
former species, the peroral administration of 0.1 mg. of the acetate daily 
from the tenth week to the fifth month led to a state of alopecia which was 
complete except for the so-called sensory hairs (52). By continuing the 
administration at this rate, it has been possible to keep rats in a state of 
nearly complete hairlessness for a year. Mice, dogs, rabbits and apes also 
exhibit this response {206). The threshold dose for epilation is 14 to 30 
mg. per kilogram in the rabbit {6l) and 8 to 17 mg. per kilogram in sheep 
{204). Young rats lose their hair more readily than do older ones (3, 4, 
14, 274, 275). Spitzer (253) believes coarse hairs are more readily lost 
than lanugo hairs. 
There is disagreement as to the ability of locally applied thallium com- 
pounds to produce epilation. It is very difficult to test this experimentally, 
since it is well known that thallium compounds may be absorbed through 
the skin in lethal amounts {201), so that a positive response might well be 9 
the result of changes in the hair-forming apparatus induced by way of the 
nerves or bloodstream rather than by direct local action. Truffi {266, 267) 
states that when applied locally in small quantity to a circumscribed area, 
depilation occurs only around the point of application. Although Buschke 
and Peiser (46) concur, Dixon {B6) is of the opinion that depilation does 
not result when thallium compounds are rubbed into the skin, but that 
thallium applied in small but unstated amounts stimulates the growth of 
hair. He found a more rapid growth of hair on the skin of a shaved rabbit 
upon which a small amount of a thallium compound had been applied, 
than had occurred in the case of another that had been shaved only. This 
stimulant action of thallium upon the growth of hair {64) has even been 
made the basis for the treatment of alopecia areata (7, 39). 
The hair of the young of chronically-poisoned rats begins to grow nor- 
mally 8 days after birth, but stops after another 8 to 12 days {46, 52). 
It cannot be said the mechanism by which thallium causes hair to be lost 
is known {100). Buschke, a dermatologist who published over 40 specu- 
lative papers that were meager in experimental details, held the action is 
mediated in some manner by alterations in the function of one or another 
of the ductless glands in turn acting upon the sympathetic nervous system. 
He based this in part upon his inability to detect local changes in the skin 
adequate to account for the loss of hair {46, 52, 55, 35, 36, 16). As already 
mentioned, there is little evidence that thallium has a specific and marked 
action upon any endocrine gland, and the administration of preparations 
derived from the ovary, testes, thyroid or parathyroid concurrently with a 
thallium compound fails to prevent the loss of hair (8, 12, 101, 13, 276, 
278). A thymus perparation seemed to increase it {l2). That the effect 
is exerted through the central nervous system is the view of Olmer and Tian 
{207) and Pohlmann {214). 
Evidence for the belief that the sympathetic system is involved is found 
in the demonstration of Buschke {46, 52) and others {203, 214,) that in 
the case of rats the baldness may be complete except for the so-called 
sensory hairs. The muscles of these hairs of the eyebrow and muzzle are 
said to be striated and innervated by cerebrospinal nerves whereas the 
body hairs have a sympathetic innervation. Chang (57), however, op- 
poses the view that the action of thallium is exerted through the nerves, 
since he observed that the loss of hair continued at the same rate in fresh 
autotransplants of skin as in the normal areas, even though there had been 
insufficient time for the development of innervation to the transplants. 
Italian observers tend to the view that the action of the metal is directly 
upon the hair follicles. Fiocco {103) described histologic changes in 
the skin and hair follicles, as well as erythema, desquamation and secon- 
dary epithelial degeneration, in chronically-poisoned animals. Mamoli 
(183) described atrophy of the skin, subcutaneous tissue, sebaceous and 
sweat glands. Hyperplasia of the stratum corneum and atrophy of the 10 
hair follicle and its inner root layer (95), and hypertrophy and hyperplasia 
of the thickened sebaceous glands, also have been described. 
Buschke and Peiser (52), unable to confirm these observations, offered 
as evidence against local damage to the follicle as a cause of the alopecia, 
the fact that the loss of hair is never permanent. Trulfi (266, 267, 268) 
maintains that there is an histologically demonstrable direct action upon 
the hair follicles. Dixon, (86) states the epidermis and sebaceous glands 
remain almost normal, but that in the dermis there is an increased density 
of fibrous tissue. In the hair follicles he found that the collection of 
epithelial cells was smaller than usual, although there were no abnormali- 
ties in the dividing cells. He attributed the interruption in the normal 
growth of hair to a failure in the process of transition from the large 
polygonal cells to the stratified cells that form the hair. Leigheb (167) 
also reported atrophy of the papillae and degeneration of the germinal 
cells of the bulb and root sheath, with a moderate degree of atrophy of 
the sweat and sebaceous glands. Others noted underdevelopment of the 
skin (14), and hyperkeratosis with microabscesses beneath the corneum 
(266, 267, 268, 273). Baumann (10), who observed a direct pynotic 
action on the nuclei of the cells of the hair follicles, testes, spleen and 
thymus, concluded that the metal produced a generalized karyolysis. It 
seems very probable that degenerative and inflammatory changes in the 
skin play an essential role in causing the alopecia (192). D’Avanco (78a) 
found that when locally applied, thallium lessens the ability of the skin of 
rabbits to reduce orthodinitrobenzene. 
POISONING IN MAN 
Munch (197, 198) in 1933-4, collected records of 778 cases of poison- 
ing by thallium, of which 46 were fatal. Other cases have been reported 
subsequently (136, 20, 154, 243, 202, 270). Jordon (149) described a case 
which followed the eating of a sandwich left on a shelf in a photographic 
laboratory, where it had become contaminated with thallium sulfate. 
Ginsburg and Nixon (114, 200) described an incident in which 11 
Mexicans were poisoned in California as a result of eating tortillas made 
from a stolen store of thallium-treated barley intended for use in the ex- 
perimental eradication of ground squirrels. Although three recovered, 
sfx died, and two remained psychotic. In a second and similar incident, 
31 persons were exposed, of whom 22 exhibited symptoms and 6 died. 
In man, the signs and symptoms are mainly referable to the nervous 
system, and the alimentary tract. When large quantities have been taken 
such symptoms become evident after about 12 to 14 hours. Symptoms in- 
dicative of damage to the digestive tract are the first to appear, disturb- 
ances of the nervous system often being delayed for 2to 5 days. Typical 
of the many descriptions of cases (22, 137, 127, 175, 54. 150, 219, 
141, 207,151,136, 20, 154, 243, 202, 270, 173, 130, 2, 205, 272, 118, 189, 
58, 260, 110, 149,106,107,221,109, 6, 113, 222, 165, 229, 193, 251, 250) 11 
is one by Unsfeld {270) in which a 24-year old girl attempted suicide by 
taking a spoonful of Zelio grains. Among the symptoms noted were colic, 
loss of sleep, neuralgic pains in the legs, and depression. A nodular ery- 
thema appeared, and there was delirum for a time. The hair was lost and 
the patient became emaciated; after partial recovery an ataxic gait per- 
sisted for more than 3 months. There also was marked atrophy of the 
muscles of the legs. In a second but less severe case, there were violent 
pains in the abdomen and loins and great weakness for several days, and 
the hair was lost after 3 weeks. 
Symptoms referable to the digestive tract include severe paroxysmal 
abdominal pain, vomiting, and in some but not all cases, diarrhea. Hem- 
orrhage and desquamation of the gastric mucosa may occur. Stomatitis, 
sometimes ulcerative, is frequent, the gum line may become bluish {216) 
and there may be salivation, in some instances of an extreme degree. 
Delirium, choreiform movement of the head and extremities, convul- 
sions, and death from respiratory failure have occurred in severe poison- 
ing. A marked preagonal rise in temperature has occurred in several 
of the fatal cases, possibly due to a lesion of the tuber cinereum. In 
those that survive after acute poisoning, and in the more chronic cases, a 
paresthesia of the hands and feet develops and progresses to a frank 
peripheral neuritis. The legs are involved more frequently than the arms. 
The cranial nerves are often affected, giving rise to ptosis, strabismus, 
facial palsy, mydriasis, and often retrobulbar neuritis and optic atrophy 
{lBl, 171, 182, 256, 258). Sometimes there is pain in the eyeball and 
transitory anisocoria. Some writers have likened the manifestations to 
those of an extrapyramidal, hepatolenticular syndrome, and others have 
thought it resembled the pseudosclerosis of Westphal-Striimpell. Peri- 
pheral neuritis, although a prominent feature of many of the cases of in- 
toxication and one noted by the earliest observers (277), has been absent 
in a few undoubted cases of poisoning by thallium {219). In several 
cases, death has been preceded by the onset of pulmonary edema or bron- 
chopneumonia, but in others it is believed to have resulted from a progres- 
sive impairment of the brain and vagus nerve {192). 
The incidence of signs and symptoms attributable to an impairment of 
the heart has been variable. Mentioned in various cases have been sinus 
tachycardia {127), bradycardia, angina pectoris {187) and increased blood 
pressure. Alterations of the electrocardiographic pattern have been at- 
tributed to injury of the vagus {230, 192). 
Salivation occurs in some patients {216), but in others there is dryness 
of the mouth and a constant sensation of thirst. In addition to alopecia, 
the onset of which is always delayed, there may be cutaneous lesions, as a 
scaly erythema {172), varioits types of eruptions and keratinization of 
the epithelium, ecchymoses and petechia. Conjunctivitis may occur and 
blebs may form on the eyelids {lO9, 216). Trophic disorders of the nails 12 
may lead to the appearance of white strips, especially on the finger nails 
{23). 
Cascio Rocco {225) and Flamm {105) have asserted that the calcium 
metabolism may be disturbed and hypochlorhydria or achlorhydria have 
been noted {139, 227). Testoni {264) found that although the urine was 
highly pigmented, it did not contain hematoporphyrin, but Moeschlin, Zol- 
linger and Luthy {192) found uroporphyrin and suggested that thallium 
affects porphyrin metabolism. Albuminuria is usual. 
In the acute cases in California there were no characteristic changes 
in the formed elements of the blood and no stippling of the erythrocytes 
{200), but Flamm {105) stated that 16 days after the administration of 
an epilating dose to children there was a 21.7 percent increase in the 
number of leucocytes, with a 39 percent increase in the lymphocytes and 
an 80 percent increase in the eosinophiles. 
Necropsies on the fatal cases in California revealed hyperemia and 
punctate hemorrhages in the gastric and upper intestinal mucosa and a 
marked fatty infiltration of the cells of the liver, with a tendency to cen- 
tral necrosis. The adrenal was the only endocrine gland affected, there 
being marked hyperemia, with small medullary hemorrhages and areas 
of necrosis and nuclear degeneration. There were profound changes in 
the central nervous system. The cortical vessels were engorged, and vari- 
ous degrees of chromatolysis were seen in the neurones, especially those 
of the pyramidal tract, third nucleus, substantia nigra, and pyramidal cells 
of the globus pallidus. The vessels were distended and there were localized 
areas of edema. In a more chronic case, there was striking edema of the 
pia-arachnoid membrane. 
In fatal cases Gettler and Weiss {112) found degenerative changes in 
the nerve cells, axones and myelin sheaths of nerves, basal ganglia and 
cerebellum, and degeneration of the optic nerve, along, with fatty infiltra- 
tion of the liver, degenerative changes in the renal glomeruli and con- 
voluted tubules. In the more acute cases, they found no characteristic 
lesions, observing only congestion of the internal organs, and stomatitis and 
punctate hemorrhages along the digestive tract. In subacute cases there 
were also congested cerebral and meningeal vessels, hyperemia and paren- 
chymatous degeneration of the kidneys, granular or fatty degeneration of 
the liver, fatty degeneration of the heart, and edema and congestion of the 
lungs. Arijewitsch (5) also made mention of central necrosis of the liver 
and damage to the renal glomeruli and tubules. Moeschlin, Zollinger and 
Luthy (192) found degenerative changes in lymph glands, hair follicles 
and the mucous membrane of the stomach and intestines, as well as degen- 
erative changes in the autonomic and peripheral nervous systems, but ob- 
served no characteristic changes in the endocrine glands. 
Since 1901, Buschke (27) has maintained an interest in the oral admin- 
istration of thallium compounds for the epilation of children prior to the 13 
treatment of tinea. Relatively safe procedures for this purpose were 
described by Cicero in Mexico City (59, 60), Peter (212), Gonzales {l2O, 
121, 122, 123) and Delgado {B2). Its use was approved by Bedford 
{11) who had one failure and 2 partial failures in 21 cases, and observed 
mild toxic signs in only 3 of these. All who used it thought it essential 
that the dose be exactly 8 mg. per kilogram, less being ineffective and more 
being dangerous. Buschke {34) recommended that the drug and the child 
be weighed by two physicians and that the procedure be supervised by a 
third to avoid error. He administered the salt in tablet form only to fast- 
ing, healthy, well-nourished children who had not yet reached the age of 
puberty. Many others have described the mode of administration in detail 
{lO4, 170, 177, 210, 213, 281, 79, 92, 80, 84, 246, 42, 102, 208, 236). 
Although some authors have held {lO5, 139) that the material is not toxic 
when administered to children before the age of puberty, Munch {196) 
states that when administered to children in the recommended dosage of 8 
mg. per kilogram, it has caused harm, and that in some cases toxic symp- 
toms have developed following the administration of half that dosage. 
Aramaki (3, 4) finds the nitrate more suitable than the acetate. 
Since Bullard {24) described a case of poisoning from the medicinal 
use of thallium, many others have been reported, 26 cases having been 
described by Levy {169), others by Huerre {141), Olmer and Tian {207), 
Neal, Appelbaum, Gaul and Masselink {202) and Karrenberg {151). 
Dowling {B9, 90, 91) believes that it produces mild symptoms in 25 per- 
cent of the cases in which it is used. Pains in the limbs are noted about 
10 days after the administration of thallium, and persist for 8 to 10 days. 
Some combine this treatment with the use of the X-ray, administering half 
an epilating dose of the latter and 4 mg. of thallium acetate per kilo- 
gram {226). 
Many accidents have resulted from miscalculation of the dosage {76, 
178, 245, 189, 152, 224). In some instances the symptoms have simulated 
those of acute abdominal disease {220), and in others, encephalitis {ll7, 
229) or polyneuritis {249). In still others, there have been psychic mani- 
festations and kidney involvement {B3). Munch {198) believes that poi- 
soning occurred in about 5.5 percent of the cases in which it has been 
used. Although he found records of 17 deaths following its use under 
what were considered improper clinical conditions, there have been at least 
6 deaths as a result of the use of the substance in the recommended dosage 
of 8 mg. per kilogram. In all, he believes that more than 600 persons 
have been poisoned to some extent as a result of the medicinal use of 
thallium. 
At one time Sabouraud {235, 231, 232, 233, 234) used an ointment con- 
taining not more than 1 percent of thallium acetate, applying each day an 
amount not more than equal to two kernels of wheat. Because of the occur- 
rence of accidents, he turned to the use of X-rays instead, but stated, how- 14 
ever, that when used with care, no harm resulted from the daily use of the 
ointment over a period of 18 months. Among others noting toxic symptoms 
from the external use of thallium for purposes of epilation are Giovannini 
{116), Criado {69), and Prieto {217). TschernoguboAV {269) maintains 
that a dose of 3-4 rag. of the acetate per kilogram of body weight in oint- 
ment form may he safely applied upon the skin of children. 
More than 51 cases of poisoning resulted from indiscriminate sale of 
an ointment known as Koremlu, which contained about 7 percent of thal- 
lium acetate {2BO, 96,171, 181, 25,126, 238). 
About 12 cases of industrial poisoning, none of which was fatal, were 
recorded by Teleky {261) and Rube and Hendricks {228). These were 
confined to three of the nine factories in which thallium compounds were 
handled, but most of the workers engaged in producing the metal or its 
salts were affected. Six of those who became ill were handlers of pyrites, 
four were exposed to thallium-bearing dusts, and two worked with the 
salts. Fairhall (99) notes the possibility of exposure during the arcing 
of thallium compounds in spectrographic laboratories, but no intoxication 
is known to have occurred. A few accidents have occurred among workers 
employing thallium salts in the control of rodents. One arose during the 
cleaning of a container in which grain impregnated with thallium had been 
kept. The spreading of such grain for the eradication of prairie dogs has 
resulted in the poisoning of sheep. 
The onset of industrial intoxication has been characterized by excite- 
ment and sleeplessness, which for a time excited no attention. After 
exposure for a few weeks or months, pain was noted in the joints of the 
lower limbs, accompanied by muscular cramps and weakness, with loss 
of the reflex of Achilles tendon. In some cases symptoms progressed to a 
polyneuritis. After a few months the hair fell out. Other symptoms were 
salivation, anorexia, vomiting, diarrhea and loss of weight, depression, 
fatigue, hysterical laughter, cyanosis, tachycardia, bradycardia {217) and 
less frequently albuminuria. In one case, a total central scotoma occurred 
about 4 months after the appearance of the first symptoms, and there 
were also lesions of the iris and crystalline lens. In another case, optic 
atrophy resulted. In his examinations of the blood of workmen exposed 
to thallium, Meyer {191) found a lymphocytosis, the lymphocytes consti- 
tuting 40 to more than 58 percent of the leucocytes. In a few cases, 7 per- 
cent of the cells were eosinophiles. Erythropenia developed gradually 
and normoblasts were found, but a punctate basophilia of the erythrocytes 
has not been noted. 
Thallium is readily absorbed through the skin and from the digestive 
tract. In experiments of Bonani and Marino {2l), thallium sulfate was 
absorbed from the esophagus of rabbits and dogs. As early as 1890, 
J. Blake, a California physician, found by spectroscopic examination that 
ABSORPTION, DISTRIBUTION AND EXCRETION OF THALLIUM 15 
thallium appeared in the lungs within a few minutes after the intravenous 
injection of a thallium salt {l7). It has also been shown, in the case of 
rabbits, that the element appears in the urine within 2 hours after 
the administration (orally presumably) of thallium sulfate (148). In the 
acute outbreak of intoxication in California, the metal persisted in the 
urine of patients for 3 weeks. The concentration in the urine of two 
persons who survived, was 2.39 mg. of thallium per liter. In chronic cases, 
2 months elapsed before the metal dissappeared from the urine. Within 
36 days, dogs excrete in their urine about 60 percent of the quantity 
administered in a single oral dose. Shaw {248) and Lansbury {164) 
estimated that rats given repeated sublethal doses, excrete daily about 0.4 
mg. of the metal per kilogram of body weight. Other data on the excretion 
of the metal have been given by Devane {B4) and by Dostrowsky {88). 
In the case of lactating rats given lethal doses, the milk contained thallium 
in amounts sufficient to delay or arrest the growth of hair, and to inhibit 
the growth and development of the young, but not to kill them {2B, 97). 
Shaw {248) found that 35 to 70 percent of the thallium administered 
orally to geese, in a dose of 20 mg. of the metal per kilogram of body 
weight, was retained in the tissues when, 15 days after the dose had been 
given, death occurred. The metal has been recovered from the kidney, 
liver, lungs, heart, spleen, intestines and bone of fatally poisoned men in 
concentrations ranging from 3 to 11 parts per million {199). Bence 
Jones {148) found the element in the liver, kidney and spleen, but not in 
the blood, of rabbits killed 2114, hours after the administration of the 
sulfate. In one man, 3.3 mg. of thallium per 100 gm. of liver, 1.6 mg. 
per 98 gm. of kidney, and 5 mg. per 100 gm. of urine were found {107). 
In rats that had ingested Zelio grains, Schee {239) found 40 to 60 mg. 
percent of the metal in the muscles, viscera and feces, but none in the 
brain, although in the case of poisoned hens, it was possible to detect 
the metal in the brain. Olmer and Tian {207) found thallium spectro- 
scopically in the concentration of 1 part per 50 millions in the cerebro- 
spinal fluid of a severely poisoned man; after removing the cells by centri- 
fugation, the amount was reduced to one-tenth of its former value. The 
metal accumulates in small amounts in the skin and hair {206). In experi- 
mental observation on rabbits, relatively large amounts were found in the 
liver and kidney with lesser amounts in the lungs, heart and urine (257). 
The metal differs from lead in that it is not retained selectively in bone, 
thallium phosphate being 50 times as soluble as calcium phosphate {112). 
Gettler and Weiss {112) who tabulated analytical data on six dogs and 
one human case, found that per unit weight the kidney, pancreas, spleen 
and muscles contained more thallium than did the liver or other organs. 
Since the element does not occur in normal tissues, the demonstration of 
as little as 0.5 mg. per 100 gm. of tissue suggests intoxication by thallium, 16 
the content ranging from 0.5 to 10.0 mg. per 100 gm. of tissue in subacute 
and fatal cases. 
Luck {174) found that eleven rats died after eating the flesh of a hen 
poisoned by thallium, but Shaw {248), from his observations of the 
amounts retained in the tissues, concludes that there is little likelihood 
that the flesh of game birds that had access to thallium because of its use 
as a rodenticide, would cause secondary poisoning in man. Relatively 
large amounts may be absorbed into the fetuses of pregnant animals {139). 
THERAPY OF POISONING BY THALLIUM 
In two carefully studied cases, Moeschlin, Zollinger and Liithy {192) 
found therapy ineffective. Morphine and its derivatives were of value in 
combating neuritic pain. Although thiamine has been suggested to lessen 
the severity of the peripheral neuritis, there is no evidence that there is 
any specific antagonism between the action of thiamine and that of 
thallium. Whether the latter plays the role of an antivitamin has not 
been investigated. Remedies promoting glomerular filtration, and other 
means of promoting the elimination of the metal, such as stomach lavage 
and the administration of saline purgatives, have been proposed. Pilo- 
carpine hydrochloride in doses of 5 mg. has been employed in acute 
intoxication, preferably on the third to fourth days {2OO, 168, 119, 149). 
Heat, stimulants, dextrose and calcium salts are regarded as of value in 
the symptomatic treatment. 
Because of the relative insolubility of the iodide of thallium. Munch, 
Ginsburg and Nixon {200) suggested that the intravenous administration 
of 0.3 to 1 gm. of sodium iodide, daily, might tend to fix the metal in the 
body in relatively insoluble form {143) and so lessen the acute symptoms 
of intoxication. They were of the opinion that the metal might be 
mobilized later by the cautious intravenous administration of from 0.3 
to 1 gm. of sodium thiosulfate, a remedy that had been employed by others 
{l9, 195, 56). They cautioned against the use of quantities that might 
liberate amounts sufficient to cause acute intoxication, and recommended 
determinations of the urinary output as a guide in choosing the correct 
dosage. On the other hand, Gettler and Weiss {112) doubt that sodium 
thiosulfate mobilizes thallium, and Buschke, Duchan and Joseph {39) 
do not recommend its use. 
Periodic examinations of men engaged in work with thallium are advis- 
able, and to avoid the possibility of the absorption of the metal through 
the skin in toxic amounts, special working clothes and gloves should be 
worn. Care should be taken to avoid the inhalation of dusts that may 
contain thallium. 
The earlier literature on thallium has been listed by Doan (87), and 
reviews of the toxicity of this element have been given by Hartnack {133, 
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