THALLIUM
POISONING
By Philip H. Chamberlain, M.D., William B. Stavinoha, B.S., M.S.,
Helen Davis, M.D., William T. Kniker, M.D., and
Theodore C. Panos, M.D.
Departments of Pediatrics and Pharmacology and Toxicology, University of Texas School of Medicine, Galveston
1170
T
HALLIUM salts have enjoyed widespread therapeutic use in the past. Because of their depilatory effect, they have long beenused to remove hair from the scalp,’ and
indeed are still being used in many places in
the treatment of ringworm of the scalp in children. Thallium has also been used in the treatment of syphilis,2 night sweats of tuber-culosis3 and dysentery.4 Industrial uses of thallium have become increasingly extensive
and important.
In more recent times, thallium salts have been in popular use as pesticides. “Zelio” paste and granules, rodenticides containing about 2% thallium sulphate, were used in Germany beginning about 1920. In 1931, “Thalgrain” was distributed over ten Cali-fornia counties to control ground squirrel
infestation.6 This preparation contained about 1% of thallium sulphate and caused an outbreak of thallotoxicosis in humans.7 Thallium has also been employed for many years in insecticides, particularly in the
Southwest, disguised in a syrup or paste.8 The potential toxicity of thallium
prepara-tions was recognized early and has been emphasized many times A report of four cases of thallotoxicosis in children has been published previously from this
100
It is the purpose of the present report to describe 14 cases of thallotoxicosis with
0 The reader is also directed to a paper by H.
Grossman in PEDIATRICS (16:868, 1955) for a
corn-pilation of data from 18 cases of thallium poisoning
reported in the American literature from 1935 to
1955. A list of commercial pesticides containing
thallium is also provided.-EDrroR.
striking and occasionally bizarre neurologic
features which deserve emphasis. The
van-ous therapeutic means will be reviewed and comments on a new approach to therapy
will be offered.
Patients
MATERIAL FOR REVIEW
A total of 14 cases of thallium poisoning was
seen between February, 1956 and December, 1956 at the University of Texas Medical Branch. In each instance, the source of poison was a preparation of 3% thallium sulphate in a
crushed vanilla wafer base used as an
insecti-cide, and marketed under the name of “Echol’s Roach Poison,” or “King Tex.” Ten of these pa-tients were admitted to the Children’s Hospital; the others were followed in the Pediatric
Out-patient Department. The youngest in this series
was 11 months of age and the oldest 6 years; the mean age was 3.4 years.
Diagnostic Methods
Diagnosis was established in all cases by de-tection of thallium in the urine. A technique for this determination has been developed by the Department of Pharmacology of the
Uni-versity of Texas Medical Branch and is to be
reported elsewhere. It represents a modification of a method described by Bambach and is based on extraction of nitric acid-digested urine with diphenylthiocarbazone (dithizon) and
sub-sequent estimation in a flame
spectrophotom-eter fitted with a photomultiplier tube. By this method there is no interference from lead, and it is possible to detect as little as 0.25 g of thallium. All hospitalized patients had serial 24-hour urine collections for determination of thallium excretion and volume.
(Accepted July 1, 1958; submitted April 9.)
PRESENT ADDRESS: (T.C.P.) Department of Pediatrics, University of Arkansas Medical Center, Little
Rock, Arkansas.
1171
Fic. 1. Neurologic manifestations of thallium poisoning.
Therapeutic Measures
Various therapeutic regimens were used. The
first three patients received calcium disodium
ethylenediaminetetraacetate (edathamil,
Ver-senate#{174}) at a dosage of 33 mg/kg twice daily,
given intravenously for 5 days. Three received
activated charcoal in different amounts by
mouth; six received potassium chloride in doses
of 3 to 9 gm daily, by mouth or intravenously.
With the appearance of Lund’s description of the beneficial use of dithizon in experimental animals,’2 this substance was given to six
pa-tients in an amount of 20 mg/kg daily, by
mouth or gastric tube, divided into two equal
doses. Length of administration ranged from 4
days to 21 days; an ammonium salt of dithizon
was administered intravenously for 1 day to
one patient. Because of the insolubility of
dithi-zon ill water, it was necessary to suspend the
required amounts of the substance in guar gum
before administration. The dithizon-guar gum
mixture was then suspended in 2 to 3 oz of
tap water by mixing with mortar and pestle.
The resultant thick gelatinous suspension was immediately given by means of a large syringe
through a nasogastric feeding tube. (This
method need not be followed in older patients
able to swallow the dithizon in capsule form.)
Each dose of dithizon was given with 100 ml
of 10% glucose solution in order to minimize the potential diabetogenic effect of dithizon which, like alloxan, appears to be more
dia-betogenic to animals when given in the fasting
state.
SUMMARY OF CLINICAL
MANIFESTATIONS
The clinical manifestations in these
pa-tients involved chiefly the central nervous system and the gastrointestinal tract. The multiplicity and frequency of neurologic in-volvement may be seen from Figure 1. No
pattern or sequence of development was discernible. It should be noted that all
pa-tients developed alopecia. According to some, this is due to damage to the sympa-thetic nervous system which supplies the scalp except for a strip of hair across the forehead.’3 However, Thyressonh4 found the highest thallium content to be in actively
growing hair follicles and the lowest in
rest-ing follicles, suggesting direct cellular
poi-soning. Two-thirds of the patients devel-oped striking ataxia and tremor. Irritability and headache were conspicuous. Six pa-tients became comatose; five experienced
Number of children
Tremor
Irritability
Headache
Coma
lyperreflex
oflvulSlOflS
Paresthesias
Ptosis
Resp. Paralysis
Path. Reflexes
Paralysis
25% 50%
.
1172 THALLIUM POISONINC
Number of children
Anorexia
Nausea - Vomit
Abd. cramps
Diarrhea
Melena
5
25% 50%
4
100%
FIG. 2. Gastrointestinal manifestations of thallium poisoning.
convulsions, in four respiratory paralysis
ensued, three required placement in a res-pinator, and a variety of peripheral palsies were observed in three.
Gastrointestinal symptoms, in contrast, were quite inconspicuous (Fig. 2). Only
three patients had abdominal cramps. Of the two with diarrhea, a questionable
epi-sode of melena occurring before admission was described in one.
Aside from demonstration of thallium in the urine, laboratory tests were helpful only in a negative sense; that is, they helped
to eliminate other causes for the presenting
complaints. In this series, the peripheral blood was usually within normal limits. Anemia was not evident and leukocytosis occurred only in those cases with
pul-monary infection, secondary to respiratory
complication. In agreement with the work of Seitz,15 basophilic stippling of the eryth-rocytes was not observed. Examination of the cerebrospinal fluid in eight patients re-vealed values for content of protein, glu-cose, chlorides and for the cell count to be within normal limits in each instance.
There were two deaths among these 14 cases. One patient survived in a vegetative state, one exhibited persistent mild tremors
after recovery and the remainder were asymptomatic or had insufficient follow-up.
Those who had not returned for
re-evalua-tion had relatively mild deficits wh#{231}nlast
seen.
ILLUSTRATIVE CASE SUMMARIES*
Case 1
R.R. (U.H. 23350M), a 23-year-old white male, first developed a mild coryza and anorexia on March 17, 1956. This was followed
in the next few days by listlessness and ataxia,
coarse tremors of hands and eventually inability to walk. On March 24, he was admitted to an-other hospital. Here a diagnosis of thallium
in-toxication was made when his hair began to
shed. During the following week he became progressively more lethargic.
By April 1, the patient was semicomatose
and diaphragmatic weakness was noted. On this date, he was transferred to the University of Texas Hospitals. The following day
respira-tory distress was such that tracheotomy and
placement in a respirator were necessary. Tetanic convulsions occurred intermittently for several days. Also, there was one episode of apnea, cyanosis and asystole, which responded
to stimulants after 15 minutes. After 9 weeks,
he was transferred from the respirator to a
rocking bed, and somewhat later he was able
to breathe alone. He remained blind, areflexic and vegetative. On July 26, he was discharged to a special nursing home. Follow-up
examina-0 Complete case reports may be obtained by
re-questing Document No. 5686 from the American
Documentation Institute, Auxiliary Publications Project, Library of Congress, Washington 25, D.C,
(Advance payment is required: $2.50 for photo.
prints or $1.75 for 35 mm microfilm. Make check
*
.
ERSrNATEDMED MORE ALERT
3CJ
4- LACTATE * .LA0ATE
DY OF LLNESS
tion, done April 14, 1957, at the age of 3/i
ears, ShO\Ve(l that he was still unable to see,
C1)Ul(l stand with support, was incontinent of
urine and feces, and was functioning generally
l)etweell the 9- aiicl 12-month levels.
Case 2
CF. (U.H. 3646J), a 3-year-old Negro male,
as noted to have SignS of a “cold” with cough,
lllil(l irri tal)ility afl(l drowsiness approximately
1 week l)efore admission. Shortly thereafter, it
vas noted that his hair was falling out. He was
l)rought to the emergency room on the day of
admission because the mother observed that he
seemed to treml)le “like he was cold,” and that
he ‘wobbled \\‘heIi he walked.” Weakness was
pronounced, and he could stand only briefly.
Examination revealed the complete absence of
scalp hair, soirniolence, cliIninisliecl tendon
re-flexes and profound weakness. The initial
im-1)ression of thalliuni intoxication VaS confirmed l)\’ the detection of large quantities of thallium
in the urine. Treatment with intravenous fluids,
edathamil, and molar sodium lactate was
given. Improvement was gradual and
appar-entlv unrelated to therapy. He was able to sit
alone after the third week of hospitalization
dll(l was able to walk after 1 month. At the
time of discharge, June 2, 1956, the patient
sas walking, although his gait sas still quite ataxic.
Follow-tip exaniination was done on
Febru-ar\ 23, 1957, at which time lie showed no
iieu-rologic deficit. According to the psychometric
evaluation, he was about 6 nionths behind the
average child of his age. Whether or not this
H
H 0
w z
0
3646
mild retardation was related to his illness or
whether it antedated the thallium ingestion
could not be determined.
Case 3
D.G. (U.H. 31714M), a 5-year-old white
male, ingested about 1 teaspoonful of
thallium-containing insecticide on September 5, 1956.
Twelve hours afterward, lie developed
somno-lence and anorexia, and several hours later lie
was admitted to another hospital. By the third
hospital day he became semicomatose,
respond-ing only to strong stimulation. He was then
transferred to the University of Texas
Hos-pitals. Examination revealed that the hair was
pulled out easily, though no frank alopecia was
present. Neurologic findings included a gross
tremor of the head and arms, horizontal
nvstag-mus and hyperactive deep-tendon reflexes.
Treatment at the referring hospital included
activated charcoal and potassium chloride.
Fol-lowing transfer to this hospital the child
be-came comatose, and dithizon, 10 mg/kg bid.,
was begun via nasogastric tube. Stead clinical
improvement followed except for a few days
when the dosage of dithizon was increased.
Satisfactory progress resumed as soon as the
dose was reduced. Dithizon was discontinued
on October 3, and lie was discharged October
20 (thirty-seventh hospital day), at which time
the gait was unsteady and the coarse tremor
of the head was still present.
Follow-up examination on February 28,
1957, revealed that he was able to run and play
with his siblings, although his gait was still
awkward and he exhibited a mild intention
ez 0 H
LJ
6
x
LU
4 0
0
-A 2 (
I
H
Ftc. 3. Depiction of clinical course of Case 2. Stippled areas indicate 24-hour urine volume. Bars indicate
urinary excretion of thallium ( mg/24 hr). Neither edathamil nor sodium lactate affected the urinary
Cd 2500
E
I 2000
0.
soo
0
z
D.G. 5y’ W. 8 #31714-M
semi -coma,
#{163}
000
I-780
H
0
“a
z
0
c.I 5 I
H
I
More alert, Stood alone,st
lry alert Only mild1,
alone 4, otosic jotoxic ,less otoxk4, incoordinotion( Dithizor. 10mg 1kg bid. p.o. 21 days
-4 1<C I 5 mEq lid. p.o. 21 days 4 .
E -3
-a
2 ..j
4
I
I
I-U
I3 5 17
FIG. 5. Case
Is 21 23 25 27 29
DAY OF iLLNESS
31 33 35 3,
1174 THALLIUM POISONING
Admitted stupor, tremors Alopecio, coma KCI
4’Act. Chorc.
4- Gradual improvement -4
4 Dithizon 0mg Ikg bid. p.o. I? doys-+
( KCI lOmEq q.i.d. o. 33 days---+
E
4 ,
-J
-a
2 4
8 9 tO II 2 3 4 5 6 17 8 9 20 21
DAY OF ILLNESS
FIG. 4. Case :3. This patient and his two siblings, who were also severely poisoned with thalliun, were considered to have exhibited definite improvement following
the administration of dithizon. Urinary excretion of thallium was not affected.
tremor of the hands. Three months later he was
completely vell.
Two sil)hngs of this patient were also
ad-mitted to this hospital at approximatel the
same time. They too, had severe thallotoxicosis
with multiple neurologic findings. They also
received the potassium chloride and dithizon,
and their course was likewise characterized by
rapid improvement and earl rehabilitation.
Case 4
C.J. (U.H. 19013H), was admitted to the
University of Texas Hospitals Oh November
11, 1956, and discharged (Mi December 11.
Two weeks before admission, the patient and
his 33k-year-old sister were found on the floor
of a trailer house which had been heavily
(luSted with “Echol’s Roach Powder.” Two
days later, a “watery” diarrhea, listlessness and
anorexia developed. On the day of admission,
he experienced a right-sided Jacksonian seizure
and was referred to the University Hospital.
Physical examination revealed a semicomatose
Negro male who was acutely ill, emaciated and
dehydrated. Blood pressure was 130/100. The
hair pulled out very easily in tufts.
Co-ordina-tion was poor and he walked with a drunken
gait. Deep-tendon reflexes were normal in the
upper extremities.
The patient was given bed rest and tube feedings, and by the fourth day he was more
alert and could follow simple commands. The
following day dithizon and potassium salts
(Triplex#{174}) were begun. B the tenth hospital
day he could stand alone, and on the twelfth
the blood pressure was normal. However, ataxia
4. Although iniprovenient probably began before therapy with
C.E.J. Syr
#35154 -M
Alert 4 gradual improvement ----+
*---Dithizon 10mg/Kg bid. p.o. 20 days- ---- __________ 4 KCI 15 mEq tid. p.o. 21 days
-3 E
‘22
.4
-I1 U
7 IC 9 21) 21 22 23
DAY OF ILLNESS
FIG. 6. Case 5, sibling of Case 4. Improvement following therapy, uiiassociated
with change in urinary excretion of thallium.
Admittid: somnolence
1’
olopecia..- 000
t11(l clioreiform jerks persisted.
At the tinie of discharge on December 11,
1956, lie was asymptomatic except for slight
unsteadiness when he walked.
Case 5
C.E.J. (U.H. 35154M), a Negro female, age
:33 ears, was admitted to the University of
Texas Hospitals on November 12, 1956, and
(lischarge(I on December 1 1. Two weeks before
admission, the patient and her brother were
found playing on a floor heavily sprinkled
with “Ecliol’s Roach Powder. A week later,
lover alxlominal pain and lethargy occurred,
SOOn followed b- anorexia, frontal headaches,
veakness of the legs and staggering. Two days
before admission, her hair canie out profuseh
during combing and there was an episode of
epistaxis. The brother was admitted on
Novem-her 11, 1956, because of a convulsion.
Physical examination revealed normal
tem-perature, pulse, respirations and blood pressure.
She was drowsy, irritable and undernourished.
The hair was quite loose, dropping out with
niinimal tugging. The left eyelids were swollen,
but the conjunctivae were normal. Fundtiscopic
eXdIiiilidtiOlTl was negative. Neurologic
abnor-mahities included ataxic gait and bilaterally
in-creased biceps and triceps tendoti reflexes.
Sensor and cranial nerve status were intact.
Along with bed rest, the patient received a
high-calorie diet and copious amounts of fluid.
On the fourth day thallium was reported in
urine oi)tained at the time of admission (Fig.
6), so potassium salts (Triplex#{174}, 45 meq of
potassiuni daily) and dithizon (10 mg/kg body
weight twice daily) were begun. After 6 (lays
of therap, dithizon was administered orally
with food. By the sixteenth hospital day she
was alert, happy and playful. Four das later
she was neurologicallv normal. After 20 days of
therapy, the drugs were discontinued, and she
was discharged still asvmptomatic a few days
later. No follow-up visits were made.
Case 6
D.L.W. (U.H. 37159M), a 2-year-old white
male, was found playing with an open jar of
insecticide on December 16, 1956; powder was
seen around the mouth and adhering to his
wet arms. None of the material was detected in
washings from gastric lavage 30 minutes later.
He was hospitalized elsewhere after a week
because of severe ptosis of the lids and alopecia.
There had been no gastrointestinal complaints.
He was treated with dimercaprol (BAL) for
“several days”; severe voniiting at that time
necessitated intravenous fluids. “Shakiness”
be-gan oh December 26, and progressed in
severity. At the time of admission to the
Uni-versity of Texas Hospitals, December 29,
speech had become unintelligible and iiiarked
ataxia had developed.
Physical examination revealed an irritable,
acutely ill, severely ataxic, hoarse child whose
hair easily pulled out in tufts. Rectal
tempera-ture, 38.9#{176}C;pulse, 160; respirations, 20; blood
pressure, 100/60. Marked bilateral ptoss dli(l
questionable photophobia were noted. Deep
tendon reflexes were hyperactive throughout.
Peripheral blood, electrolytes and nonprotein
Admitted encepholitis
4,
alopeclo, ataxia
250-Resp. failire, elev. BR
sposticit
Convilsions
4- Dithizon 0mg 1Kg bid. p.o
+KCI 3OmEqIV/day’
ifShk
ithiion IV.
I
r4
csJ
U,
E
-2
E
0
.c
Fi(;. 7. Case 6. Despite gastric lavage within 30 minutes of thallium
inges-tion, death occurred on the twentieth (lay. Thallium was also undouhtedh
al)sorhed froni the skin in this patient. Although increased urinary excretion
of tlialliuiii followed the administration of potassium, the clinical course was
not altered.
‘3 4 5 6 7 8
Day of Illness
(‘EATH
9 20
1176 THALLIUM POISONING
M.L.B., a 3-year-old Negro female, was
DL.W. 2yr.cl’ U 37I59M
vere normal. Urinalysis showed a trace of
albuniin, 2 + tcetOfle, 8 to 10 ervthirocvtes and
innhlmerai)le leukocvtes per microscopic field.
Fasting 1)100(1 sugar was elevated on admission
and on fun r successive (leterniinations.
Initial therapy consisted of thianiine
hydro-chloride, 100 mg t.i.d., urging of fluids, and
(lithiZoli, 20 lug; kg la orall (Fig. 7). By
January 1, he as soniewliat more alert, but
l)egan Voliliting iiiterrnittently. On January 3,
he l)ecanie coniatose and developed circuITlOIal pallor with flushing of the upper body.
Breath-ing became shallow and irregular; blood
pres-sure rapidly rose to 180/130, and episodes
of opisthotonus, spasticitv of arnis, and flushing
of the upper body became frequent and severe.
Because of vomiting, 9 mg of dithizon (as the
ammoniuni salt) in 5% glucose solution was
ad-ministered intravenously 011 January 4, and
repeated after 7 hours. However, 5 hours later,
vomiting, cessation of breathing and
disappear-atice of pulse necessitated placement in a
respirator, larvngoscopv and suctioning, and
in-tensive therapy for shock, to no avail.
Permis-sioll for necropsv was not obtained.
Case 7
admitted 011 July 29, 1956, and expired August
4. Five days before admission she became
irritable; a physician found a “red throat” and
prescribed antibiotics. Listlessness persisted,
and in the next days, poh-dypsia, polyuria,
course tremors of the extremities alid unsteady
gait appeared. On July 27, the cerebrospinal
fluid was reported as negative. Lethargy
deep-ened into coma and she was admitted to this
hospital.
Physical examination revealed a flaccid,
comatose, underdeveloped child. Blood
pres-sure was unobtainable. Deep tendon reflexes
were absent.
Peripheral blood, carbon dioxide and
chlor-ide content of the blood and roentgenograms
of the long bones were within normal limits.
Urinalysis showed 3+ albumin, 1+ sugar, 1+
acetone, and 12 to 15 leukocytes. In the blood
the fasting sugar was 193 mg/100 ml and
non-protein nitrogen was 78.6 mg/100 ml.
Adrenocortical hormones, vitamin K,
anti-biotics and fluids were given intraveiiously. The
only improvement was return of the blood
pressure to normal. The next day, respiratory
paralysis ensued and the gag and swallowing
reflexes disappeared. A tracheotomy was
res-pirator. Nor#{232}pinephrine, intravenously, was
necessary to maintain blood pressure. A mild
convulsion reinforced the possibility of lead
intoxication, so edathamil was started, 33 mgI
kg tvice daily.
On August 1, a history for exposure to
thallium on July 17 was obtained; and the
hair now could be pulled out easily. The same
day, it was erroneously reported that the urine
contained large quantities of lead, corrected
to thallium after spectographic analysis the next
day. At that time, norepinephrine
administra-tion could be discontinued, and she was re-moved from the respirator with return of ade-quate breathing. Edathamil was discontinued.
She received feedings of skimmed milk by
nasogastric tube but laboratory findings of
alkalosis, hypochloremia, hyponatremia and
hvpopotassemia necessitated intravenous
solu-tions of sodium and potassium chloride.
On Augtist 3, the patient was returned to the respirator; polyuria and deterioration of the electrolyte pattern increased thereafter. On
August 5, when the chloride in the serum was
60 meq/l, the blood pressure became
unob-tamable, cyanosis returned, and the patient
expired.
Post-mortem examination revealed edema of
the brain. Microscopically, nerve cells showed
acute degenerative changes, and Purkinje
cells were frequently absent. The liver was
en-larged and showed fatty degeneration. The
kid-neys were pale and swollen; although the
glomeruli were essentially uninjured, the
tubu-lar epithelium showed degeneration and
desquamation.
COMMENTS ON CLINICAL
MANIFESTATIONS
The clinical manifestations of acute thal-hum poisoning have been described by
many authors. In general, neurologic and gastrointestinal disturbances dominate the clinical picture. Alopecia, however, is the most common finding. Nervous system
in-‘olvement is described as ranging from
minor paresthesias of limbs, headache and
somnolence to convulsions, coma and death. Actually, every possible neurologic sign or
symptom has been mentioned, and virtually
any combination of these can occur in any
single case. Gastrointestinal symptoms,
like-vise, may #{244}onsist of anything from vague
abdominal pains or anorexia to severe
dys-function, including hematemesis,
desquama-tion of gastric mucosa, bloody diarrhea, etc.
Other findings which have been described
are: skin rashes, muscular atrophy, cardiac abnormalities, hypertension, polydipsia and anemia.
Figures 1 and 2, drawn from this series,
demonstrate that the neurologic
manifesta-tions overshadow the gastrointestinal
in-volvement to a considerable extent. Except for anorexia, nausea and vomiting (certainly nonspecific indications of disease),
gastro-intestinal symptoms were relatively
insig-nificant. Most previous reports have not
em-phasized this great predominance of neuro-logic over gastrointestinal manifestations, so evident in this series.
Without a history of ingestion or exposure to thallium-containing substances, the diag-nosis of thallotoxicosis may be exceedingly
difficult. Any child with unexplained
alo-pecia should be suspected of being poisoned
with thallium. Impending alopecia may readily be demonstrated by gentle tugging
of the scalp hair which becomes dry, brittle and loosened. Several days later, spon-taneous shedding of tufts of hair begins,
resulting ultimately in patchy alopecia or complete baldness. If any unusual neuro-logic findings coexist with alopecia, the
di-agnosis of thallotoxicosis should be strongly
considered. It should be remembered that
alopecia secondary to thallium ingestion
does not occur until 7 to 10 days after ex-posure.
Demonstration of thallium in the urine is
the best diagnostic procedure. Any amount
of thallium in the urine should be con-sidered abnormal, and when present may
be detected for many weeks after ingestion. However, it should be emphasized that the present report does not include several sib-lings of patients in this series, who had identifiable amounts of thallium in their urine without signs of intoxication.
Because severe damage to the nervous system may result shortly after ingestion of
the poison, permanent neurologic deficits
1178 THALLIUM POISONINC
alopecia appears. As a matter of fact, the
severest cases in the present series devel-oped spectacular neurologic signs within a
few days after ingestion. In such cases, diag-nosis is more difficult. Neurologic symptoms may be so confusing that differential diag-nosis must include infectious, degenerative,
traumatic, neoplastic and toxic etiologies. As illustrated in this report, certain neuro-logic findings were more suggestive than others. The unusual signs of ataxia and
tremor, appearing as they did in almost
two-thirds of the patients, were often the earliest and most useful aids in distinguishing this entity. Likewise, somnolence and weakness were present in the same number of cases. It is imperative, therefore, that the physi-cian confronted with a child presenting bi-zarre neurologic complaints, with or
with-out alopecia, should consider
thaflotoxico-sis as a possibility.
PHARMACOLOGY AND TOXICOLOGY
Thallium is absorbed readily through
both the skin and gastrointestinal tract. It
is distributed rapidly and nearly uniformly to all parts of the body, with largest distri-bution in the intracellular compartment. Elimination occurs very slowly through the gastrointestinal tract and the kidneys.
Bar-clay et al.16 found that in the human,
thaI-hum excretion is largely urinary as
con-trasted to the rat in which the excretion in the feces is roughly double that in the
416 In renal clearance studies in the rabbit, Lund17 found that approximately
60 of thallium filtered by the glomeruli is reabsorbed in the tubules.
An effective antidote would have to mobilize and increase the excretion of
thai-hum effectively or, preferably, actively
detoxify the thallium intraceilularly. The search for a suitable antidote has led to the
use of pilocarpine, diuretics, sodium iodide
and dimercaprol. Lack of effect from these
compounds has been emphasized by Lund.12
Dimercaprol, in particular, has been often used but is of little 19 In 1956, Lund’2 found that orally administered po-tassium salts and charcoal gave partial
pro-tective effects in rats, and a chelating agent (dithizon), used in the quantitative assay
for thallium, was 100% protective in rats which were given 30 mg/kg of thallium sul-fate subcutaneously, a dose that produced 100% lethality in controls. (An increase in
thallium excretion of 75% in the urine and
33%
in the feces resulted in animals treated with dithizon, compared to controls.)No significant increase in renal excretion
of thallium was noted in any of the patients given dithizon. This is of itself not
indica-tive of a lack of action, for cystine has been
found to exert very little protective action in acute poisoning even though urinary ex-cretion of thallium is increased 60%.12
Further, aurin tricarboxylic acid has been found to protect against beryllium poison-ing without increasing the excretion of
beryllium.20 The mechanism by which
dithi-zon exerts its protective effect is not known. It is not likely that chelation occurs in vivo, for in vitro a pH of 9 to 10 is necessary for
chelation of thallium.
The administration of dithizon is not without possible attendant dangers. One
author2l has reported a diabetogenic effect
with dithizon in rabbits, but other workers22 have not confirmed this in dogs. Jensen23
produced goiter in rats with dithizon. In all
patients treated, no increase in urinary sugar occurred, but the possibility of a
dia-betogenic effect should be guarded against by the concomitant administration of ade-quate glucose. Lund’s finding of synergy with thallium with excessive doses of
dithi-zon was confirmed in a single case. The condition of D.G. (Case 3) who received 40 mg/kg/day of dithizon deteriorated, but
again improved when the dose was de-creased to 20 mg/kg/day.
The principal toxic effects of thallium,
as mentioned previously, are on the central
nervous system, gastrointestinal tract and
the hair follicles. Severe damage to the
renal tubules may also occur. Other less certain sites of toxicity are the sympathetic nervous system and the endocrine glands.
usual amount given to produce epilation in
ring worm of the scalp. Yet doses ranging from 6 to 40 mg/kg may be fatal to
experi-mental animals. Gettler and Weiss5 estimate
the MLD for dogs as 12 to 15 mg/kg. This
probably corresponds well with the lethal
dose for humans. It has been pointed out
that as a child approaches puberty, he is
much more susceptible to thallium toxicity/
and doses that may be harmless in a
younger child may well be fatal to an
ado-lescent.
COMMENTS ON MANAGEMENT OF
PATIENTS IN PRESENT REPORT
Cases 1 and 2
The first two patients illustrate the
na-tural course of severe thallium poisoning.
Case 1 is the only one of three cases in this
series requiring a respirator that survived.
This is the only case of the entire series that
retains severe neurologic deficits. This could
be due to: a) massive thallium intoxication
(his urinary excretion of thallium was many
times higher than that of any other patient),
or b) anoxic cerebral damage suffered
dur-ing the long period of apnea and asystole. In neither of these two cases was the exact date of ingestion known. However, if one estimates that alopecia occurs
approxi-matelv 10 days after ingestion, it will be
noted that general and neurologic
improve-ment began in the fourth week. The
thal-hum excretion in Case 2 stabilized at a low
level (below 1 mg/24 hr) during the fifth
week after ingestion. It may be noted that
I4 found that experimentally
poi-soned rats had excreted most of the injected
metal by the end of the fourth week. Yet
it appears that in the natural history of
severe thallotoxicosis the actual period of
recuperation is likely to extend for a period
of some months.
No benefit is believed to have occurred
following any of the types of therapy given
these patients. The sodium iodide was given
Case 2 in a different hospital; however,
clinically, he subsequently seemed to get
worse. Edathamil apparently had no effect on these patients, either on their clinical
condition or on urinary excretion of thai-hum. In Case 2, it was felt that the patient improved following the first course of
ther-apy with sodium lactate, but it should be noted that the patient was actually getting better before this therapy was started.
Again, there was no significant effect of this substance on the urinary excretion of
thal-hum.
It is important to note that in these cases,
as well as the others that follow, there is no
correlation between urinary volume and renal excretion of thallium.
Cases 3, 4, and 5
The second group of three cases contrast with Cases 1 and 2, in that more specific
therapy was attempted. All had dithizon and
potassium chloride, and one had charcoal
soon after ingestion. Case 4 and Case 5 were not started on dithizon until 20 days
after ingestion, and Case 4 was actually
im-proving several days before this. The most remarkable thing about these two cases was
that they were clinically well within 30 days after ingestion, although they had been severely ill. Urinary thallium reached a low level during the fourth week.
Case 3 was critically ill. He had been
treated at another hospital with potassium chloride and charcoal within 3 days after ingestion. Dithizon was begun the day fol-lowing transfer to University of Texas Hos-pitals. Improvement was noted the next day and was fairly complete in 2% weeks. ThaI-hum excretion stabilized at a low level on
the seventeenth day, a fact which was per-haps related to the early administration of potassium chloride and charcoal. The course
of Case 3 is even more noteworthy since he is the only patient who had quantities of thallium in the urine approaching those of Case 1, and yet his course was exceedingly
brief for this disease. It may be added that the siblings who received the same therapy also responded well, and in fact became
asymptomatic by the time of discharge some
3 weeks after admission.
It is rather difficult to ascribe any effect
1180 THALLIUM POISONING
agent alone, because they all received drugs
in combination. It is possible to relate the
rapid disappearance of thallium in the urine in Case 3 to the early administration of
charcoal and potassium chloride. The
potas-sium chloride seemed to have caused a marked rise in the urinary excretion of thai-hum, and the charcoal would be expected
to cause a similar increase in fecal excretion,
though it was not possible to substantiate the
latter statement with laboratory evidence.
These preparations seem to exert their greatest effectiveness when given early.
Per-haps at this time the thallium is not yet so
firmly established in the cells. It must be emphasized, however, that in spite of in-creased excretion of thallium, the clinical condition of this patient was not improved until dithizon was given.
While dithizon apparently had no effect
on the excretion of thallium in these cases, it was the clinical opinion of those
observ-ing the cases that definite improvement did follow its addition to the therapeutic
regi-men, and that the course was shortened con-siderably. No adverse effects of dithizon
were noted.
Cases 6 and 7
The two patients who died showed
sev-eral interesting features. Case 7 developed severe damage to the renal tubules with
subsequent electrolyte disturbance that
could not be controlled. This probably was aggravated by the large amounts of fluids and glucose solution administered with norepinephrine and edathamil early in the
hospital course. Another pitfall in the
con-sideration of thallotoxicosis, illustrated by
this case, is the failure of the usual chemical analysis of the urine for heavy metals to
distinguish between lead and thallium.
Spectrophotometric analysis was necessary
to make this distinction.
Case 6 was the only patient in this group
who was seen immediately after thallium ingestion and who received gastric lavage promptly. It has already been noted that thallium is rapidly absorbed from the
gas-trointestinal tract and the skin, and it is
apparent that a large amount of it was ab-sorbed through the skin in this patient, as well as probably from the stomach. This emphasizes the necessity of washing the poison from the skin as a part of the
emer-gency procedure.
Case 6 was also unique in the degree of
vomiting, which eventually necessitated
giv-ing the dithizon intravenously. He was the only patient to receive the drug in this
manner. It was believed that his death was not related to the medication. However, comment should be made on the fact that Kadota’s21 rabbits receiving intravenous
di-thizon (at four to ten times this dosage)
de-veloped severe hypoglycemia about 12
hours after injection, and died in
convul-sions unless given large amounts of glucose. Case 6 had convulsions prior to the
ad-ministration of dithizon and they continued
during the rest of his course. The terminal event took place approximately 12 hours after the first dose of dithizon. It was thought that the immediate cause of death
was aspiration of vomitus, but no blood
specimen was obtained for glucose deter-mination, and a necropsy was not granted. The patient had received glucose intra-venously throughout the day of death.
Attention is directed to the effect of
potas-sium on the urinary excretion of thallium in
this case. While large amounts were ex-creted by the kidneys, it did not seem to
alter the over-all toxicity nor the clinical
course of the patient.
RECOMMENDED MANAGEMENT OF
THALLOTOXICOSIS
This regimen is offered only as a guide for management until the efficacy of dithi-zon, potassium chloride and activated
char-coal are better evaluated or until a more
specific agent is found.
Recent Ingestion, Without Symptoms
1. Gastric lavage.
2. Wash off any thallium-containing ma
ARTICLES
4. Potassium chloride, 3-5 gm daily orally, for 5 to 10 days.
5. Urine specimen (s) to be tested for
presence of thallium.
6. Careful observation for alopecia and/ or neurologic signs for at least 2 weeks.
Symptoms of Thallium Intoxication, with
History of Ingestion or Detection of
ThaI-hum in Urine
1. Gastric lavage, if there is any
pos-sibility of thallium remaining in the
stom-ach.
2. Potassium chloride, 3 to 5 gm daily. 3. Dithizon, 10 mg/kg twice daily, for at
least 5 days. The length of treatment may
be cautiously extended depending upon the
clinical status.
SUMMARY AND CONCLUSIONS
Fourteen children with thallium
poison-ing are described.
Alopecia and neurologic symptoms domi-nate the clinical picture. In the absence of
alopecia, the diagnosis depends upon a high degree of suspicion in regard to any child presenting bizarre neurologic complaints with acute onset.
The best means of confirming a diagnosis of thallotoxicosis is by finding thallium in
the urine.
Dithizon appeared to be beneficial treat-ment in five of six severely ill patients. Further cautious trials of this drug are
in-dicated.
On the basis of the few patients studied, it appears that increased urinary excretion of thallium is not correlated with urine
volume, clinical improvement or the use of dithizon.
REFERENCES
1. Felden, B. F. : Epilation with thallium ace-tate in the treatment of ringworm of the
scap in children. Arch. Dermat., 17:182,
1928.
2. Pozzi, S., and Courtade, A. : Note sur le
traitement de Ia syphilis par le thallium.
Gaz. med. Paris., 55:147, 1884.
3. Combemale: Lecture. Bull. Acad. med.,
39:208, 1898.
4. Munch,
J.
C. : Human thallotoxicosis. J.A.M.A., 102:1929, 1934.5. Gettler, A. 0., and Weiss, L. : Thallium
poisoning. III. Clinical toxicology of thallium. Am.
J.
Clin. Path., 13:422, 1943.6. Kellogg, E. S.: California Ground Squirrel
Control Program, Special Publication 109. Department of Agriculture, State of California, 1931.
7. Munch,
J.
C., Ginsburg, H. M., and Nixon, C. E. : The 1932 thallotoxicosis outbreak in California. J.A.M.A., 100:1315, 1933.8. Popenoe, C. H. : A new use for thallium
compounds (not original). Am.
J.
Pharm.,98:693, 1926.
9. Heyroth, F. F. : Thallium : a review and
summary of medical literature. Pub.
Health Rep., Suppl. 197. Washington, D.C., Supt. Documents, 1947.
10. Grulee, C. C., Jr., and Clark, E. H. : Thai-lotoxicosis in a pre-school nursery. Am.
J.
Dis. Child., 81:47, 1951.11. Bambach, K. : Estimation of traces of lead and thallium in pharmaceutical chem-icals. Indust. & Eng. Chem., Anal. Ed., 12:63, 1940.
12. Lund, A. : The effect of various substances
on the excretion and the toxicity of thal-hum in the rat. Acta pharmacol. et
toxicol., 12:260, 1956.
13. Buschke, A., and Peiser, B. : Die Wirkung des Thallium auf das Endokrine system. Klin. Wchnschr., 1:995, 1922.
14. Thyresson, N. : Experimental investigation
on thallium poisoning in the rat. Acta
dermat.-venereol., 31:3, 1951.
15. Seitz, A. : Experimentelle Thalliumvergif-tung. Kiln. Wchnschr., 9:157, 1930. 16. Barclay, R. K., Peacock, W. C., and
Karnof-sky, D. A. : Distribution and excretion of
radioactive thallium in the chick embryo,
rat and man.
J.
Pharmacol. & Exper.Therap., 107:178, 1953.
17. Lund, A. : Distribution of thallium in the
organism and its elimination. Acta
pharmacol. et toxicol., 12:251, 1956.
18. Flesch, P., and Goldstone, S. B. : Effect of thallium on sulfhydryl compounds in vitro.
J.
Invest. Dermat., 15:345, 1950. 19. Pastinszky, S., Simon, N., and Andrassy,K. : Die Wirkung von Dimercaptopropa-nol (BAL) auf die experimentelle
Thal-liumvergiftung. Acta dermat.-venereol.,
31:331, 1951.
20. White, M. R., and Schubert,
J.
: Studies onani-1182 THALLIUM POISONING
mals and on distribution of Be. Arch.
Biochem., 52:133, 1954.
21. Kadota, I. : Studies on experimental
dia-betes mellitus, as produced by organic
reagents.
J.
Lab. & Clin. Med., 35:568,1950.
22. Alcalde, V., Colas, A., Grande, F., and
Peg, V. : Ineficacia de la ditizona como agente diabet#{243}geno en el perro. Rev.
espafl. fisiol., 8:175, 1952.
23. Jensen, K. A. , and Kjerulf-Jensen, K.:
On the relation between goitrogenic
ef-feet and chemical constitution. Acta
pharmacol. et toxicol., 1 :280, 1945.
SUMMARIO IN INTERLINGUA
Invenenamento
Per
Thallium
Esseva studiate 14 casos de intoxication per
thallium in subjectos de etate pediatric. Omne le subjectos deveniva malade post ingestion de
un pesticida continente 3% de sulfato de
thallium. Omnes disveloppava alopecia. Le
10 qui esseva hospitalisate habeva significative
manifestationes del systema nervose central,
i.e. ataxia, debilitate, somnolentia, e tremor (in
9 casos); irritabilitate (in 7 casos); mal de
capite, coma, hyperreflexia (in 6 casos);
con-vulsiones (in 5 casos); e paresthesias, ptosis, e
paralyse respiratori (in 4 casos). Eveniva duo
mortes, e Un patiente supervive in un stato de
vegetation. Un exhibi un persistente tremor de
leve grados. Le resto es asymptomatic.
Le symptomas gastro-intestinal esseva pauco
conspicue. Solmente tres patientes habeva
crampos abdominal. Un episodio questionabile
de melena esseva describite pro un del duo
patientes con diarrhea.
Le diagnose depende, ante le disveloppa-mento de alopecia, del attention prestate al indicios que face suspicer le possibilitate de invenenamento per thallium, specialmente in
casos con bizarre disturbationes neurologic.
Sever injurias neurologic, un permanente deficit
neurologic, e mesmo morte pote resultar ante
que alopecia deveni evidente (usualmente 7 a 10 dies post le exposition). Alopecia in un patiente pediatric debe semper esser reguardate como indicio del possibilitate de thalhiotoxicosis. Imminentia de alopecia pote esser demonstrate per dulcemente tirar al capillatura pro vider
Si illo se distacha.
Identification de thaffium in le urina es le melior manovra diagnostic. Un technica pro
iste objectivo es describite. Quantitates usque
al minimo de 0,25 microgrammas pote esser
detegite. Le detection de non importa qual quantitate de thallium in le urina debe esser considerate como anormal, sed illo non es necessarimente aceompaniate de manifesta-tiones de intoxication. Le therapia es discutite. Ii pare que le uso de dithizona merita caute
