mr
y
January 1992
FINAL
DRINKING WATER CRITERIA DOCUMENT
FOR
THALLIUM
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
cvl
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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TABLE OF CONTENTS
. I.
II.
III.
IV.
V.
LIST OF TABLES .
FOREWORD
SUMMARY
PHYSICAL AND CHEMICAL PROPERTIES ...... . .
A. General Properties -.
B. Source, Production, and Use ....;....
C. Environmental Fate and Stability .....
D. Summary
TOXICOKINETICS .
A. Absorption
8. Distribution
C. Metabolism
D. Excretion
E. Bioaccumulation and Retention
F. Summary •;.... .
HUMAN EXPOSURE
HEALTH EFFECTS IN ANIMALS .
A. Short-term Exposure
. 1. Lethality
2. Other Effects '
B. Long-term Exposure ...
1. Subchronic Toxicity . .
2. Chronic Toxicity ......
C. Reproductive/Teratogenic Effects
D. Mutagenicity
1. Gene Mutation Assays (Category 1} ...
2. Chromosome Aberration Assays (Category 2) ....
3. Other Mutagenic Mechanisms (Category 3)
E. Carcinogenicity . . '
F. Summary . .
Page
V
vi
1-1
II-l
II-l
II-l
II-3
II-4
III-l
IIM
III-2
III-1C
111-10
111-14
111-14
IV-1
V-l
V-l
V-l
V-l
V-4
V-4
V-7
V-7
V-10
V-10
V-13
V-14
V-16
V-16
iii
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TABLE OF CONTENTS (cont.)
Page
VI. HEALTH EFFECTS IN HUMANS '. VI-1
A. Clinical Case Studies VI-1
B. Epidemiological Studies VI-10
C. High-Risk Populations VI-11
D. Summary , VI-11
VII. MECHANISMS OF TOXICITY VII-1
A. Effects on Ion Transport VII-1
B. Effects on Mitochondria VII-2
C. Effects on the Nervous System . .,.-.... VI1-3
1. In vivo Effects VII-3
2. In vitro Effects VII-4
D. Cytotoxicity VII-5
E. Effects on Cartilage Formation VII-6
F. Interactions VII-6
1. Interactions with Potassium ..... VII-6
2. Aversion to Saccharin VII-8
G. Summary VII-8
VIII. QUANTIFICATION OF TOXICOLOGICAL EFFECTS VII1-1
A. Procedures for Quantification of Toxicological
Effects VIII-1
1. Noncarcinogenic Effects VIII-1
2. Carcinogenic Effects VIII-4
B. Quantification of Noncarcinogenic Effects for
Thallium VIII-6
1. One-day Health Advisory VIII-6
2. Ten-day Health Advisory VIII-6
3. Longer-term Health Advisory VIII-6
4. Reference Dose and Drinking Water Equivalent
Level . . VIII-11
C. Quantification of Carcinogenic Effects for
Thallium VIII-13
1, Categorization of Carcinogenic Potential .... VIII-13
2. Quantitative Carcinogenic Risk Estimates .... VIII-14
D. Summary VIII-14
IX. REFERENCES . IX-1
iv
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LIST OF TABLES
Table No. Page
II-l Physical and Chemical Properties of Thallium and Some
Thallium Compounds II-2
III-l Intracellular and Tissue Distribution of Different
Thallium Species in Rats . III-3
III-2 Thallium Concentrations in Tissues of Pregnant Rats
and Fetuses at 72 Hours After Oral Dosing III-5
III-3 Tissue Distribution of Thallium in Rats Following
Intraperitoneal Doses of Thallous Sulfate ....... II1-8
III-4 Tissue Distribution of Thallium in Rats Administered
Thallium in Drinking Water Compared to Untreated
Controls III-ll
V-l Summary of Lethality Data on Thallium in Laboratory
Animals V-2
V-2 Genotoxicity of Thallium in Various Test Systems. . . . V-ll
VI-1 Case Studies Involving Thallium Poisoning VI-2
VIII-1 Summary of Candidate Studies for Derivation of the
Ten-day Health Advisory for Thallium VIII-7
VIII-2 Summary of Candidate Studies for Derivation of the
Longer-term Health Advisory for Thallium VIII-8
VIII-3 Summary of Quantification of Toxicological Effects
for Thallium VIII-15
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FOREWORD
<•
Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires the Administrator of the Environmental Protection Agency to publish
Maximum Contaminant Level Goals (MCLGs) and promulgate National Primary Drinking
Water Regulations for each contaminant, which, in the judgment of the
Administrator, may have an adverse effect on public health and which is known or
anticipated to occur in public water systems. The MCLG is nonenforceable and is
set at a level at which no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin of safety. Factors considered in
setting the MCLG include health effects data and sources of exposure other than
drinking water.
This document provides the health effects basis to be considered in
establishing the MCLG. To achieve this objective, data on'pharmacokinetics,
human exposure, acute and chronic toxicity to animals and humans, epidemiology,
and mechanisms of toxicity were evaluated. Specific emphasis- is placed on
literature data providing dose-response information. Thus, while the literature
search and evaluation performed in support of this document was comprehensive,
only the reports considered most pertinent in the derivation of the MCLG are
cited in the document. The comprehensive literature data base in support of this
document includes information published up to April 1987; however, more recent
data have been added during the review process and in response to public
comments.
When adequate health effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime) are included in this document. These values are not
used in setting the MCLG, but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
James R. Elder
Director
Office of Ground Water and Drinking Water
Tudor T. Davies
Director,
Office of Science of Technology!
vi
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I. SUMMARY
Thallium (T1) occurs in the environment in sulfides and selenides
containing various proportions of copper, silver,, arsenic, and lead. The main
valence states of thallium are +1 and +3. Trivalent thallium (e.g., T1(OH)2*)
will be the predominant species of ionic thallium in natural waters in
equilibrium with atmospheric oxygen. The common salts of TV1 are slightly to
moderately soluble in water. In 1984, no thallium was produced in the United
States; all consumers of thallium were supplied by imports. Thallium is
currently used in the manufacture of lenses and jewelry, in electrical and
electronic equipment, in mineralogy^ and in medicine as ^Tl for radioactive
myocardial imaging. Laboratory modeling of thallium transport indicates that
thallium will exchange among water, vegetation, and fish, but not with sand.
Levels of thallium in the range of 3.7 ng/L to 88.3 ?g/L have been reported in
natural waters.
It is estimated that the absorption of thallous nitrate from the
gastrointestinal (GI) tract of rats is 100% of the dose; absorption in dogs
and humans is at least 62 and .61%, respectively. Cutaneous absorption of
thallium has been documented but not quantified. Following absorption,
thallium is rapidly and unevenly distributed throughout the body in mammals.
The tissue distribution of thallium in rats has been found to be largely
independent of the valence state of the orally administered salt.
Furthermore, the intracellular distribution of thallium was found to be
largely the same regardless of whether TV1, TV3, or organometallic thallium
was administered orally to rats. After rats were administered a single oral
dose of thallium nitrate, the highest levels of.thallium were found in the
kidney, followed by the salivary glands, testes, muscle, bone, GI tract,
spleen, heart, liver, hair, skin, and brain. Following dietary administration
of thallium salts to rats, the highest levels of thallium were also found in
the kidneys, and the lowest levels were found in the brain. A slightly
different distribution was found after a single oral dose of "TINO, was
administered to a female human cancer patient. The highest levels of thallium
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were found in scalp hair, followed by the kidney, heart, and spleen; lower
levels were found in the nervous tissue.
Several studies indicate that the transplacental transfer of thallium in
mammals is rapid. Thallium has been found in fetal tissues within 30 minutes
after oral dosing of pregnant mice and rats. In these studies, fetal levels
rarely exceed 10% of those observed in maternal tissues, but fetal levels
amounting to 50% of maternal levels have been reported.
Studies have also been performed on the distribution of thallium after
intraperitoneal administration of thallium to mice and rats and intravenous
administration of thallium to humans. In mice, thallium was found to be
present in the epididymis and deferent ducts 24 hours after intraperitoneal
dosing. In rats dosed intraperitoneally with wTI-labeled thai!oussulfate,
the tissue distribution of thallium was largely independent of dose in the
range of 0.00021 to 10,256 »g Tl/kg. In humans, after intravenous dosing, the
volume of distribution of Tl was consistent with its migration into the intra-
cellular space.
No information was found on the form or speciation of valence states of
thallium in mammals. Based on similar intracellular and tissue distribution
of thallium in rats orally dosed with TV* and Tl** salts, it is suggested that
biochemical conversion of TV* and Tl1* into a single species occurs in vivo.
In rats, thallium is excreted primarily via the feces. The ratio of
fecal to urinary excretion of thallium has been found to vary from 2 to 5.
Thallium is excreted directly into the lumen of the intestinal tract, with
limited excretion occurring via the bile. In contrast to rais, Ihe ratio of
fecal to urinary excretion of thallium was greater than 30 in a human patient
dosed orally with thallous sulfate. The biological half-life of thallium in
rats has been reported to be 7.3 days in one study and 3.3 days in another
study. A mean whole-body half-life of 9.8 days has been reported in humans.
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The acute oral LOM of various thallium compounds in mice and rats
ranges from 16 to 46 mg Tl/kg.
Degenerative changes in mitochondria of the,kidneys, liver, brain,
intestines, and liver have been observed subsequent to subcutaneous or
intraperitoneal injections of thallium salts. Similarly, subacute toxicity
studies in rats revealed histopathological changes in the brain, kidney,
liver, and intestines. No studies of lifetime exposure to thallium compounds
were available.
Rats dosed by gavage with thallous sulfate at 0, 8.1, 40.5, or 202.4 tig
Tl/kg/day for 90 days exhibited moderate but significant elevations in serum
enzymatic (SCOT and LDH) activities and elevations in serum sodium and
calcium; however, no histopathological effects were reported. In the absence
of histopathology, this study provides a No-Observed-Adverse-Effect Level
(NOAEL) of 0.2 mg Tl/kg/day. No Lowest-Observed-Adverse-Effect Level (LOAEL)
is defined by this study. .
Administration of thallous acetate to rats in the diet for up to 15
weeks provided a LOAEL of 1.2 mg Tl/kg/day and a NOAEL of 0.4 mg Tl/kg/day,
based on the appearance of alopecia in the rats after 2 weeks on the diet. No
histopathological changes were found at the time of sacrifice. Administration
of thallium sulfate at levels of approximately 1.4 mg Tl/kg body weight
(bwj/day in the drinking water for up to 36 weeks produced abnormal electro-
physiological parameters and histopathological findings in nervous tissue.
Subcutaneous administration of thallous acetate (at an initial dose of
7.8 to 15.5 mg Tl/kg, followed by weekly doses of 3.S mg Tl/kg) for up to 24
weeks produced histological changes in the kidney, brain, and liver of rats.
In a 60-day reproduction study, rats exposed to thallium sulfate in the
drinking water at 740 *g Tl/ kg/day exhibited adverse effects in sperm cell
maturation and motility, and alterations in Sertoli cells and in the
epithelium of the seminiferous tubules.
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Several studies Indicate that thallium, salts are .teratogenic In mammals.
However, teratogenic doses are close to doses causing maternal toxicity. A
teratology study In mice dosed, by gavage, with thallous chloride at levels of
2.6 and 5.1 mg Tl/kg/day on days 6 through 15 of gestation provided a NOAEL
for developmental toxicity of 2.6 mg Tl/kg/day and a LOAEI/of 5.1 mg Tl/kg,
based on post1mplantat1on losses. In a parallel group of mice dosed with
thallous acetate at levels of 2.3 and 4.7 mg Tl/kg/day, teratogenic effects
were observed at both dose levels.
In pregnant rats orally administered thallous acetate -or chloride at
levels of 3, 4.5, or 6 mg thallium salt/kg/day (2.6, 3.8, and 5.1 mg
Tl/kg/day) on days 6,to 15 of gestation, all of the dams died at the two
higher doses. Significant incidences of wavy ribs and dumbbell-shaped
sternebrae were noted for both salts at the lower dose. Teratogenic effects
were observed at both dose levels in pregnant rats intraperitoneally
administered thallous sulfate at 2.0 or 8.1 mg Tl/kg/day on days 12 through 14
of gestation. -
Intraperitoneal administration of thallous sulfate to 6- and 9-day-old
rat pups at doses of 16 and 32 mg Tl/kg/day produced adverse effects on
calcification and hyppplastic cartilage. An unspecified thallium salt at
levels of 3 to 100 jig/ml produced dose-related growth retardation in 10.5-day-
old rat embryos in culture.
Some thallium salts have been found to be clastogenic in both rat
somatic and germinal cells, to damage bacterial and rodent DNA, and to enhance
IQ vitro viral transformation of hamster cells. Thallium compounds have not
been evaluated In gene mutation assays suitable for the detection of metal
mutagens.
No studies on the carcinogenic potential of thallium were found.
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Numerous reports were found on the effects of thallium ingestion In
humans. Neurologic symptoms may range from mild peripheral neuropathy to
irreversible coma and death. It is suggested that cardiac and pulmonary
distress may dominate the acute phase of toxicity. The minimal lethal dose of
thallium has been estimated to be 0.2 to 1.0 g (2.9 to 14.2 mg/kg for a 70-kg
adult) in humans.
The mechanism of thallium toxicity has not been elucidated, in vitro
studies indicate that the thallous ion may replace 1C in activation of the •
(Na*-IC)-dependent ATPase of rabbit kidney and rat erythrocytes. Likewise,
uptake of thallium into rat erythrocytes is inhibited by 1C, .and thallous ion
may stimulate Na* efflux and inhibit 1C influx into human erythrocytes.
Similarly, interactions between 1C and TV have been reported In vivo
and in organ culture. It was observed in rats that the LD$0 for thallous
nitrate increased with an increase of 1C levels in the diet. In rats and
dogs, the urinary excretion of thallium increased with an increase in K*
intake. Furthermore, Infusion of K* increased the renal clearance and.
mobilization of thallium from tissues. In in vitro studies of mammalian limb
development, it was observed that thallium-induced teratogenesis was affected
by the ratio of Tr/fC in the medium.
In vitro studies with mitochondria indicate that thallium may interfere
with potassium movement across the mitochondria! membrane and may also
uncouple oxidative phosphorylation, thus interfering with energy metabolism in
the mitochondria. Furthermore, thallium may bind to mitochondria! proteins
and is known to produce degenerative changes in mitochondria and other
.organelles.
*, '• *
Several in vivo and In vitro studies indicate that thallium may produce
disturbances at the presynaptic level of nerve impulse transmission and ultra-
structural damage of neurons. Cytotoxic effects of thallium include the
production of decreased cloning efficiency of Chinese hamster ovary (CHO)
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cells in culture, and a decrease 1n the mitotlc rate of hair follicle cells
after subcutaneous dosing in rats.
No suitable data are available for calculating the One-day or Ten-day
Health Advisory (HA) values. Using a NOAEl of 0.2 mg Tl/kg/day based on the
absence of histopathological effects in rats dosed orally in a 90-day study,
Longer-term HAs of 7.0 and 20.0 *g Tl/L were calculated for a 10-kg child and
a 70-kg adult, respectively. It is recommended that the Longer-term HA for a
10-kg child be used as a conservative estimate of the One-day and Ten-day HAs
for a 10-kg child. Using a NOAEL of 0.2 mg Tl/kg/day based on the absence of
histopathological effects in rats dosed orally in a 90-day study, a Reference
Dose (RfD) of 0.07 Mg Tl/kg/day and a Drinking Water Equivalent Level (DWEL)
of 2.0 »g Tl/L were calculated. No estimations of excess cancer risk were
performed.
., Thallium salts are^designated as a hazardous substance under Section
311(b)(2)(A) of the Federal Hater Pollution Control Act and further regulated
by the Clean Water Act Amendments of 1977 and 1978. These regulations apply
to discharges of these substances.
The reportable quantity of thallium salts, when discharged into or upon
the navigable waters and adjoining shorelines of the United States, is 1,000
pounds (454 kg}.
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II. PHYSICAL AND CHEMICAL PROPERTIES
A. GENERAL PROPERTIES
Thallium, a bluish-white heavy metal with an atomic number of 81 and
atomic weight of 204.383, is very soft, Inelastic, and.easily fusible
(Windholz, 1983; Clayton and Clayton, 1981). It forms alloys with other
metals and readily amalgamates with mercury. Thallium metal is insoluble in
water and is soluble in HNO, and H,S04 (Uindholz, 1983). The main valence
states of thallium are +1 and +3. A valence state of +2 is known but is rare
and very unstable (Cotton and Wilkinson, 1980). Trivalent thallium (e.g.,
T1(OH)2*) will be the predominant Ionic species of thallium in both seawater
and freshwater in equilibrium with atmospheric oxygen (Batley and Florence,
1975). Thallium metal is very reactive, but is slower in bulk reactions
because of the formation of coatings of T120 over the surface. When heated to
decomposition, toxic fumes of thallium are emitted. Table II-l summarizes the
physical and chemical properties of thallium and some Tl compounds.
B. SOURCE, PRODUCTION, AND USE
It is estimated that thallium constitutes 0.003% (0.7 ppm) of the
Earth's crust. Thallium is found to occur mainly in the rare minerals
.crookesite (TlCuAg)2Se, orabite (TlAs2SbS$), lorandite (TlAsS,), and
hutchinsonite (TlAgCu)jS.AsaS, + PbS.As2S3). It is also found in pyrites and is
recovered from the roasting ore in sulfuric acid production (Weast, 1986;
Clayton and Clayton, 1981). Lorandite found in gold ore is approximately eox^
thallium. On the ocean floor, magnesium nodules contain some elemental
thallium. Although thallium is widely distributed, it is not plentiful. Even
deposits of main thallium minerals are so small that, at present, they have no
commercial significance (Clayton and Clayton, 1981). The main emissions from
commercial sources are flue dusts from pyrites (FeS2), lead and zinc smelters,
or refineries as a result of cadmium production (Clayton and Clayton, 1981).
II-l
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Table II-l. Physical and Chemical Properties of Thallium and Some Thallium
Compounds
Chemical
Synonym
Melting
Molecular point
Might CO
Boiling
point
CO
Solubility
Thallium
Thallium
acetate
Thallium
azide
Thallium
bromide
Thallium
carbonate
Thallium
chloride
Thallium
ni trate
Thailie
oxide
Thallium
sulfate
Dimethyl
thallium
bromi de
Ramor
Thallous
acetate
204.383 303.5
263.42 131
246.39 330(vac)
Thallous 284.28 approx.
bromide 460
Thallous 468.75 273
carbonate
Thallium
mono-
chloride
Thallous
nitrate
(alpha)
239.82
430
266.40
Thallium 456.78
sesquloxlde
Eccothal. 504.85
thallous
sulfate
314.34
206
717
632
1457*10 Insoluble In hot or cold
water; soluble In HNO, and
H,SO,; slightly soluble in
htl.
Very soluble in water at
20*C; Insoluble in
acetone.
Insoluble in alcohol and
ether; very soluble in
not water; slightly
soluble In cold water.
815 Soluble In water 0.5 g/L
(2S'O and 2.5 g/L
(68*0; soluble in
alcohol; insoluble in HBr
and acetone.
Soluble 1n water 40.3 g/L
(15*O and 272.0 g/L
(lOQ'C): insoluble in
alcohol, ether, and
acetone.
720 Soluble in water 2.9 g/L
(15.6'C) and 24.1 g/L
(99.35*0: insoluble In
alcohol and acetone;
(alpha) decomposes in
acid.
430 Soluble in water 9.6 g/L
(20*C) and 4.1 g/L
(100'C); insoluble in
alcohol; soluble in
acetone.
Insoluble 1n water.
Decomposed by HC1 and
H,S04.
Decom- Soluble in water 48.0 g/L
poses (20*C) and 191.4 g/L
(100*O; insoluble in
alcohol, ether, and
acetone.
SOURCE: Adapted from Sax (1984); Clayton and Clayton (1981); Weast (1986); Windholz (1983).
' 11-2
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Use of thallium as a sulfate in rodent poison has been banned in the
United States since 1972. U.S. production was curtailed to a very small
amount in 1974. Although thallium production was banned, extractable U.S.
reserves in lead, iron, and zinc ores totaled 266 tons in 1974. U.S. imports
account for 1,500 pounds of thallium compounds (Clayton and Clayton, 1981).
In 1984, the United Stated reported no thallium production; all consumer
demand for thallium was supplied by imports (HSOB, 1987).
Thallium rodenticide poisonings have been reported in other countries,
such as Spain, Denmark, Great Britain, and India. During World War II, the
properties of the bromoiodide crystals in thallium, which transmit radiation
of very long wavelengths, were found to be of value in detection and signaling
equipment where visible radiation must be absent (Clayton and Clayton, 1981).
In addition, because of its high refractive index, thallium is incorporated
into the production of optical lenses and imitation precious jewelry.
Thallium can also be alloyed with mercury in switches and closures that
operate at subzero temperatures (Windholz, 1983; Arena, 1979). Other
scientific and technological applications of thallium are seen in ionizing
radiation counters; semiconductors (photoresistors, photocells, vidicons); and
gas discharge and luminiscent tubes. Thallium formyl malonate (Clerici fluid)
is used in mineralogical analyses and in geological and mineralogical research
with rocks and ores (Shabalina and Spiridonova, 1979). Thallium-201 is
currently finding widespread medical application in myocardial imaging,
although thallium ointments are no longer used in medicine because of their
extreme toxicity (Clayton and Clayton, 1981). Currently, thallium is finding
application in experimental high-temperature superconductors (Waldrop, 1988).
C. ENVIRONMENTAL FATE AND STABILITY
Wallwork-Barber et al. (1985) studied the transport of thallium in a
laboratory ecosystem consisting of water, sand, vegetation, and fish. A 7-
liter glass aquarium was filled with 1 inch of sterilized and washed sea sand
and 6 liters of distilled water. Goldfish and the submergent aquatic
angiosperms Valliapenia and Ceratophyilum were then added. Tracer levels of
II-3
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'"Tl plus thallous nitrate were added to a concentration of 100 ng TI/mL.
Transport of thallium among the four components of the ecosystem was measured
for 220 hours. Exchange of thallium was observed among water, vegetation, and
fish. Transport between sand and the other community components was not
observed. The concentration of thallium 1n water decreased from the Initial
value of 100 ng TI/mL to a final value of approximately 60 ng TI/mL. Final
concentrations of thallium 1n sand, fish, and vegetation were on the order of
50, 1,750, and 1,450 ng Tl/g, respectively. Deficiencies of this study
included the short duration, which did not allow for development of algae,
plankton, and excretion buildup in the sand that would have permitted more
thallium accumulation. ~ •
Several authors have studied thallium levels in natural waters. Batley
and Florence (1975) reported mean thallium levels of 13.0 ng/L for Pacific
Ocean surface waters off the coast of Australia and 3.7 ng/L for freshwater
samples from Woronora Weir (Australia). These authors concluded that
trivalent thallium is the predominant valence species of thallium in both
seawater and freshwater in equilibrium with atmospheric oxygen. Matthews and
Riley (1969) reported mean thallium levels of 10.1 and 18.7 ng/L for water
samples from the Bay of Biscay (Spain) and the Irish Sea, respectively. Zitko
(1975) reported thallium levels In the range of 2.5 to 88.3 *g/L in water
samples from three rivers draining a base-metal mining area in New Brunswick,
Canada.
D. SUMMARY
Thallium occurs in the environment in sulfides or selenides containing
various proportions of copper, silver, arsenic, and lead. The main valence
states of thallium are +1 and +3. A valence state of +2 is known but is less
stable and rare. Trivalent thallium (e.g., Tl(OH),*) will be the predominant
valence state of ionic thallium in natural waters in equilibrium with
atmospheric oxygen. Solubility of some thallous salts in water ranges from
0.5 g/L to 48 g/L at temperatures of 15 to 258C. In 1984, there was no
reported U.S. production of thallium; all consumers were supplied by imports.
II-4
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Thallium is currently used 1n the manufacture of lenses and jewelry, in
electrical and electronic equipment, in mineralogy, and in medicine for
myocardial imaging as its radioactive "71 isotope. Use of thallium as a
rodenticide in the United States was discontinued in 1972. A study in a model
ecosystem consisting of water, sand, vegetation, and fish indicated that
thallium exchanged among water, vegetation, and fish but not between sand and
other community components. Levels of thallium in the range of 3.7 ng/L to
88.3 f.g/1 have been reported in natural waters.
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III. TOXICOKINETICS
A. ABSORPTION
Thallium is readily absorbed following oral and dermal administration of
soluble thallium salts. Ziskoven et al. (1983) detected thallium in maternal
kidney and brain and in fetuses of pregnant Wistar rats and Kissleg mice by 10
minutes after the animals were administered thallous sulfate orally at a dose
level of 8 mg Tl/kg.
Lie et al. (1960) administered "71, as thallous nitrate, to male Wistar-
derived rats by six routes: oral (767 *g Tl/kg), intravenous (38 »g Tl/kg),
intramuscular (96 »g Tl/kg), subcutaneous (96 »g Tl/kg), intratracheal (123 *g
Tl/kg), and intraperitoneal (146 Mg Tl/kg). The body burden of "71, as
percent of dose, was similar for all routes of exposure and was found to decay
with a single exponential function, which extrapolated to 100% at zero time,
regardless of route of administration. On this basis, the author concluded
that thallium is completely absorbed from the gastrointestinal (SI) tract.
Shaw (1933) administered a single oral dose of thallium sulfate (25 rng
Tl/kg) to one dog. At least 61.6% of the dose was absorbed from the GI tract,
as measured by recovery of thallium in urine after 36 days.
Thallium can be absorbed through the skin as evidenced by the toxicity
of topically applied thallium ointments. Munch (1933) reviewed 51 case
histories of women treated for thallium poisoning following external
application of an ointment containing thallous acetate at a concentration of 3
to 8%. In 29 cases, between 2 and 24 ounces of the ointment (approximately 53
to 636 mg Tl/kg for a 5.5% ointment and a 50-kg woman) had been applied an
unspecified number of times. By several weeks after application, neurological
and gastrointestinal symptoms and alopecia were observed.
IIM
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Hallopeau (1898, as cited in Heyroth, 1947) reported that guinea pigs
died without any loss of hair within 48 hours after a cutaneous application of
an ointment containing 50% of an unspecified thallium salt.
B. DISTRIBUTION
Lie et al. (1960) studied the tissue distribution of thallium in male
Wistar rats. Some animals were dosed with **T1, as thallium nitrate., by the
oral route (767 Mg Tl/kg) and by five other routes as indicated above. In
orally dosed animals, over the first 7 days, the highest levels of thallium
per gram of tissue were found in kidney (4.71% of the body burden per gram of
tissue), followed in decreasing order by salivary glands (1.08%), testes
(0.88%), muscle (0.79%), bone (0.74%), GI tract (0.62%), spleen (0.56%), heart
(0.54%), liver (0.52%), respiratory system (0.49%), hair (0.37%), skin
(0.37%), and brain (0.27%). For all routes of administration, the half-life
for thallium was 3.3 days. Except for hair, which accounted for 60% of the
body burden after 21 days, the relative concentrations of thallium in tissues
were largely independent of time.
Downs et al. (1960) studied the tissue distribution of thallium in
Wistar rats of unspecified sex. The animals were fed a diet containing
thallous acetate at a concentration of 0.003% (approximately 1.4 mg Tl/kg body
weight/day, assuming 15 g of diet/day and a body weight of 250 g). After 63
days on the diet, the highest levels of thallium were found in kidney (24 Mg
Tl/g wet tissue), followed by liver, bone, spleen, lung, and brain. Levels in
these other tissues decreased from 16 »g Tl/g wet tissue in liver to 5 *g Tl/g
wet tissue in brain.
Sabbioni et al. (1980) studied the intracellular and tissue distribution
of different thallium compounds in rats. Male Sprague-Dawley rats were dosed
orally with 3.15 mg Tl/rat (approximately 16.2 mg Tl/kg) as M1Tl-labeled
dimethyl thallium bromide, thallous sulfate, or an unspecified salt of
trivalent thallium. Tissues were removed 16 hours after dosing and assayed
for radioactivity. As summarized in Table III-l, monovalent and trivalent
thallium have similar intracellular and tissue distributions. Highest values
III-2
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Table III-l. Intracellular and Tissue Distribution of Different Thallium
Species in Rats*
Organ or
cell fraction TV TT Dimethyl -Tl
Average thallium content in tissues
Organ _ fas 'percent of
Kidneys 6.80 6.10 0.56
Liver 3.80 2.90 0.12
Testes 3.70 3.90 0.07
Salivary glands 1.21 1.32 0.02
Heart 0.65 0.51 0.06
Brain 0.57 0.75 0.02
Subcellular Average thallium content in subcellular
fraction from fractions from kidney (as percent of
kldnev _ total kidney homooenatel _
Nuclei . 26.1 26.5 • 23.2
Mitochondria 9.7 10.8 10.6
Lysosomes 14.6 18.5 15.6
Microsomes 9.0 . ' 8.1 8.4
Cytosol 40.6 36.1 42.2
•Rats were sacrificed 16 hours after oral administration of 3.15 mg Tl/rat
(approximately 16.2 mg Tl/kg) as W1T1-labeled inorganic TV* or Tr* ions, or
dimethyl thai Hum bromide.
SOURCE: Adapted from Sabbioni et al. (1980).
III-3
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were found In kidney for all forms of thallium. As shown in Table III-l,
levels of thallium in tissues from the organometallie compound dimethyl
thallium bromide were much lower than those observed for the inorganic salts.
The intracellular distribution of thallium was similar for all three thallium
species.
Sabbioni et al. (1982) reported transplacental transfer of thallium in
pregnant rats dosed orally and intraperitoneally with thallium salts. In one
series of experiments, COBS rats were injected Intraperitoneally with thallous
sulfate (2 *g Tl/rat) plus 50 »Ci of "*T1 (specific activity not specified),
as the sulfate salt (approximate dose, 10 *g Tl/kg for a .body weight of 200 g)
on day 13 of pregnancy. By 4 hours postdosing, *°Tl was detected in the
placenta (0.23% of the dose/g of tissue) and in the fetal liver and brain
(0.07 and 0.04% of the dose/g of tissue, respectively). Maternal levels of
thallium in the liver and brain amounted to 0.37 and 0.05% of the dpse/g of
tissue, respectively. In a parallel series of experiments, pregnant rats were
administered, on day 17 of gestation, thallium sulfate, by gavage, at a dose
level of 10 mg Tl/kg. As summarized in.Table III-2, by 72 hours postdosing
fetal levels of thallium in liver and brain were approximately half those
observed in the corresponding maternal organs.
Ziskoven et al. (1983) observed rapid distribution of thallium into
maternal brain and kidney and fetal portions of the uterus in rats and mice.
Pregnant Kiss!egg mice and Wistar rats were administered an oral dose of
thallous sulfate (8 mg Tl/kg) on days 10 and 9 of gestation, respectively.
Thallium levels in tissues were assayed starting at 10 minutes after dosing in
rats, and at 30 minutes after dosing in mice. Thallium content of tissues was
not explicitly specified. Instead, tissue levels were glvsn in relative
units. Rapid absorption and distribution of thallium were indicated by its
presence in maternal brain and kidney and in fetal tissue at the start of
sampling in both species. Maximum levels of thallium were found in fetal
tissue at 1 hour in rats and at 4 hours in mice. These values were
approximately tenfold lower than levels found in maternal kidney. Thallium
III-4
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Table III-2. Thallium Concentrations in Tissues of Pregnant Rats and Fetuses
at 72 Hours After Oral Dosing"
Average thallium
concentrations
Tissue (Mg T1/g of tissue)
Pregnant rats
Kidney 60.2
Liver . 18.5
Salivary glands 10.6
Brain ' 18.4
Small intestine6 57.8
Blood 2.0
fetuses
Live , 8.9
Brain 10.1
Whole fetus 29.0
Amniotic fluid 0.9
Placenta 18.2
"Pregnant rats were administered thallous sulfate (10 mg Tl/kg) by gavage.
"Intestinal wall plus contents.
SOURCE: Adapted from Sabbioni et al. (1982).
III-5
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levels in maternal brain and kidney of rats were not different from those in
the respective organs in mice.
Barclay et al. (1953) studied the tissue distribution of 204T1 in a female
cancer patient weighing 45.4 kg and orally administered 1.8 ?g of Tl N03
(approximately 4 ng Tl/kg). Starting at an unspecified time after the
radioactive dose was administered, the patient received an oral dose of 45 mg
thallium sulfate (approximately 36 mg Tl/kg) every 3 days for a total of five
doses. Peak levels of thallium observed in blood 2 hours after radioactive
dosing amounted to approximately 3% of the administered dose. At 48 hours
postdosing, blood radioactivity amounted to approximately 1.5% of the dose.
Following the death of the patient 24 days after the initial "*T1 dose,
analysis of tissue radioactivity indicated that thallium was widely and
unevenly distributed throughout the organs. It was estimated that
radioactivity in tissues amounted to 45% of the dose. Levels of thallium in
tissues were represented on a relative scale, as percent per gram of the
average body distribution per gram (i.e., the total body radioactivity at
death/weight of patient in grams). Highest tissue levels were found in scalp
hair (420% per gram), followed by renal papilla (354%), renal cortex (268%),
heart (236%), and spleen (200%). Intermediate levels were found in adrenal
medulla (157%), pancreas (129%), liver (125%), rib marrow (124%), and adrenal
cortex (109%). Lower values were found in nervous tissue (70 to 13%), ovary
and capsule (54%), and abdominal subcutaneous fat (6.7%).
A series of intraperitoneal and intravenous studies indicate extensive
tissue distribution and transplacental transfer of thallium. Andre et al.
(I960) studied the distribution of thallium in 10 adult white mice dosed
intraperitoneally with "*nf as thallous sulfate, at a level .of 5 mg/kg (4 mg
Tl/kg). Autoradiographic examination of thallium distribution was performed
at various times, up to 28 days after dosing. At 1 hour after dosing, there
was a heavy accumulation of radioactivity in bone tissue. High concentrations
were also noted in the kidney (particularly in the medulla), in the pancreas,
and in the large intestine. In animals sacrificed more than 24 hours after
injection, the epididymal and deferent ducts showed a high accumulation of
III-6
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radioactivity. At this time, radioactivity was also found in the gastric and
intestinal mucosa, and in the pancreas and salivary glands. Signs of thallium
excretion were seen in the mucosa of the stomach and small intestine. In
animals sacrificed 10 days or more after dosing, concentrations of thallium in
the renal medulla and epididymis were still high, and concentrations in bone
had decreased. Concentrations of thallium in the central nervous system (CNS)
were somewhat higher than in the liver, and a high concentration of thallium
could be seen in hair. At 28 days after dosing, thallium was still detectable
in the renal medulla. Blood levels of thallium were low at the outset and
undetectable after several days.
Sabbioni et al. (1980) examined the effect of dose level on the
distribution of thallium in rat tissues. Sprague-Dawley male rats were dosed
intraperitoneally with ""TV-labeled thallous sulfate at levels of 0.00004, 2,
20, or 2,000 »g Tl/rat (approximately 0.00021, 10.3, 102.6, or 10,256 »g
Tl/kg, respectively). As shown in Table III-3, negligible differences in the
distribution pattern of "71 were found in the tissue distribution of thallium
by 16 hours after dosing, regardless of the wide range of doses employed.
01 sen and Jonsen (1982) administered "71 as thallium sulfate (50 *Ci, of
unstated specific activity) to NMRI/BOM albino mice via the intraperitoneal
route on day 15 of pregnancy. Using autoradiographic techniques, thallium
could be seen within the fetuses by 15 minutes after dosing. Maximum fetal
levels of thallium were seen at 2 to 4 hours after injection and decreased
thereafter. In parallel, unspecified experiments at the same dose level,
transplacental transfer was detected in mice injected on days 5 to 16 of
pregnancy.
Rade et al. (1982) administered to pregnant rats an intraperitoneal dose
of thallous sulfate (2 *g/rat) plus 50 uCi of carrier-free Z01»2«n, salt
unspecified, on day 13 of pregnancy. Peak thallium levels were reached at 4
hours after dosing in most maternal tissues (except for brain and muscle), in
placenta, and in whole fetuses. At this time, mean thallium levels in fetal
liver and brain amounted to 0.07 and 0.04% of the dose/g of wet tissue,
III-7
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Table III-3.
Tissue Distribution of Thallium in Rats Following
Intraperitoneal Doses of Thallous Sulfate*
Average thallium content in tissues fas percent of dose. «o Tl/ko)
Tissue 0.00021 10.3 102.6 10,256
Kidneys
Liver
Testes
Lung
Heart
Muscle"
Brain
Blood"
4.65
1.70 *
1.10
0.20
0.20
28.35
0.23
0.34
5.65
2.16
1.22
0.20
0.28
27.54
0.23
0.34
5.10
2.60
1.70
0.26
0.20
33.21
0,31
0.34
4.90
2.80
1:30
0.40
0.47
40.98
0.27
0.51
•Male Sprague-Dawley rats were dosed intraperitoneally with MTI-labeled
thallous sulfate at levels of 0.00004, 2, 20, or 2,000 »g Tl/rat
(approximately 0.00021, 10.3, 102.6, or 10,256 »g Tl/kg, for body weights in
the range 190 to 200 g). Animals were sacrificed at 16 hours after dosing.
"Body mass was estimated to be 30% weight.
'Calculated for blood volume of 63 ml/kg.
SOURCE: Adapted from Sabbioni et al. (1980).
III-8
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respectively. Maximum levels of thallium in maternal brain were observed at
24 hours after dosing and amounted to 0.090% of the dose. Total body burden
of thallium was found to decay with an average half-life of 64.2 hours (2.7
days). An unspecified half-life, but of the same magnitude as above, was
reported for thallium in the placenta and in the whole fetus.
Gibson and Becker (1970) studied levels of thallium in maternal and
fetal blood of pregnant rats. Pregnant Sprague-Dawley rats were infused
continuously on day 20 of gestation with "Tl, as thallous sulfate, at du»ca
of 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/min/kg. These infusion rates
correspond to 0.16, 0.32, 0.64, 1.3, 2.6, and 5.2 mg Tl/min/kg. Thirty-two
minutes after the initiation of infusion, maternal blood levels of thallium
were approximately 15 times higher than fetal blood levels, on a weight basis,
at the lowest dose, and approximately 30 times higher at the highest dose
(e.g., approximately 450 nmol/ml and 15 to 16 nmol/g in maternal and fetal
blood, respectively).
Talas et al. (1983) studied the pharmacokinetics of thallium in humans.
Each of five female and five male patients was administered intravenously a
tracer dose of M1T1, as thallium chloride (less than or equal to 106 and 130
ng/kg for male and female patients, respectively). Levels of radioactivity
were serially assayed in plasma for up to 1 day after dosing, and the data
were analyzed in terms of a two-compartment model. For the central
compartment, the distribution volume was found to be 0.26 L/kg, which is
similar to the adult's extracellular volume of about 0.2 L/kg. Distribution
into the peripheral compartment was very fast (t1rt - 3.9 min). The total
volume of distribution was found to be 4.23 L/kg, which is much larger than
the average total body water volume in humans (0.6 L/kg). This large observed
total volume of distribution is consistent with a migration of thallium into
the intracellular space. The average terminal half-life of thallium was
determined to be 2.15 days.
The distribution of thallium administered via drinking water has been
studied in two subchronic studies. Manzo et al. (1983) studied the effects
III-9
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of thallium sulfate in the drinking water at 10 ing T1/L for 36 weeks
(approximately 1.4 mg Tl/kg bw/day, assuming a weight of 200 g). Compared to
untreated controls, thallium was found to accumulate most in the kidney,
followed by the heart, brain, bone, skin, and blood (see Table 111-4}.
Formigli et al. (1986) studied the effects of thallium on the testes.
Hale Wistar rats were administered 10 ppm thailous sulfate in drinking water
(approximately 740 »g Tl/kg bw/day, based on a reported consumption of 270 Mg
Tl/rat weighing in the range of 0.35 to 0.38 kg). After 60 days' treatment,
6.3 j*g Tl/g tissue was found in the testes of treated rats compared with less
than 0.08 «g Tl/g tissue in untreated controls.
D. METABOLISM
No information was found on the form and speciation of valence states of
thallium in mammals. Based on the observation that oral dosing with TV* and
Tla* salts (Table III-l) produces a similar intracellular and tissue
distribution of thallium in rats, Sabbioni et al. (1980) suggested a
biochemical conversion of TV* and Tl3* into a single chemical species.
0. EXCRETION
Lehmann and Favari (1985) studied the excretion of thallium in female
Wistar rats. The animals were administered thailous sulfate by gavage at a
dose of 12.35 mg/kg (approximately 10 mg Tl/kg). By day 8 postdosing, 32% of
the dose was eliminated in feces and 21% in urine. Based on excretion data,
the authors estimated that residual thallium in the test animals decreased
with a half-life of 7.3 days.
Lie et al. (1960) reported that in Wistar rats dosed orally with 204T1 as
thallous nitrate (767 nq Tl/kg), the ratio of fecal to urinary excretion of
thallium increased from about 2 to 5 between days 2 and 16 after dosing, and
decreased thereafter to about 3 by day 20. The ratios of fecal to urinary
excretion were similar, regardless of whether dosing was oral, intravenous,
111-10
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Table III-4. Tissue Distribution of Thallium 1n Rats Administered Thallium
In Drinking Water Compared to Untreated Controls
Tissue
Kidney
Heart
Skin
Bone
Brain
Blood
Tl-treated rats
(*9 Tl/g tissue)
17.15 ± 1.23
6.89 ± 0.60
2.57 ± 0.22
7.71 ± 0.88
6.11 ± 1.03
0.67 ± 0.08
Untreated rats
Tl/g tissue)
0.038 ± 0.011
0.070 ± 0.010
0.040 ± 0.013
0.119 ± 0.023
0.088 ± 0.011
0.045 ± 0.006
Ratio
451
98
63
65
69
15
III-ll
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Intraperitoneal, Intravenous, or intramuscular. The biological half-life of
thallium was determined to be 3.3 days. By 21 days, residual radioactivity in
tissues amounted to 1% of the dose.
Shaw (1933) administered a single oral dose of thallous sulfate (25 mg
Tl/kgj to one dog. Excretion of thallium in urine amounted to 32 and 61.6% of
the dose at 3 and 36 days after dosing, respectively. No data for excretion
in feces were given.
Barclay et al. (1953) studied the excretion of thallium in a female
patient with osteogenic sarcoma. The patient was dosed orally as described
above (see Distribution). In 5.5 days, the patient had excreted 15.3% of the
radioactive dose in urine, and in 3 days only 0.4% in the feces. It was found
that 3.2% of the amount of thallium in the body was excreted per day. Based
on the daily excretion of thallium, it was calculated that at the time of
death, 24 days after dosing, radioactivity in tissues amounted to 45% of the
administered dose.
Other studies using the intravenous, Intraperitoneal, or subcutaneous
routes indicate that the thallium is excreted into the intestinal tract of
rats, with little excretion via the bile. Lund (1956) studied the excretion
of rats administered 204T1 intraperitoneally, as thallous sulfate, at a dose of
10 mg/kg (approximately 8.1 mg Tl/kg). At 25 days postdosing, excretion in
urine and feces amounted to 26.4% and 51.4% of the radioactive dose,
respectively; and 10.3% of the dose was recovered from the carcass as .
nonexcreted material. To study biliary excretion of thallium, the common bile
duct was severed between ligatures, thus preventing secretion of bile into the
GI tract. The rats were then dosed subcutaneously with 204T1, as thallous
sulfate, at a dose of 3 mg/kg (2.4 mg Tl/kg). By day 8 postdosing, rats with
severed bile ducts excreted 13.4 and 16.7% of the dose in urine and feces,
respectively. Control rats, with intact bile ducts, excreted 13.1 and 19.0%
of the same radioactive dose in urine and feces, respectively. The authors
concluded that Tl was not excreted in bile to any great extent. To study
intestinal secretion of thallium, rats were dosed subcutaneously with ""Tl, as
111-12
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thallous sulfate, at a dose level of 2.2 rag/kg (1.8 mg Tl/kg). The contents
of portions of the 61 tract were analyzed for radioactivity at various times
for up to 80 hours after dosing. Radioactivity was found in the contents of
stomach, ileum, colon, and rectum throughout the 80-hour observation period.
Gregus and Klaassen (1986) studied the excretion of thallium in male
Sprague-Dawley rats. The animals were intravenously administered 201T1-labeled
thallium nitrate plus nonradioactive Tl-nitrate at a dose of 10 mg Tl/kg.
Over a 4-day period, excretion of thallium in urine and feces amounted to 10.2
and 34.4% of the dose, respectively. During the first day after dosing,
excretion in urine and feces amounted to 3.58 and 14.3% of the dose,
respectively. To study biliary excretion, bile duct-cannulated rats were
administered intravenously ao*Tl-labeled thallium nitrate plus thallium
chloride at dose levels of 1, 3, 10, and 30 mg Tl/kg. Two hours after dosing,
0115 to 0.16% of the dose was excreted in bile independently of dose. The
authors estimated that the 24-hour excretion of thallium in bile was only one-
seventh of that excreted in feces on the first day (i.e., 14.3% of the dose).
Thus, they concluded, biliary excretion accounted only partly for fecal
excretion of thallium.
Talas and Wellhoner (1983) studied the excretion of thallium in rabbits.
Two rabbits were injected intravenously with a tracer dose of *TI, as
thallium chloride (less than 2 »g Tl/kg), plus 5.5 *mol of thallium acetate/kg
(1.1 mg Tl/kg). At 48 hours after dosing, excretion in urine and feces
averaged 10.5 and 9.8% of the dose, respectively. Thallium levels in the
contents of stomach plus small and large intestines averaged a total of 19.4ft— •
of the dose. Contents at the time of sacrifice averaged only 0.02% of the
dose.
Henning and Forth (1982) studied the excretion of thallium into the gas-
trointestinal tract of rats in situ. The rats were dosed intravenously with
"*!!, as thallous sulfate, at a dose level of 1.85 x 10'* mmol/kg (7.5 mg
Tl/kg}. The stomach and 7-cm-long segments of jejunum, ileum, colon
ascendens, and colon descendens were perfused in situ to measure excretion of
111-13
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thallium into the gastrointestinal tract. By 1 hour after dosing, excretion
of thallium in the jejunal segment amounted to about 0.55% of the dose, and
excretion in the ileal and colonic segments was in the range of 0.3 to 0.5% of
the dose. Thallium excretion via the stomach was very small, amounting to
less than 0.05% of the dose.
E. BIOACC'JMULATIOH AND RETENTION ' -
Several single-dose studies (discussed above, Sections III.B,
Distribution, and III.D, Excretion) provide estimates for the biological
half-life of thallium in mammals.
Lie et al. (1960) calculated a biological half-life of 3.3 days for
thallium in rats, following dosing of the animals by the oral and five other
routes. Except for hair, other tissues were considered to have similar half-
lives for thallium. Based on the half-life of 3.3 days, the author estimated
that with daily dosing, the body burden of thallium would reach equilibrium in
20 days. With five daily exposures per week, excluding weekends, it was
estimated that the body burden of thallium would reach equilibrium in 30 days.
Likewise, Lehmann and Favari (1985) and Rade et al. (1982) have reported half-
lives in rats of 7.3 and 2.7 days, respectively.
Atkins et al. (1977) conducted retention studies, using whole-body
counting, in normal human volunteers dosed intravenously with a single
unspecified dose of M1T1. These studies indicated a mean whole-body
disappearance half-life of 9,8 days for the isotope, with a range of 7.4 to
12.4 days.
F. SUMMARY
In an oral dosing study in rats, it was estimated that 100% of. the
labeled thallous nitrate was absorbed from the GI tract. In the dog, it was
estimated that at least 61.6% of an oral dose of thallous nitrate was absorbed
by the GI tract. Toxic signs in humans and mortality in guinea pigs have
111-14
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followed the cutaneous application of thallium salts, indicating dermal
absorption of thallium.
Several studies indicate that thallium is extensively distributed in the
tissues following absorption. In oral-dosing studies with thallous salts, the
tissue distribution of thallium was found to be uneven, with a strong prefer-
ence for kidneys. The tissue distribution appeared to be somewhat dependent
on the species and duration of dosing.
In a single-dose study in rats, highest levels of thallium were found in
kidney, followed in decreasing order by salivary glands, testes, muscle, bone,
GI tract, spleen, heart, liver, hair, skin, and brain. A similar tissue
distribution was found when the rats were dosed by five other routes. In
another study with rats fed thallous acetate for 63 days, highest levels were
found in kidneys, followed by liver, bone, spleen, lung, and brain. However,
in a female cancer patient, highest levels were found in scalp hair, followed
by kidney, heart, and spleen. Lower levels were found in the brain.
Autoradiographic and compartmental modeling studies after parenteral
dosing confirm the extensive tissue distribution of thallium observed in the
oral studies. Furthermore, it was found that in rats dosed intraperitoneally
with M1Tl-labeled thallous sulfate at levels in the range of 0.00021 to 10,256
*g Tl/kg, the pattern of tissue distribution of radioactivity was essentially
independent of dose.
Autoradiographic examination of mice dosed intraperitoneally with
"Tl-labeled thallous nitrate revealed accumulation of thallium in bone and
kidney by 1 hour, and in the epididymis and deferens ducts at 24 hours after
dosing. Subchronic studies of rats administered thallium in drinking water
confirm that thallium accumulates preferentially in the kidney and testes.
In another study, the total volume of distribution for thallium.after
intravenous dosing of human adults was found to be 4.23 L/kg, which is much
III-15.
-------
larger than the total body water volume in humans. This result is consistent
with a migration of thallium into the intracellular space.
Several authors have studied the transplacental transfer of thallium,
which appears to be rapid and yields fetal concentrations that are lower than
those observed in the mother. After oral dosing, thallium was present in
maternal brain and kidney, and in fetal tissue, within 30 minutes after
pregnant mice and rats were orally administered thallous sulfate. Thallium
levels in fetal tissue, .at their maximum level, were about 10% of those
observed in maternal tissues for both species. In another study in which
pregnant rats were dosed orally with thallous sulfate on day 17 of gestation,
fetal levels of thallium in liver and brain were approximately 50% of the
respective maternal levels. . .
In studies of transplacental transfer after parenteral dosing, it was
observed that thallium appears in fetal tissues by 15 minutes after intraperi-
toneal administration of thallous sulfate in mice. In another study, in preg-
nant rats dosed intraperitoheally with thallous sulfate, peak thallium levels
were seen at 4 hours in most maternal tissues, in fetuses, and in placenta.
Maternal, fetal, and placental levels of thallium appeared to decrease with
half-lives of the same magnitude. • Continuous venous infusion of thallous
sulfate into pregnant rats at doses in the range of 0;16 to 5.2 mg Tl/kg/min
resulted in maternal thallium levels that were 15 to 30 times higher than
those in fetal blood, respectively.
The comparative tissue distribution of TV* and TV* has been studied in
rats. In rats dosed orally with TV* or TV* salts, or the organometallic
compound dimethyl thallium bromide, the tissue distribution of thallium was •
very similar in the case of the two salts. It was also observed that the
intracellular distribution of thallium for the three compounds was very '
similar. These observations have led to the suggestion that there is a
biochemical conversion of TV* and Tl3* into a single species. .
I.II-16
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Several authors have studied the excretion of thallium in rats. In one
study, after single oral dosing with thallous sulfate, 32% of the dose was
eliminated in feces and 21% in urine over an 8-day period. In another study,
the ratio of fecal to urinary excretion of thallium ranged from 2 to 5 in rats
dosed orally or parenterally regardless of the route of administration. Other
studies using the intravenous, intraperitoneal, or subcutaneous routes
indicate that thallium is excreted into the lumen of the intestinal tract of
rats, with little excretion via the bile. In a human female cancer patient
dosed orally with radiolabeled thallous sulfate, excretion of thallium
amounted to 15.3% in urine over 5.5 days, and to only 0.4% in feces over 3
days.
Based on single oral dosing, the biological half-life of thallium in
rats has been reported as 7.3 days in one study and as 3.3 days in another
study. A mean whole-body half-life of 9.8 days has been reported in humans
dosed intravenously with IOOT1.
111-17
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IV. HUMAN EXPOSURE
To be provided by Science and Technology Branch, OOW.
IV-1
-------
V. HEALTH EFFECTS IN ANIMALS
A. SHORT-TERM EXPOSURE
1. Lethality
The acute oral LOH values for various thallium compounds in mice and
rats range from 16 to 46 ng TVkg. Values for the lowest oral doses of
thallium compounds showing any lethality (LD^) in guinea pigs, rabbits, and
dogs are in the range of 5 to 30 mg Tl/kg. These values are summarized in
Table V-l.
2. Other Effects
The following studies indicate that acute dosing with thallium produces
degenerative changes in mitochondria of the kidney, liver, and brain, and
causes deposition of lipofuscin bodies in brain neurons.
Herman and Bensch (1967) studied the acute effects of thallium in
Sprague Oawley rats of both sexes. A total of eight rats (sex ratio
unspecified) were administered thallous acetate subcutaneously at a dose level
in the range of 20 to 50 mg/kg (15.5 to 38.8 mg Tl/kg). The animals were
sacrificed at various times up to S days after dosing for necropsy and
histopathological assessment. Necropsy findings were unremarkable except for
mottled kidney in one rat and changes at the corticomedullary Junction in two
rats. Light microscopy revealed renal casts, moderate enteritis, and moderate
to severe colitis. At 58 hours after dosing, renal mitochondria contained
electron-dense particles. At 5 days, there were severe degenerative changes
in many mitochondria in all renal tubules. These changes included swelling,
partial loss of cristae, and formation of myelin-like structures.
Mitochondria! changes were also present in the liver, brain, and small
intestine. In this study, the authors did not specify all the dose levels or
the doses at which the effects were observed; thus, no NOAEL or LOAEL can be
derived from this study.
V-l
-------
Table V-l. Summary of Lethality Data on Thallium in Laboratory Animals
Route of
Species/sex admin.*
Mouse/M
Mouse/M
Moc/se/M
Mouse/M
Mouse/M
Mouse/M
Mouse/M
Mouse/M
Mouse/NSB
Mouse/NS
Mouse/NS
Mouse/M
Mouse/M
Mouse/M
Rat/F
Rat/M
Rat/F
Rat/F
Rat/F
Guinea pig/F
Guinea pig/M,F
Rabbi t/F
Rabbi t/M
Dog/M,F
Dog/M
po
po
po
po
po
po
po
po
po
ip
ip
iv
sc
sc
po
po
po
ip
ip
po
po
po
po
- po
po
Compound
T1C1
T1C1
T12CO,
T12COS
•' T12S04
T12S04
T12S04
T1NO,
T1CH,C02
T1C1
T1CH,C02
T12S04
T12S04
j
T12S04
T120S
T12S04
T1CH,C02
TL20,
T1CH3C02
T1CH,C02
T1A
T1CH,CO,
T1A
T1CH,C02
T120,
Lethal dose
(ng Tl/kg)
20 (LDJ
26 (LD,J
18 (LDJ
22 (LD,J
19 (LDJ
28 (LD,J
46 (LDJ
25 (LDJ
27 (LDJ
20 {LDJ
29 (LDJ
33 (LDJ
22 (LDJ
41 (LDJ
39 (LDJ
16 (LDJ
32 {LDJ
72 (LDJ
23 (LDJ
12 (L0u)e
5 (LDJ
19 (LDLJ
30 (LDJ
20 (LDJ
30 (LDLJ
Reference
Tikhova (1964)
Tikhova (1964)
Tikhova (1964)
Tikhova (1964)
Tikhova (1964)
Tikhova (1964)
Truhaut (1959)
NIOSH (1985)
NIOSH (1985)
NIOSH (1985)
NIOSH (1985)
Truhaut (1959)
Danilewicz et al .
(1979)
Truhaut (1959)
Downs et al. (1960)
Danilewicz et al .
(1979)
Downs et al . (1960)
Downs et al. (I960)
Downs et al . (1960)
Downs et al. (1960)
Downs et al. (1960)
Downs et al. (I960)
Downs et al . (1960)
Downs et al. (1960)
Downs et al. (1960)
*po • oral; ip - intraperitoneal; Iv
bNS « Sex not specified.
CLDLO * Lowest dose showing any lethality.
intravenous; sc - subcutaneous.
V-2
-------
Woods and Fowler (1986} studied the structural and biochemical changes
Induced by thallium In rat liver. Hale Sprague-Dawley rats were administered
thallic chloride tetrahydrate Intrapen'toneally at doses of 0, 50, 100, or 200
mg/kg (0, 26.7, 53.4, or 106.8 mg Tl/kg). The animals were sacrificed at 16
hours after dosing for ultrastructural and biochemical studies of liver
tissue. Ultrastructural studies of hepatocytes showed, at all three doses,
mildly swollen mitochondria, Increased numbers of electron dense autophagic
lysosomes, doserelated loss of r1bosomes from the endoplasmic reticulum (ER),
and proliferation of the rough ER segment. Surface density measurements cf
mitochondria! and smooth and rough ER membranes Indicated dose-related
increases in the surface densities of both the outer and inner mitochondria!
membranes, and of the rough ER. Increases in both the outer and Inner
mitochondrial membranes were associated with Increases in the enzymatic
activities of monoamine oxidase and ferrochelatase. These two enzymes are
integral components of the outer and inner mitochondrial membranes,
respectively. In contrast, malate dehydrogenese, which is located in the
mitochondrial matrix, was not affected. Similarly, structural changes in the
ER were associated with decreased enzymatic activities for microsomal NAOPH
cytochrome (P-450) reductase, aniline hydroxylase, and aminopyrine
demethylase.
*
Herman and Bensch (1967) studied the subacute effects of thallium in
Sprague-Dawley rats of both sexes following subcutaneous administration for up
to 16 days. A total of four rats (sex ratio unspecified) were administered
two to three weekly doses of thallium acetate, each dose consisting of 10 to
15 mg/kg (7*8 to 11.6 mg Tl/kg). The animals were sacrificed as signs of
toxicity appeared, I.e., at days 10, 12, 14, and 16 after the start of dosing.
Light microscopy revealed an extensive region of acute necrosis in the
mesencephalon of two rats. Mild colitis was present in two animals. Electron
microscopy revealed mitochondrial granules in kidney and liver cells. Many
dense bodies were seen in the cytoplasm of the cells of the loops of Henle and
the distal convoluted tubules. In the brain, Upofuscin bodies were sometimes
present in the neuronal cytoplasm. However, the authors did not specify all
the dose levels used or the doses at which the effects were observed. Thus,
the NOAEL or LOAEL cannot be obtained from this study.
V-3
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B. LONG-TERM EXPOSURE
1. Sufachronic Toxicltv . ,
Stoltz et al. (1986) studied the subchrom'c toxicity of thallium in
Sprague-Dawley rats. Groups of 20 male and 20 female rats were dosed daily by
gavage for 90 days with thallium sulfate at levels of 0.01, 0.05, or 0.25
mg/kg/day (8.1, 40.5, or 202.4 #g Tl/kg/day, respectively). Two similar
groups were used as untreated and vehicle (water) controls. Increased
shedding of hair and rough coat were observed in all dose groups. No
significant differences in body weight gain or food consumption patterns were
observed throughout the study. Increased lacrimation and exophthalmos were
present at all dose levels.
Clinical chemistry revealed changes in serum enzymes and electrolytes.
In males, apparent dose-related elevations in the enzymatic activities of
serum glutamic-oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH)
were observed. SGOT was significantly elevated above both control groups at
the two higher dose levels, whereas LDH was significantly elevated at all dose
levels with respect to untreated controls. However, it was not possible to
confirm that the increases in SGOT and LOH were dose-related because of
scattering (p <0.05) of the data points. Serum levels of sodium and calcium
were significantly (p <0.05) elevated at all dose levels when compared to
untreated controls and at the two higher doses when compared to vehicle-
treated controls. Serum glutamic-pyruvic transaminase (SGPT) was unaffected.
A slight hypoglycemia, significant with respect to both control groups, was
observed at the high-dose level, In females, significant, dose-related
increases in serum sodium were observed-at 30 and 90 days of treatment; and
significant, dose-related increases in SGOT and LDH activities were present, at
30 days but not at 90 day?. The authors noted that Increased activity of SGOT
and LDH (about 1.3-fold in males), together with unchanged SGPT activity, is
consistent with some degree of extrahepatic damage. The possible site of
extrahepatic damage was not identified. However, the authors speculated that
V-4
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the subtle changes In electrolytes, coupled to Increases In enzymatic
activities, could reflect an effect on renal function. The kidney is a major
target for thallium distribution in rats (Lie et al.t 1960; Sabioni et al.,
1980), and histopathqlogical effects on rat kidney have been reported at
higher doses (Herman and Bensch, 1967).
Alopecia was observed in dosed animals, although it was not clear if it
was due to thallium. Histological examination of a skin area showing alopecia
in four females revealed hair follicle atrophy in only one case at.the highest
dose level. No treatment-related gross or light-microscopic findings were
reported. Electron microscopic evaluation of tissues was not performed.
Based on the absence of gross or histopathologic findings, this study defines
a NOAEL of 0.2 mg Tl/kg/day. No LOAEL is defined by this study.
Downs et al. (.I960) studied the toxicity of thallous acetate and thallic
oxide in rats fed the compounds for approximately 15 weeks. . In a first series
of experiments, four groups of 10 weanling rats (5 males, 5 females) received
dietary levels of thallous acetate at 0, 5, 15, and 50 mg/kg diet for 15 weeks
(corresponding to approximately 0, 0.4, 1.2, and 3.9 mg Tl/kg body weight/day
for 100-g young rats, respectively, assuming a food consumption of 10
g/kg/day). Two groups of rats added several weeks later were placed on diets
containing 0 and 30 mg thallous acetate/kg diet for 63 days (corresponding to
0 and 2.4 mg Tl/kg body weight/day, respectively). Mortality among test
animals and controls was high. The highest dose produced 100% mortality by
week 12. There was 80% mortality among the animals fed thallous acetate at 30
mg/kg of diet.- By week 15, 40% (two/sex) of the control animals died. In the
remaining dose groups, mortality amounted to 40% and 20% in animals fed
thallous acetate at levels of 1.2 and 0.4 mg/kg of diet, respectively. There
was.no effect on weight gain at the two lower dose levels, and there was a
moderate depression in weight gain with the diet containing thallous acetate
at 30 mg/kg diet. The only significant finding at necropsy was moderate to
marked alopecia, first seen at 2 weeks of treatment, in rats fed thallous
acetate at levels of 15 and 30 mg/kg of diet. No histopathological changes
were reported.
V-5
-------
Based on alopecia in rats fed thallous acetate at 15 mg/kg diet, a LOAEL
of 1.2 mg Tl/kg body weight/day was determined, With a NOAEL of 0.4 mg Tl/kg
body weight/day.
In the second series of experiments by Downs et al. (I960), six groups
of 10 weanling rats (5 males, 5 females) received thallic oxide in the diet at
levels of 0, 20, 35, 50, 100, and 500 mg/kg diet for 15 weeks. These values
approximately correspond to 0, 1.8, 3.1, 4.5, 9.0, and 44.8 mg Tl/kg body
weight/day for 100-g young rats. All rats fed diets containing 50 mg thallic
oxide/kg/day or more died, within 8 weeks of treatment. Only one male and
three female rats that received thallic oxide at a level of 35 mg/kg/day
survived the treatment period. There was marked alopecia by week 4 in rats
fed thallic oxide at levels of 20 and 35 mg/kg diet. At termination, necropsy
of the survivors revealed a significant elevation in kidney weights for
females receiving 20 and 35 mg thallic oxide/kg diet/day and for males
receiving 20 mg thallic oxide/kg diet/day. Histologic examination of lung,
liver, kidney, and brain showed no effects attributable to thallium ingestion.
Histologic examination of skin sections showed considerable atrophy of hair
follicles.
Nanzo et al. (1983) studied the effects of thallium in 80 female
Sprague-Oawley rats administered thallium sulfate in the drinking water at 10
mg Tl/L for 36 weeks. This corresponds to approximately 1.4 mg Tl/kg body
weight/day assuming a body weight of 200 g. The mortality rate was 15 and 21%
after 40 and 240 days of treatment, respectively. Hair loss appeared after 32
days of treatment and involved about 20% of the animals thereafter. Abnormal
electrophysiological parameters were observed in 10 of 16 rats at day 240
posttreatment. These findings Included a 44% decrease in the amplitude of
motor action potentials (NAP), a 30% decrease in the amplitude of the sensory
action potential, and a 25% Increase in MAP latency. Histologic examination
of sciatic nerve samples from six treated rats revealed morphological changes
in three. These changes Included Wallen an degeneration of scattered fibers
and vacuolization and lamination of the myelin sheath of about 10% of the
V-6
-------
fibers. Electron microscopic examination of fibers with Wallerian
degeneration showed complete destruction of the axon, with mitochondria!
degeneration, neurofilamentous clustering, and evidence of extensive lysosomal
activity.
Herman and Bensch (1967) studied the effects of thallous acetate
administered by subcutaneous injection to Sprague-Dawley rats for at least 24
weeks. A total of 15 rats (sex ratio unspecified) received an initial
subcutaneous injection of thallium acetate in the range of 10 to 20 mg/kg (7.8
to 15.5 mg Tl/kg), followed by weekly subcutaneous injections of the same
chemical at 5 mg/kg (3.9 mg Tl/kg), for at least 24 weeks (approximately 0.6
mg Tl/kg/day). The animals were serially sacrificed at various times (4 to 26
weeks) after the initial injection. Light microscopic examination revealed no
effects, except mild colitis in one rat 28 days after the initial injection.
Electron microscopic examination of the kidneys showed accumulation of debris
in the lumen of the convoluted tubules and progressive changes in the
mitochondria of the tubule cell. By 12 weeks, many cup-shaped mitochondria
were present and, in some mitochondria, partial loss of cristae was evident.
In liver cells there were also degenerative changes in mitochondria. In all
animals glycogen was abundant, and the endoplasmic reticulum was plentiful and
sometimes slightly dilated. In brain, lipofuscin bodies were often numerous
in the cytoplasm of neurons. Mitochondria! granules were seen in mucosal
cells of the large and small intestines.
2. Chronic Toxicitv
No chronic toxicity studies were found in the available literature.
C. REPRODUCTIVE/TERATOGENIC EFFECTS
In a reproductive toxicity study, Formigli et al. (1986) reported that
groups of 10 male Wistar rats received 10 ppm thallous sulfate in their
drinking water (approximately 740 *g Tl/kg body weight/day, based on a
reported thallium consumption of 270 i»g Tl/rat and body weight in the range of
V-7
-------
350 to 380 g) for 30 or 60 days. Control animals were pair fed. No
abnormalities in testicular morphology or biochemistry were observed after 30
days; however, males exposed to thallium for 60 days exhibited epididymal
sperm with increased numbers of immature cells and significantly reduced
motility. Histological examinations revealed disarrangement of the tubular
epithelium; in addition, Sertoli cells had cytoplasmic vacuolization and
distension of the smooth endoplasmic reticulum. Testicular beta-glucuronidase
activity was significantly reduced in the thailiurn-treated males. Plasma
testosterone levels were unaffected. Testicular thallium concentration was
6.3 jtg/g for treated animals and less than 0.08 ng/g in pair-fed controls.
In a teratogenicity study, Claussen et al., (1981) administered thallous
acetate or thallous chloride to pregnant Wistar rats, by gavage, at doses of 0
(control), 3, 4.5, or 6 mg/kg on days 6 through 15 of gestation. The adminis-
tered doses correspond to 0, 2.3, 3.5, and 4.7 mg Tl/kg/day for the acetate,
and to 0, 2.6, 3.8, and 5.1 mg Tl/kg/day for the chloride, respectively.
Maternal mortality was 100% at 4.5 and 6 mg/kg for both salts. For the
control and 3 mg/kg chloride-salt- and acetate-salt-treated groups, 17, 15,
and 12 respective litters were delivered by cesarean section and examined for
skeletal alterations; 11, 11, and 7 cesarean-deliversd litters were examined
for visceral alterations; and 14, 14, and 12 litters were maintained for 21
days postpartum. Significantly increased incidences of wavy ribs and
dumbbell-shaped sternebrae were noted in both thallium-treated groups at 3
mg/kg when compared to controls. In addition, slightly increased postnatal
mortality was noted at this dose level. The NOAEL for developmental toxicity
was not established because of the presence of effects at all levels tested.
In another series of experiments, Claussen et al. (1981) treated NMRI
mice with thallous acetate or thallous chloride by gavage on days 6 through 15
of gestation at doses of 0, 3, or 6 mg/kg. The applied doses correspond to 0,
2.3, and 4.7 mg Tl/kg/day for the acetate, and to 2.6 and 5.1 mg Tl/kg/day for
the chloride, respectively. The numbers of control litters examined
skeletally and viscerally were 28 and 13, respectively. Postpartum
examinations were conducted on 24 litters. For the groups receiving the
V-8
-------
chloride salt, 24, 11, and 17 litters were examined at 3 mg/kg, respectively,
and 20, 12, and 15 Utters were examined at 6 mg/kg. For the groups exposed
to the acetate salt, 20 and 9 litters were examined skeletally and viscerally,
respectively, at 3 mg/kg, and 24 and 12 respective litters were examined at 6
mg/kg. No adverse effects of thallous chloride were noted at 3 mg/kg;
however, slightly increased postimplantation loss was noted at 6 mg/kg for
both cesarean-delivered and reared litters. Postnatal mortality was also
slightly increased at 6 mg/kg thallous chloride. For groups receiving
thallous acctitc, s slight reduction in fetal weights was noted at 6 mg/kg,
and slightly increased incidences of cleft palate were present at 3 and 6
mg/kg. Based on the above information, the NOAEL and LOAEL for developmental
toxicity were 2.3 and 5.1 mg Tl/kg/day, respectively, for thallium.
Gibson and Becker (1970) administered aqueous thallous sulfate
intraperitoneally to Sprague-Dawley rats at 2.5 mg/kg (six rats/group) on days
8 to 10 or 12 to 14 of gestation, or at 10 mg/kg (three rats/group) on days 12
to 14 of gestation. The applied doses correspond to 2.0 and to 8.1 mg
Tl/kg/day, respectively. On gestation day 21, all thallium-treated groups had
significantly reduced fetal weights. Dosing on days 12 to 14 produced
significantly increased incidences of missing or unossified vertebral bodies
at both dose levels. The incidences of hydronephrosis were increased at 2.0
mg Tl/kg/day in the group dosed on gestation days 8 to 10 when compared with
controls, and the differences reached statistical significance for the group
dosed with 2.0 mg Tl/kg on gestation days 12 to 14; the incidence of
hydronephrosis was comparable to controls at 8.1 mg Tl/kg. The NOAEL for
developmental toxicity could not be established because of the presence of
effects at all levels tested in this study.
Nogami and Terashima (1973) administered thallous sulfate postnatally to
6- and 9-day-old rat pups at doses of 20 and 40
-------
sulfate inhibits the synthesis of cartilage mucopolysaccharides in rat
fetuses.
Anschutz et al. (1981} cultured 10.5-day-old rat embryos for 48 hours in
human serum. The embryos were exposed to thallium at concentrations of 3, 10,
30, or 100 itg/ml. Dose-related growth retardation was evident at all levels.
Complete growth inhibition was reported at 100 »g/ml. At 3 »g/mi, no gross
abnormalities were evident; however, cytotoxicity to the central nervous
system was detected microscopically.
0. MUTAGENICITY
Published is viLtro and in vivo genetic toxicology assays with thallium
compounds have been categorized into gene mutation assays (Category 1),
chromosome aberration assays (Category 2), and studies that assess other
mutagenic mechanisms {Category 3). The findings from the studies are
summarized in Table V-2 and are discussed below.
1. Gene Mutation Assays (Category 1)
a. Reverse mutation in DTokarvotgs
Three investigators (Oehnen, 1979, as cited in Claussen et al., 1981;
Kanemastu et al., 1980} reported that thallium compounds (T1C2H302, T1C1, and
T1NO,) gave negative responses in Salmonella thvohimurium mammalian roicrosome
reverse mutation assays (Ames tests} in the presence or absence of rat liver
S9 activation. £. tvohimurium strains TA1535, TA1537, TA1538, TA98, and TA100
were assayed. Although the results were uniformly negative, limitations of
the Ames assay for detection of metal-induced mutagenesis make these results
inconclusive (McCann et al., 1975}. Similar problems are encountered in
interpreting the inactivity of T1NO, in the Escherichia coli tryptophan
reverse mutation spot test conducted by Kanematsu et al. (1980}.
V-10
-------
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V-12
-------
No gene mutation assays In higher biological systems were found In the
open literature.
2. .Chromosome Aberration Assays (Category 2)
a. Somatic cells
Zasukhina et al. (1981) exposed triplicate cultures of rat embryo
fibroblasts to 10"* and 10"' M T1,CO, for 24 hours and analyzed approximately
300 metaphase cells for chromosome aberrations. No cytotoxic effects were
reported; however, significant Increases 1n the total number of aberrations
and the percent of cells with aberrations were seen at both levels. The
effect was clearly dose dependent, and the predominant types of aberrations
were chromosome and chromatid breaks. Although this study provides acceptable
evidence of an in vitro mammalian cell clastogenic effect, the results have
not been confirmed.
b. Germinal cells
Zasukhina et al. (1981, 1983} also performed a rat dominant lethal assay
with Tl,COj at dosages of SxlO"4, 5x10"*, and 5x10" mg/kg body weight. An un-
reported number of male rats were administered dally oral doses at these
levels for 8 months. Following exposure, males were mated with untreated
females (number not specified). Females were sacrificed on the 20th day of
pregnancy, and the uterine content of 16 controls and 18 females per dose
group were scored for total Implants, corpora lutea, live Implants,
preiraplantation loss, and postImplantation loss. These parameters were used
to calculate overall embryonic mortality; statistical analyses were not
performed. Based on the number of corpora lutea and total implants, 5x1 (T*
mg/kg T1ZCO, had an adverse effect on fertilization. Data presented for other
parfhieters were difficult to interpret because of the inclusion of
preimplantatlon losses in the final calculations and apparent typographical
errors in some of the calculations. The results Indicated that a dose-related
Increase in postimplantation loss accompanied exposure to T1,CO,. However,
V-13
-------
the report did not-contain a statistical analysis of the data, and data were
Insufficient to perform Independent statistical analyses; therefore, the study
results could not be verified. Furthermore, it was not possible to verify the
accuracy of the dose levels administered.
3. Other Mutaqenic Mechanisms (Category 3)
a. DNA damage/repair in bacteria
" Kanematsu et al. (1980) exposed the Bacillus suht.n-u, DNA repair-
competent strain H17 (rec*), and the DNA repair-deficient strain M45 (rec~),,
to a single dose (0.001 H) of nonactivated T1N03; T1NO, caused preferential
inhibition of N45, indicating that damage to ONA had occurred. This "rec"
assay with a single dose 1s supportive evidence for a genotoxic response.
b. ONA damage/viralreactivation in mammalian cells
Thallium carbonate was evaluated for the potential to cause DNA strand
breaks and viral reactivation in three rodent cell lines by Zasukhina et al.
(1981, 1983). The initial experiments involved a 24-hour exposure of mouse
embryo cells (CBA and C57BL/6) and rat embryo fibroblasts to 10~* through 10"*
M TljCOj, and the compound was reported to be noncytotoxic. Following
exposure, aliquots of cells were lysed; the DNA was eluted, precipitated, and
counted by liquid scintillation; parallel viable cell aliquots were allowed a
24-hour, recovery in the absence of T1aC03. Although negative control results
were not presented, the summarized data indicated that significant and dose-
related increases in the formation of single-strand DNA were observed in -^
C57BL/6 cells and rat cells, but not in CBA cells. The damage induced by
TljCO, was completely repaired by the C57BL/6 cells, within 24 hours of
compound removal, showing that the DNA damage was via an identifiable
mechanism. The rat fibroblast DNA "rec" repair mechanisms were not as
efficient; i.e., cells exposed to IQ~* M T1COS repaired <20% of the DNA damage
at 24 hours postrecovery.
V-14
-------
In a related experiment, the three cell lines were Infected with
vaccinia virus, treated with similar concentrations of T1C03 for 24 hours, and
assayed for virus survival. A decrease in virus liter was seen in all
cultures exposed to 10"4 M T1CO,. As expected from the earlier results, the
preferential rescue of recombined viral variants was higher in C57BL/6 in rat
fibroblast than in CBA cells. In concurrence with the initial experiments,
the rat fibroblast exhibiting the least efficient DNA repair systems showed
the greatest degree of viral reactivation. The studies were well conducted
and provide conclusive evidence that Tl,CO, causes primary ONA damage in
mammal 1 an eel1s.
c. In vivo sister chromatid exchange (SCEV
Claussen et al. (1981) administered 5 and 10 mg/kg T1C1 by oral gavage
(two dosings in a 24-hour period) to Chinese hamsters and collected bone
marrow cells for SCE induction. No appreciable increases in SCEs were
observed; however, neither dose was toxic to the animals or was cytotoxic to
the target cells.
d. In vitro cell transformation
Casto et al. (1979) evaluated 38 metal salts including Tl(CzHaO,) for the
potential to enhance simian adenovirus (SA7) transformation of Syrian hamster
embryo cells (HEC). Primary HECs were pretreated with four concentrations of
T1(CjH30,) ranging from 0.025 to 0.2 M for 18 hours, infected with SA7, and
plated for survival and transformation. Thallous acetate at 0.1 and 0.2 mM
Induced significant (p <0.01) and dose-related enhancement of viral
transformation. The 4.3-fold increase in transformed foci at 0.2 mM was
accompanied by a 51% reduction in cell survival. The 0.1 mM concentration was
not cytotoxic; however, the transformation frequency was increased by a factor
of 2.2 as compared to the negative control. The lower concentrations (0.025
and 0.05 mM) were biologically inactive.
V-15
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-------
E. CARCINOGEN I CITY
No carcinogen i city studies for thallium were found.
F. SUMMARY
The acute lethality of thallium has been characterized in several animal
species. The oral LDM of thallium compounds in mice and rats ranges from 16
to 46 mg Tl/kg. The oral LD^ value for thai lie oxide in rats is reported to
be 59 mg Tl/kg. The lowest oral dose showing any lethality in guinea pig:,
rabbits, and dogs is in the range of 5 to 30 mg
In acute experiments involving subcutaneous dosing in rats, thallous
acetate (15.5 to 38.8 mg Tl/kg} produced degenerative changes in mitochondria
of kidneys, liver, brain, and intestines. These changes included swelling,
partial loss of cristae, and formation of myelin-like structures.
Intraperitoneal injection of thallic chloride (26.7 to 106.8 mg Tl/kg)
produced ultrastructural changes in mitochondria, increased numbers of
autophagic lysosomes, and changes in the endoplasmic ret i cut urn (ER) in liver
of rats. Enzymatic activities associated with the mitochondria! membranes and
the ER were Increased and decreased, respectively.
-In subacute studies with rats, subcutaneous administration of two to
three weekly doses of thallous acetate (7.8 to 11.6 mg T1 /kg/dose) produced
histopathological changes in brain, kidney, liver, and intestines. Acute
necrosis was observed in the mesencephalon of two out of four rats. Electron
microscopy showed mitochondria! granules of kidney and liver cells.- >
In long-term exposure studies, female rats were administered thallium
sulfate In the drinking water for up to 36 weeks (approximately 1.4 mg Tl/kg
body weight/day). Reported findings included alopecia, abnormal
electrophysiologlcal parameters, and histopathologic changes in the sciatic
nerve. The histopathological changes included Vlallerian degeneration of
scattered fibers, vacuolizatlon and lamination of the myelin sheath, and
degenerative changes in mitochondria.
V-16
-------
In another study, rats were administered thallous sulfate by gavage at
doses of 8.1, 40.5, or 202.4 *g Tl/kg/day for 90 days. Moderate, but
significant, elevations of serum glutamic-oxaloacetic transaminase (SCOT) and
of Na* and Ca2* were reported for males at the two higher dose levels.
Although lactate dehydrogenase (LOH) was increased on the average, the
increase was not statistically significant. In females, both SCOT and LDH
were moderately, but significantly, elevated at 30 days at the two higher
doses, but not at 90 days. Sodium was moderately, but significantly, elevated
at all dose levels, both at 30 days and 90 days. No histopathologic effects
were observed. In the absence of histopathological effects, this study
defines a NOAEL of 0.2 -mg Tl/kg/day. No LOAEL is defined by this study.
In a dietary administration study, in rats fed diets containing thallous
acetate for up to 15 weeks (initial dose of 0.4 to 3.9 mg Tl/kg body
weight/day), alopecia was observed after 2 weeks on the diet in rats initially
dosed with 1.2 mg Tl/kg bw/day or higher. This study defines a LOAEL of 1.2
mg Tl/kg bw/day and a NOAEL of 0.4 mg Tl/kg bw/day. In a parallel study, rats
received thallic oxide in the feed for up to 15 weeks (initial dose of 1.8 to
44.8 mg Tl/kg bw/dayj. There was 100% mortality at the three higher dose
levels. Alopecia and a significant elevation in kidney weights were observed
at the lowest dose level.
Subcutaneous administration of an initial dose of thallous acetate (7.8
to 15 mg Tl/kg), followed by weekly doses of 3.9 mg Tl/kg for up to 24 weeks,
produced histological changes in kidney, brain, and liver of rats. These
changes included progressive degeneration in the mitochondria of liver and
kidney and lipofuscin granules in neurons. No chronic toxicity studies were
found in the available literature.
In reproductive toxicity studies, male Wistar rats exposed to thallium
sulfate (740 »g Tl/kg/day) 1n drinking water for 60 days exhibited adverse
effects on sperm cell maturation and motility. In addition, histological
examinations revealed alterations in the epithelium of seminiferous tubules
and in Sertoli cells.
V-17
-------
In teratogenlcity studies, pregnant Wistar rats dosed by gavage at
levels of 3.5 to 5.1 mg Tl/kg/day on days 6 through 15 of gestation suffered
100% mortality. Lower doses of 2.3 to 2.6 mg Tl/kg/day were associated with
developmental effects.including wavy ribs and dumbbell-shaped sternebrae in
fetuses, and postnatal mortality.
Pregnant NMRI mice dosed by gavage with thallous acetate or chloride at
levels of 2.3 to 5.1 mg Tl/kg/day on days 6 through 15 of gestation had
increased postimplantation losses, decreased fetal body weights, and increased
incidences of cleft palate and postnatal mortality in their litters.
Pregnant Sprague-Dawley rats given ip injections of thallous sulfate at
2.0 to 8.1 mg Tl/kg/ day on days 12 to 14 of gestation had litters with
reduced fetal body weight, increased Incidences of unossified vertebral
bodies, and hydronephrosis.
Thallium compounds have not been evaluated in gene mutation assays that
are suitable for the detection of metal mutagens. However, assays in the
remaining categories of genetic endpoints suggest that the T12C02 is
clastogenic'ln both rat somatic and germinal cells, T1NO, causes DNA damage in
bacteria, T1,C03 induces primary DNA damage in rodent cell cultures, and
TKCjHjOJ enchances in vitro viral transformation of hamster cells. All of
the assays demonstrating a positive response require independent confirmation
before definitive conclusions can be drawn. When viewed collectively,
however, the weight of evidence suggests that thallium is genotoxic and has
the potential to interfere with a wide variety of mechanisms that maintain
genetic integrity. No studies on the carcinogenic potential of thallium were
found.
V-18
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VI. HEALTH EFFECTS IN HUMANS
Thallium, a slow but persistent systemic poison, is absorbed rapidly from
the gastrointestinal tract (Gosselin et al., 1984). Gosselln et al. (1984)
give thallium a toxicity rating of 5, I.e., extremely toxic. Cases of
thallium poisoning have decreased in the United States since thallium was
banned as an Ingredient in pesticides and rodenticides in 1972. Thallium
toxicity is one of the most complex known to man, with symptomatology being
nonspecific owing to multiorgan involvement. Symptoms may appear rapidly, but
more commonly are delayed. Gradual development of mild gastrointestinal
disturbances, polyneuritis, encephalopathy, tachycardia, skin eruptions,
stomatitis, amorphic changes of the skin, and skin hyperesthesia (mainly in
the soles of the feet and tibia) are commonly seen. The hallmark of thallium
poisoning in humans is the onset of alopecia (Saddique and Peterson, 1983).
A. CLINICAL CASE STUDIES
Table VI-1 briefly outlines various case studies dealing with thallium
poisoning. In addition, several studies are included in which human health
effects and symptomatology are presented in more detail to give a better
understanding of the complexity of thallium poisoning.
Bank et al. (1972) described five case studies involving patients
suffering from thallium Intoxication as determined by urinary analysis. All
five patients exhibited neurologic symptoms ranging from mild peripheral
neuropathy to.irreversible coma and death. Alopecia, a relatively late
manifestation of thallium poisoning, was observed in four of the five
patients. In the first two cases, a 27-year-old man and his 25-year-old wife
were admitted to the hospital within 5 days of one another. Both patients
complained of severe pain in the legs, feet, thighs, abdomen, and the anterior
portion of the chest, as well as malaise, and subjective dysesthesias of the
hands. Thallium poisoning was suspected after the appearance of marked
alopecia of the scalp and body after approximately 3 weeks. Exposure levels
to thallium were not determined. To facilitate thallium excretion in urine,
VI-1
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the husband was given potassium chloride (15 mEq) orally three times daily,
and his wife was given orange juice as a form of potassium supplementation.
Both treatments were discontinued due to the resulting increase in the
patients' subjective symptoms. Approximately 10 weeks after the onset of
intoxication, all sensory symptoms cleared and hair began to grow. Although a
thorough search was conducted, no exogenous source of thallium was detected.
The remaining cases are summarized in Table VI-1.
Cavanagh et al. (1974) cite three cases of thallium poisoning due to
ingestion of crystalline thallous acetate. The crystals were dissolved in
water and poured into each victim's beverage. Two of the victims, 56- and 60-
year-old males, each ingested a total dose of approximately 0.93 g of thallous
acetate in three and two divided doses, respectively. The third victim, a 26-
year-old male, ingested approximately 0.31 g of thallous acetate in a single
dose (approximately 3.4 mg Tl/kg, assuming a body weight of 70 kg). All three
were hospitalized with complaints of diarrhea, vomiting, weakness, and
paresthesia of the hands and feet.
The first two victims (the 56- and 60-year-old males) developed bilateral
facial nerve weakness and poor palatal motion, muscle deterioration, and
increasing respiratory difficulty. Both died of cardiac arrest within 1 month
following the onset of symptoms. Postmortem examination revealed edema and
early bronchiopneumonia in the lungs and necrosis in the liver and kidney
cortex in one of the victims and hemorrhagic bronchiopneumonia and edema in
the lungs and centrilobular congestion in the second victim. Primary damage
was to the central and somatic nervous system. The third victim gradually
improved, although alopecia developed, diarrhea remained, and numbness with
;
sensory loss was noted. Within several weeks, hair regrowth was seen and
health returned to normal.
Roby et al. (1984) report four cases indicating (contrary to previously
reported descriptions of acute thallium poisoning) that cardiac and pulmonary
distress may dominate the acute stages of this illness. Prior to this report,
VI-8
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most case descriptions of myocardial distress were limited to electrocardio-
graphic (£CG) abnormalities and sinus tachycardia.
A 51-year-old woman was referred to the hospital after complaining of
chest and abdominal pains of 1 day's duration. Numbness and weakness of legs
and hands were also noted. Upon admission, an electrocardiogram revealed
frequent ventricular ectopic beats. Pulse and blood pressure fluctuated with
periods of bradycardia (20 beats/min) and hypotension (to 70/40 mrnHg). Serial
electrocardiograms showed flattening of T-waves, prominent U-waves, a
prolonged QT interval, and frequent ectopic beats, but no evidence of
myocardr -nfaretion. One week after admission, the ECG showed that 16% of
all beat -e ventricular ectopic beats. Thallium poisoning was suspected
after sev•:• weeks upon onset of alopecia, encephalopathy, and peripheral
neuropathy. Two years after the poisoning, the patient still showed
persistent ventricular ectopy. She remains neurologically disabled and is in
the care of a nursing home. The remaining three cases are outlined in Table
VI-1.
According to several authors, the minimum lethal dose for thallium i.n
adult humans is 0.2 to 1.0 g (Grunfeld and Hinostroza, 1964; Clayton and
Clayton, 1981; Heath et al., 1983; Moeschlin, I960).
Ha.ior Target Organs
a. Cardiooulmonarv effects
In many cases, cardiac manifestations constituted the primary
nonneurological problem encountered in thallium poisoning. Problems such as
T-wave abnormalities and refractory atrial fibrillation have been reported in
individuals with no prior history of cardiac disease. It has been concluded
that the similarity of thallium to potassium causes interference with the
sodium-potassium cellular interaction in reference to T-wave abnormalities
(Roby et al., 1984).
VI-9
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b'. Neurologic effects
Thallium behaves much like potassium In the body (see Chapter VII). It
substitutes for potassium and depolarizes nerve membranes, causing
demyellnization and axonal destruction. Effects from thallium poisoning are
also seen in the cranial and autonomic nerves, spinal ganglia, posterior
columns, anterior horn cells, and areas of cortex and basal ganglia (Gastel,
1978). Neurologic symptoms usually appear within Z to 5 days after IngestIon
of thallium.
c. Gastrointestinal effects
Excretion of thallium 1s primarily through the feces. However, thallium
toxicity causes paralysis of the small intestine, and fecal excretion
therefore becomes almost impossible (Saddique and Peterson, 1983).
In severe cases of thallium poisoning, hypoacidity or anacidity of the
gastric juices usually occurs. This is probably due to the direct damage of
acid-secreting epithelium. It might also occur directly upon absorption of
the poison or on secondary secretion of the metal into the gastrointestinal
tract (Moeschlin, 1980).
B. EPIDEMIOLOGICAL STUDIES
Three medical surveys were conducted between 1979 and 1981 in a
population living hear a cement plant that emitted dust containing thallium.^
To determine thallium levels of individuals in that population, 24-hour urine
-samples (Till) were analyzed for thallium content. The majority of the
population had significantly elevated urinary thallium levels (range:
<0.1-76.5 mg/l) as compared with an "unexposed" reference population (mean
TIU: 0.3 mg/L). Using 0.9 mg/L as the upper normal limit of TIU level for
"nonexposed" subjects, the following was determined: 84.5% of the test
population in the first survey exceeded the TIU upper normal limit. In the
second and third surveys, approximately 62 and 78%, respectively, had TIU
VI-10
-------
levels exceeding the upper normal limit. The decrease in thallium intake was
achieved, through advise of authorities, because the population largely
avoided the consumption of homegrown, potentially contaminated foodstuffs
(Dolgner et al., 1983).
Other available studies, such as Munch et al. (1933) and Reed et al.
(1963), deal with thallium poisoning outbreaks due to the ingestion of
thallium-containing rodenticides or medicine. An outbreak of thallium
poisoning (thallotoxicosis) was observed in 1932. A Mexican laborer illegally
obtained a 100-pound sack of thalgrain (thallium-laden barley) and distributed
it to two families. In all, approximately 31 persons were exposed, 14 were
hospitalized, and 6 died from acute thallium poisoning (Munch et al., 1933).
C. HIGH-RISK POPULATIONS
No population has been identified as being at high risk for thallium
toxicity. Increased thallium body burdens from environmental exposures have
been shown for individuals living near one particular cement plant.
D. SUMMARY
There is an extensive body of literature concerning thallium poisoning
(thallotoxicosis) from accidental or suicidal ingestion of pesticides or
rodenticides that contain thallium. The number of cases involving thallium
poisoning in humans,has dramatically decreased since its use was banned in
1972. Several authors conclude that the minimum lethal dose for humans is 0.2
to 1.0 g.
Thallium is a complex poison because of its multiorgan involvement.
Neurologic symptoms, which predominate thallotoxicosis, may range from mild
peripheral neuropathy to irreversible coma and death. It is now suggested
that cardiac and pulmonary distress may dominate the acute stages of this
illness.
VI-11
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It was found that thallium can arise as a by-product In the dust from
zinc and lead smelting processes or cement refineries. Medical surveys were
conducted near a cement refinery In an attempt to determine if individuals in
that area were being exposed to abnormally high levels of thallium. It was
concluded that the "test" population had urine thallium concentrations 62 to
84% higher than the upper normal limit (0.8 jtg/L) of a "nonexposed" reference
population.
No population has been identified as being at high risk for thallium
toxicity. Increased thallium body burdens can result from environmental
exposure as evidenced by residents living in close proximity to one particular
cement plant.
VI-12
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VII. MECHANISMS OF TOXICITY
The studies discussed In the following sections of this chapter indicate
that thallium may substitute for potassium in activation of the (Na*-K*)-
dependent ATPase and may be taken up by mitochondria where it disrupts
oxidative phosphorylation. These effects may be related to some of the
In vivo and ia vitro effects on the nervous system reviewed below.
A.. EFFECTS ON ION TRANSPORT
Britten and Blank (1968) reported that thallium (administered as
thallous acetate) replaced potassium ion in the activation of the (Na*-K*)-
dependent ATPase of rabbit kidney in vitro. Both thallium and potassium
produced comparable maximal activities. However, thallium ion had a tenfold
higher affinity for the enzyme (half-maximal ATPase activities were observed
in the ranges of 0.16 x 10'1 to 0.20 x 10" M and 1.2 x 10'3 to 3.0 x 10" M for
thallium and potassium, respectively).
Cavieres and Ellory (1974) studied the effect of thallium on the sodium
pump in human erythrocytes. Incubation of *4Na*-loaded erythrocytes in the
presence of varying concentrations of thallous chloride in a potassium-free
medium resulted in a concentration-dependent efflux of sodium into the medium.
Half-maximal activity was seen between 0.03 and 0.05 mM external thallium. In
another series of experiments, 0.05 to 0.15 mM thallous chloride competitively
inhibited the ouabain [a(Na*-K*J-dependent ATPase inhibitorj-sensitive influx
of *V into human erythrocytes Incubated in the presence of 0.06 to 0.39 mM
K*. It appeared that more than one thallium ion must bind for the competitive
inhibition to occur. The relative TT/K* affinity ratio for the K* sites of
the sodium pump was estimated to have a value of 3 to 5.
Gehring and Hammond (1964) studied the uptake of thallium by rabbit
erythrocytes JJQ vitro. When the erythrocytes were incubated in the presence
of 204T1, as thallium nitrate at a concentration of 0.0938 mmol/L, uptake of
thallium was biphasic with half-lives of 9.8 and 165 minutes. The ratio of
VIM
-------
internal to external thallium concentrations averaged 8.7 at the end of a
2-hour period. When ouabain (0.1 mmol/L) or potassium (5 mmol/L) was added,
the fast component of uptake was eliminated and the half-life of the slow
component increased to 289 minutes for ouabain and to 277 minutes for
potassium. The uptake of thallium was also reduced by lowering the incubation
temperature to 4°C and by adding fluoride, an inhibitor of glycolysis. The
inhibitory effect of potassium suggested to the authors that there is an
Interrelationship between potassium and thallium with regard to the uptake of
thallium by rabbit erythrocytes.
Barrera and Gomez-Puyou (1975) studied the effect of thallium on the
movement of potassium ion across the mitochondrial membrane in vitro. Leakage
of potassium ion front rat liver mitochondria was reduced by about 50% in the
presence of thallous sulfate at a concentration of 8 mM. The uptake of
potassium ion by potassium-depleted rat liver mitochondria was also found to
be inhibited by thallium; the extent of the inhibition depended on the
relative concentrations of thallium and potassium in the incubation medium.
Using 8 mM thallous sulfate, inhibition of potassium uptake amounted to about
75 and 50% with potassium concentrations of 25 mM and 50 mM, respectively.
The observation that the inhibitory effect of thallium is more marked at the
higher thallium to potassium ratio suggested to the authors that competition
exists between the two cations. Binding of thallium to mitochondrial protein
was observed in parallel experiments, using 204T1 as thalTous sulfate. At
8 mM thallous sulfate, about 12 nmol of thallium were bound per mg of
mitochondrial protein.
B. EFFECTS ON MITOCHONDRIA
Melnick et al. (1976) reported that thallous acetate uncoupled oxidative
phosphorylation In rat liver mitochondria in vitro. The effect was observed
with half-maximal intensity at 6.5 mM thallium. The effect was attributed to
active accumulation of thallium by energized mitochondria. The'mechanism of
the effect was not elucidated.
VII-2
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C. EFFECTS ON THE NERVOUS SYSTEM
1. In vivo effects
Hasan et al. (1977) studied the effects of thallium on the corpus
striatum of the rat; To assess biochemical parameters, male albino rats were
injected intraperitoneally with thallous acetate (5 mg Tl/kg) daily for 7
days. At sacrifice, brain weights of the treated rats did not differ
significantly froni controls. Succinic dehydrogenase (SDA), monoamine oxidase
(MAO), acid phosphatase (AP), guanine deaminase, and protease (cathepsin)
activities were significantly decreased In the corpus striatum of the treated
animals. Protein content of the corpus striatum was significantly increased,
presumably because of decreased lysosomal activity, which was evidenced by the
decreases in activities of cathepsin and AP. To assess the electrophysiologic
effects of thallium, the firing rate of 27 neurons in the caudate nucleus was
recorded in five rats prior to intravenous administration of thallium acetate
(10 mg Tl/kg), followed by the recording of neuronal activity for 3 to 4 hours
after dosing. Similar recordings were conducted in controls before and after
dosing with physiological saline. Thallium acetate caused a significant
increase in the firing rate of 79% of the investigated neurons in the caudate
nucleus. This increase could have been due to a direct stimulation of caudate
neurons or to an imbalance of neurotransmitters, as suggested by the decrease
in MAO activity. .
Marwaha et al. (1980) studied the effect of thallium on
catecholaminergic transmission in the rat cerebellum. Adult male Sprague-
Oawley (SO) rats were injected Intraperitoneally with thallous acetate (4
mg/kg) daily, for 1 week. (It was not clear whether the dose referred to
thallium or to thallous acetate.) Recordings of electrophysiological activity
of single neurons revealed a significant increase in the spontaneous discharge
rate of Purkinje neurons in the thai Hum-treated rats. In parallel
experiments, the authors observed that neither direct stimulation of the locus
ceruleus, which is linked to the Purkinje neurons by a norepinephrine-
containing pathway, nor administration of amphetamine, haloperidol, or
VII-3
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6-hydroxydopamine had any effect on spontaneous discharge rate of Purkinje
neurons of the thallium-treated rats. Based on these observations, the
authors concluded that thallium exposure disrupts central catecholaminergic
transmission in central neurons.
Hamilton et al. (1985) investigated the correlation between levels of
lipid peroxidation in various regions of the brain and behavioral pattern
changes in rats treated with thallium. Hale rats were injected .
intraperitoneally with thallous acetate, 6 mg/kg/day (4.7 mg Tl/kg/day) for 7
days. . At days 4, 8, 12, and 21,. groups of rats were sacrificed for assessment
of lipid peroxidation in the brain. Lipid peroxidation was found in various
regions of the brain and decreased in the following order: cerebellum, brain
stem, corpus striatrum, hippocampus, cortex, and midbrain. Changes in motor
activity observed after dosing were consistent with cerebellar injury.
Hasan et al. (1978).also reported ultrastructural changes in rat
cerebellar neurons. The animals were dosed intraperitoneally with thallous
acetate (5 mg Tl/kg/day) for 7 days. Electron microscopic examination of
cerebellar neurons revealed abnormally shaped mitochondria, electron dense
bodies (often vacuolated), well-developed Golgi zones, and maltilamellar
bodies (some of these within mitochrondria). The authors speculated that
thai Hum-induced alterations in the mitochondrion might be associated with the
formation of the multilamellar bodies.
2. In vitro effects
Spencer et al. (1973) studied the ultrastructural changes in nerve
tissue exposed to thallium in vitro. Combination cultures for dorsal root
ganglia, spinal cord, peripheral nerve, and muscle from fetal mice were
exposed to either thallous acetate (10 »g/mL) or to thallous sulfate (5 to 10
pg/mL) for up to 4 days. Exposure to thallous sulfate for 24 hours produced
vacuolization In peripheral nervous system (PNS) fibers of both dorsal roots
and their distal outgrowths. Longer exposure led to increased vacuolization,
progressive fiber distortion, and retraction of myelin from the nodes of
VII-4
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Ranvier. Nerve impulses, however, were still able to propagate along the
nerve fibers. Electron microscopic examination of axons of PNS fibers
revealed a sequential pattern of mitochondria! destruction. After 2 to 8
hours of exposure to thallous salts, the mitochondria were enlarged. Within
24 to 48 hours, the mitochondrial matrix became a vacuole bounded by the
original mitochondrial membrane. Comparable but less severe changes were seen
in dorsal root ganglion neurons and in central nervous system fibers.
Wiegand et al. (1984) studied the effect of thallium on spontaneous
transmitter release at the rat neuromuscular junction. Changes in the
frequency of spontaneous miniature endplate potentials (MEPPs) were used.as an
indicator of the effect of thallium on spontaneous release of transmitter
quanta from presynaptic nerve terminals. Recordings of HEPPs were done from
neuromuscular junctions of the rat phrenic nerve-diaphragm preparation
in vitro. Incubation with thallous acetate at concentrations of 1 and 0.5 mM
resulted in a tenfold increase in the frequency of MEPPs within 30 and 180
minutes, respectively. The authors concluded that thallium increased the
spontaneous release of transmitter quanta from presynaptic terminals. The
mechanism of the effect was not elucidated.
Windebank (1986) studied the inhibitory effect of thallium on neurite
outgrowth from dorsal root ganglion (DRG) neurons. ORG explants from E15 rat
pups were cultured in the presence of thallous nitrate at concentrations in
the range of 10"a to 10*7 M. Neurite outgrowth was measured for up to 80 hours
of incubation. Complete inhibition and 50% inhibition of neurite outgrowth
occurred at 4.8 x 10"4 and 1.3 x 10"4 M thallous nitrate, respectively.
0. CYTOTOXICITY - '
Cavanagh and Gregson (1978) studied the effect of thallium on the
proliferation of hair follicle cells in rats. Wistar rats (aged 4 oP7 days)
were administered thallous sulfate subcutaneously at a dose of 30 mg/kg (24 mg
Tl/kg) and were sacrificed at various times thereafter. There was a marked
decline in mitotic rate of hair follicle cells over a 48-hour period after
VII-5
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treatment. In-parallel studies with 7-day-old pups, at the same thallium
dose, no significant effects were observed on cell cycle parameters of hair
follicle cells.
Tan et al. (1984) examined the cytotoxicity of thallium and other metal
ions in Chinese hamster ovary (CHO) cells in vitro. The cloning efficiency of
CHO cells was reduced by 50% (CDM) when cultured in the presence of 150 *M
thallous nitrate.
E. EFFECTS ON CARTILAGE FORMATION
Nogami and Terashima (1973) studied in vivo the incorporation of MS into
mucopolysaccharides in thallium-treated rats. SO rats were administered
Intraperitoneal injections of thallous sulfate at dose levels of 16 and 32 mg
Tl/kg, respectively, on days 6 and 9 after birth. On day 18 after birth, the
rats were injected with an unspecified dose of "SO, and were sacrificed 3
hours later for removal of cartilage from long bones. Histological
examination revealed severely hypoplastic columnar cartilage of the long bones
and defective zones of calcification. Incorporation of "S into cartilage
mucopolysaccharides in the thallium-treated rats was found to be reduced to
50% of that observed in controls.
F. INTERACTIONS
1. Interactions With Potassium
In addition to the direct Interactions of thallium with potassium ion at
the molecular level, reviewed above, other authors have studied
thallium/potassium interactions at the organismal level. These interactions,
reviewed below, are reported to result in alterations in the acute toxicity
and in vitro teratogenic potential of thallium depending on the relative
thallium/potassium levels.
VII-6
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Gehring and Hammond (1967) studied the interaction between thallium and
potassium in rats and dogs. Sprague-Dawley male rats were maintained on low
potassium commercial diets supplemented with either 0,, 15.5, or 25 mEq
potassium per 100 g of diet for at least 3 days prior to thallium dosing.
Groups of five rats from each of the above three groups were dosed
intravenously with ^Tl, as thallium nitrate, at tracer level (<0.1 mg Tl/kg)
or at 10 mg Tl/kg. Urine and feces were collected for 14 days to assess
excretion of tnallium. Total excretion of thallium increased with an increase
in potassium intake. In the animals dosed with tracer level: cf thallium,
total excretion of thallium amounted to 65.0, 83.3, and 86.0% of the dose, for
the low, medium, and high potassium diets, respectively. In the animals
administered the high thallium dose, total excretion of thallium amounted to
52.7, 64.7, and 79.2% of the dose, for the low, medium, and high potassium
diets. The Increased thallium excretion was due solely to an increase in
urinary excretion of thallium. In parallel experiments in rats, it was
observed that the intravenous LDM for thallium nitrate increased from 12.5 to
14.5 mg Tl/kg for rats maintained on diets containing 15.5 and 25 mEq
potassium per 100 g of diet, respectively.
The interaction between potassium and thallium was further studied in
dogs. The dogs were fed diets containing potassium at 0.3 or 25.3 mEq/100 g
of diet and were dosed intravenously with "T1, as thallium nitrate at a dose
level of 5 mg Tl/kg. Urinary excretion of thallium was 30 to 40% of the dose
for the low-potassium diet and 80 to 90% of the dose for the high-potassium
diet at 2 weeks postdosing. The authors also found that infusion of potassium
increased the.renal clearance of thallium and increased the mobilization of ^
thallium from tissues. The above observations, together with their finding
that 1 to 4 mH thallous Ion may substitute for potassium in activating rat
erythrocyte (Na*-K*)-dependent ATPase in vitro, suggested to the authors that
the uptake and release of thallium and potassium may be interrelated.
Neubert and Bluth (1985) studied the effect of varying concentrations of
thallium and potassium on mammalian limb development in culture. When limbs
of 11-day-old embryos of an unspecified mammalian species were incubated in
VII-7
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the presence of 6 mM potassium and of 15 »M thallium (anlon unspecified),
differentiation of the cartilaginous bone anlagen was slightly impaired. When
the concentration of thallium was raised to 50 »M, clear-cut abnormal
development of the scapula and paw skeleton occurred. The effect was partly
prevented by raising the concentration of potassium ion to 17 mM.
2. Aversion to Saccharin
Peele et al. (1986) studied the aversion to «cch»rin induced in rats by
thallium administration. Male, Long-Evans, 40-day-old rats on a water
deprivation schedule received an initial exposure to 0.1% sodium saccharin in
water for 30 minutes followed 20 minutes later by oral or intraperitoneal
dosing with thallous sulfate at levels of 0, 2.5, 5, 10, or 20 mg/kg
(corresponding to 0, 2.0, 4.0, 8.1, or 16.2 mg Tl/kg). Two days later the
rats were offered a choice between the saccharin solution and water, followed
by oral or intraperitoneal dosing with thallium as above. The cycle
choice/thallium dosing was then repeated two more times. Vehicle-treated and
nontreated rats consistently preferred the saccharin solution. The rats dosed
orally with thallium showed a robust, dose-dependent aversion to saccharin for
all three choice trials. The intraperitoneally dosed rats developed only a
marginal aversion to saccharin, which occurred only at the highest dose level.
The nature of the route specificity for the development of saccharin aversion
was not elucidated.
G. SUMMARY
The mechanism of action of thallium has not been elucidated. Some
studies indicate that thallium may substitute for potassium in activation of
(NA*-K*)-dependent ATPase or it may be taken up by mitochondria, where it
disrupts oxidative phosphorylation.
Thallous ion replaced potassium in the activation of (Na*-IC)-dependent
ATPase from rabbit kidney, with a half-maximal activity at 0.16 to 0.20 mM.
VII-8
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Likewise, thallous ion at 1 to 4 mH was found to substitute for potassium ion
in activation of the (Na*-K*)-dependent ATPase activity from rat erythrocytes.
Thallium uptake into rabbit erythrocytes was reported to be fast and to
produce internal to external thallium concentrations in the ratio of 8.7 to 1.
Uptake of thallium was inhibited by 5 mM K*. In experiments with human
erythrocytes, 0.03 to 0.05 mM external thallous ion stimulated the efflux of
"Na* into a potassium-free medium and competitively inhibited, at external
concentrations of 0.05 to 0.15 mM, the ouabain-sensitive influx 4ZK* in
erythrocytes. The relative n*/K* affinity for K* sites of the sodium pump was
estimated to be in the range of 3 to 5.
In experiments with rat liver mitochondria, 8 mM thallous ion inhibited
leakage of potassium by 50% and inhibited potassium uptake (at 25 mM K*) by
75%. The inhibition of potassium uptake was dependent on the TT/K* ratios,
indicating competition between the two ions. Binding to mitochondria! protein
was also observed at 8 mM thallous ion. Oxidative phosphorylation was found
to be inhibited by thallous ion, with a half-maximal activity at 6.5 mM
thallium. Several IQ yjvo and IQ vitro effects of thallium appear to have
been related to disturbances at the level of presynaptic events.
In la vivo studies, intraperitoneal dosing of rats with thallous acetate
(5 ing Tl/kg) for 7 days produced a decrease in enzyme activities, including
monoamine oxidase (MAO) of the corpus striatum. With a single dose of 10 mg
Tl/kg, an increase in firing rate of neurons of the caudate nucleus was
observed. In another study, an increase in the rate of discharge of Purkinje
neurons was observed in rats injected with thallous acetate. The effect was
attributed to catecholaminergic transmission in central neurons.
In rats dosed with thallous acetate (4.7 mg Tl/kg/day) for 7 days, lipid
peroxidation was found in several brain regions. Changes in motor activity
observed after dosing were consistent with cerebellar injury. Likewise,
dosing of rats with thallous acetate (5 mg Tl/kg/day) for 7 days resulted in
ultrastructural damage to cerebellar neurons.
VII-9
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In In vitro studies, exposure of combination cultures of dorsal root
ganglia-spinal cord-peripheral nerve to thallous acetate (0.04 mM) or sulfate
(0.01 to 0.02 mM) produced mitochondria! degeneration in central and
peripheral neurons. Incubation of rat phrenic nerve-diaphragm preparations
with thallous acetate (0.5 to 1 mM) produced an increase in spontaneous
release of transmitter quanta from presynaptic terminals. ThaTlous nitrate
(1.3 x 10"* M) produced a 50% inhibition of neurite outgrowth from rat dorsal
root ganglion neurons.
Cytotoxic effects have been reported for thallium in vitro and in vivo.
Cloning efficiency of CHO cells was Inhibited 50% by 150 »M thallous nitrate.
Subcutaneous administration of thallous sulfate (24 mg Tl/kg) to 4- or 7-day-
old rats produced a marked decline in mitotic rate of hair follicle cells over
a 48-hour period after treatment.
Intraperitoneal administration of thallous sulfate to 18-day-old rats
inhibited the incorporation of MS04 into cartilage mucopolysaccharides by 50%.
Besides interactions with potassium at the molecular level, there have
been reports of TT/K* interactions at the organ or tissue level. Total
excretion of thallium increased with an increase in potassium intake in rats
and dogs dosed with thallous nitrate and maintained on low-or high-potassium
diets. Furthermore, 1t was observed in rats that the LDM for thallous
nitrate Increased with an increase of potassium 1n the diet. In dogs, it was
observed that infusion of K* increased the renal clearance and the
mobilization of thallium from tissues. In in vitro studies of mammalian limbv—•-
development, it was observed that the extent of thallium-induced teratogenesis
was affected by the ratio of TT/K* in the medium.
Dose-dependent aversion to saccharin flavor in drinking water was devel-
oped in rats after one exposure to 0.1% sodium saccharin in water followed 20
minutes later by oral dosing with thallous sulfate at levels of 2, 4, 8.1, or
16.2 mg Tl/kg. •
VII-10
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VIII. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
The quantification of toxicological effects of a chemical consists of
separate assessments of noncarcinogenic and carcinogenic effects. Chemicals
that do not produce carcinogenic effects are believed to have a threshold dose
below which no adverse, noncarcinogenic health effects occur, while
carcinogens are assumed to act without a threshold.
A. PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS
1. Noncarcinoqenic Effects
In the quantification of noncarcinogenic effects, a Reference Dose (RfD),
formerly called the Acceptable Daily Intake (ADI), is calculated. The RfD is
an estimate (with an uncertainty spanning perhaps an order of magnitude) of a
daily exposure of the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious health effects during
a lifetime. The RfD is derived from a No-Observed-Adverse-Effect Level
(NOAEL), or Lowest-Observed-Adverse-Effect Level (LOAEL), identified from a
subchronic or chronic study, and divided by an uncertainty factor(s). The RfD
is calculated as follows:
RfD - (NOAEL or LOAEL)
Uncertainty factor(s)
mg/kg bw/day
Selection of the uncertainty factor to be employed in the calculation of
the RfD is based on professional judgment while considering the entire data
base of toxicological effects for the chemical. To ensure that uncertainty
factors are selected and applied in a consistent manner, the Office of
Drinking Water (ODW) employs a modification to the guidelines proposed by the
National Academy of Sciences (NAS, 1977, 1980) as follows:
VIII-1
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. An uncertainty factor of 10 is generally used when good chronic or
subchronic human exposure data identifying a NOAEL are available and
are supported by good chronic or subchronic toxicity data in other
species.
. An uncertainty factor of 100 is generally used when good chronic
toxicity data identifying a NOAEL are available for one or more
animal species (and human data are not available), or when1 good
chronic or subchronic toxicity data identifying a LOAEL in humans are
available.
• An uncertainty factor of 1,000 is generally used when limited or
Incomplete chronic or subchronic toxicity data are available, or when
good chronic or subchronic toxidty data identifying a LOAEl, but not
a NOAEL, for one or more animal species are available.
The uncertainty factor used for a specific risk assessment is based
principally on scientific .judgment rather than scientific fact and accounts
for possible intra- and interspecies differences. Additional considerations,
which may necessitate the use of an additional uncertainty factor of 1 to 10,
not incorporated in the NAS/ODW guidelines for selection of an uncertainty
factor include the use of a less-than-lifetime study for deriving an RfD, the
significance of the adverse health effect, pharmacokinetic factors, and the
counterbalancing of beneficial effects.
From the RfD, a Drinking Water Equivalent Level (DUEL) can be calculated.
The DWEL represents a medium-specific (i.e., drinking water) lifetime
exposure, a$ which adverse, noncarcinogenic health effects are not anticipated
to occur. The DWEL assumes 100% exposure from drinking water. The DUEL
provides the noncarcinogenic health effects basis for establishing a drinking
water standard.
VIII-2
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For Ingestion data, the DWEL 1s derived as follows:
DWEL - RfD x (body weight in kol
Drinking water volume in L/day
where:
Body weight - assumed to be 70 kg for an adult.
.„ Drinking water volume • assumed to be 2 L per day for an adult.
In addition to the RfD and the DWEL, Health Advisories (HAsJ for
exposures of shorter duration (One-day, Ten-day, and Longer-term) are
determined. The HA values are used as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
The HAs are calculated using an equation similar to the RfD and DWEL; however,
the NOAELs or LOAELs are identified from acute or subchronic studies. The HAs
are derived as follows:
HA » fNOAEL or LOAEL) x fbwl
(UF) x ( L/day)
•i/L (.
Using the above equation, the following drinking water HAs are developed
for noncarcinogenic effects:
1. One-day HA for a 10-kg child ingesting 1 L water per day.
2. Ten-day HA for a 10-kg child ingesting 1 L water per day.
3. Longer-term HA for a 10-kg child ingesting 1 L water per day.
4. Longer-term HA for a 70-kg adult ingesting 2 L water per day.
The One-day HA calculated for a 10-kg child assumes a single acute .expo-
sure to the chemical and is generally derived from a study of less than 7 days
duration. The Ten-day HA assumes a limited exposure period of 1 to 2 weeks
and is generally derived from a study of less than 30 days duration. The
Longer-term HA is derived for both a 10-kg child and a 70-kg adult and assumes
an exposure period of approximately 7 years (or 10% of an individual's
VIII-3
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lifetime). The Longer-term HA 1s generally derived from a study of subchronic
duration (exposure for 10% of an animal's lifetime).
2. Carcinogenic Effects
The EPA categorizes the carcinogenic potential of a chemical, based on
the overall weight of evidence, according to the following scheme:
• Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between
exposure to the chemical and human cancer.
• Group B: Probable Human Carcinogen. Sufficient evidence of
carcinogenlcity 1n animals with limited (Group Bl) or
Inadequate (Group B2) evidence in humans.
• Group C: Possible Human Carcinogen. Limited evidence of
carcinogenicity in animals in the absence of human data.
• Group D: Not Classified as to Human Carcinooenicitv. Inadequate
human and animal evidence of carcinogenicity or for which no
data are available.
• Group E: Evidence of Noncarcinogenicitv for Humans. No evidence of
carcinogenicity in at least two adequate animal tests in
.- different species or in both adequate epidemiologic and
animal studies.
If toxicological evidence leads to the classification of the contaminant
as a known, probable, or possible human carcinogen, mathematical models are
used to calculate the estimated excess cancer risk associated with the inges-
tion of the contaminant in drinking water. The data used in these estimates
usually come from lifetime exposure studies in animals. To predict the risk
for humans from animal data, animal doses must be converted to equivalent
VIII-4
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'•*.
human doses. This conversion includes correction for noncontinuous exposure,
less-than-lifetinie studies, and for differences in size. The factor that
compensates for the size difference is the cube root of the ratio of the
animal and human body weights. It is assumed that the average adult human
body weight is 70 kg, and that the average water consumption of an adult human
is 2 liters of water per day.
For contaminants with a carcinogenic potential, chemical levels are cor-
related with a carciryjgenic risk estimate by employing a cancer potency (unit
risk) value together with the assumption for lifetime exposure via ingestion
of water. The cancer unit risk is usually derived from a linearized
multistage model with a 95% upper confidence limit providing a low-dose
estimate; that is, the true risk to humans, while not identifiable, is not
likely to exceed the upper limit estimate and, in fact, may be lower. Excess
cancer risk estimates also may be calculated using other models such as the
one-hit, Weibull, logit, and probit. There is little basis in the current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than any
others. Because each model is based on differing assumptions, the estimates
that are derived for each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement. In most cases, only studies using
experimental animals have been performed. Thus, there is uncertainty when the
data are extrapolated to humans. When developing cancer risk rate levels,
several other areas of uncertainty exist, such as the incomplete knowledge
concerning the health effects of contaminants in drinking water; the impact of
the experimental animal's age, sex, and species; the nature of the target
organ system(s) examined; and the actual rate of exposure of the internal
targets in experimental animals or humans. Dose-response data usually are,
available only for high levels of exposure, not for the lower levels of
exposure closer to where a standard may be set. When there is. exposure to
VIII-5
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more than one contaminant, additional uncertainty results from a lack of
Information about possible synergistic or antagonistic effects.
B. QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR THALLIUM
1. One-day Health Advisory
The lethal effects of thallium ingestion have been documented in
children, adults, and laboratory animals. In humans, ingestion of doses of
about 3 to 15 mg/kg have been shown to cause death. A variety of thallium
salts have been tested 1n rats and mice, with oral LDsos ranging from 16 to 46
mg Tl/kg. No studies were found that identified a NOAEL or LOAEL based on
appropriately sensitive endpoints of toxiclty suitable for derivation of a
One-day HA value. Because of concern for the serious health effects
associated with exposure to thallium, it 1s recommended that the Longer-term
HA value for the 10-kg child, 7.0 «g Tl/L, be used as a conservative estimate
of the One-day HA value.
2. Ten-dav Health Advisory
No suitable toxiclty studies following repeated dosing were found in the
available literature. Table VIII-1 summarizes two developmental toxicity
studies in which rats and mice were administered thallium over a 10-day
period. Both studies define a LOAEL of 2.3 mg Tl/kg/day, the lowest dose
tested. These studies were not appropriate for determining the 10-day HA;
serious developmental effects were observed at this dose, and similar doses (3
to 15 mg/kg) may be fatal to humans. Because of concern for the serious
health effects associated with exposure to thallium, it is recommended that
the Longer-term HA value for the 10-kg child, 7.0 #g T1/U be used as a
conservative estimate of the Ten-day HA value.
3. Longer-term Health Advisory
Table VIII-2 summarizes the studies considered for derivation of the
Longer-term HA values for thallium. All subchronic studies were done with
VIII-6
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Table VIII-1. Summary of Candidate Studies for Derivation of the
Ten-day Health Advisory for Thallium
Species Route
Exposure
duration
Endpoints
NOAEl IOAEL
(mg Tl/kg (mg Tl/kg
bw/day) bw/day) Reference
Rat
Oral
Mouse Oral
10 days
(days 6 to
15 of ges-
tation),
10 days
(days 6 to
15 of ges-
tation):
Develop-
mental
toxicity
Develop-
mental
toxicity
NO4
NO
2.3 Claussen
. et al. (1981)
2.3 Claussen
et al. (1981)
•ND • Not determined.
VIII-7
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Table YII1-2.
Summary of Candidate Studies for Derivation of the Longer-term
Health Advisory for Thallium
Route
Oral
(diet)
Exposure
duratl on
(weeks)
13
Endpoints
Enzyme levels and
electrolytes In
HOAEL
(mg n/kg
bw/day)
0.2
LOAEL
(mg Tl/kg
bw/day)
m ^
Reference
Stoltz et al. (1986)
Oral
(diet)
Oral
(drinking
water)
Oral
(drinking
water)
Subcutaneous
15
36
24
serum
Neurot ox1 dty,
axonal destruction,
mortality
Reduced sperm
motlllty. Increased
numbers of Immature
epididymal sperm
cells, vacuolization
of SertoH cells
Hlstopathological
changes in kidney.
liver, brain at the
electron microscopic
level
0.4
1.2
1.4*
0.74*
-*
Downs et al. (1960)
Kanzo et al. (1983)
Formlgll et al. (1986)
0.6C
Herman and Bensch
(1967)
'Only one dose level was administered.
*Zasukh1na et al. {1981, 1983) have also reported reproductive effects of thallium in rats. However, from
data present In their report 1t was not possible to assess the statistical significance of their results or
verify the accuracy of the dose levels administered.
eAn Initial subcutaneous Injection (in the range of 7.8 to 15.5 mg H/kg) was administered, followed by
weekly subcutaneous injections at 3.9 mg Tl/kg (approximately 0.6 mg Tl/kg/day for a 7-day week).
VIII-8
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rats. Several endpoints of toxicity were noted including increased mortality
(Manzo et al., 1983); alopecia (Stoltz et al., 1986; Downs, 1960; Nanzo
et al., 1983); histopathological changes observed at the light microscopic
level in nerve cells (Manzo et al., 1983) and testes (Formigli et al., 1986);
and at the electron microscopic level, effects on the liver, brain, and kidney
(Herman and Bensch, 1967). It is not possible to determine which of these
effects is the most sensitive endpoint of toxicity. Studies performed at the
lowest doses failed to test for testicular toxicity of effects at. the electron
microscopic level. In no study is a range of doses tested that demonstrates a
relationship between thallium toxicity and administered dose.
Two subchronic studies have reported on the toxicity of thallium
administered in drinking water. Manzo et al. (1983) reported axonal
destruction and increased mortality 1n rats administered 1.4 mg Tl/kg/day in
the drinking water for 36 weeks, and Formigli et al. (1986) reported decreased
sperm motility, epididymal sperm with increased numbers of immature cells, and
Sertoli cells showing cytoplasmic vacuolization in rats administered 0.74 mg
Tl/kg/day, in the drinking water, for 60 days. Neither study is suitable for
derivation of the Longer-term HA. In both studies, serious effects were
observed at the one dose tested, and no data on the dose-response relationship
are provided for extrapolating effects to lower doses.
Herman and Bensch (1967) reported histopathological changes in kidney,
liver, and brain of rats dosed subcutaneously with thallium. Following an
initial subcutaneous injection (precise dose unspecified, in the range of 7.8
to 15.5 mg Tl/kg)V rats were administered weekly subcutaneous injections of tx-
3.9 mg Tl/kg, generally once each week (approximately 0.6 mg Tl/kg/day), for
up to 24 weeks. The uncertainty in the dosing protocol, the relatively high
levels of thallium administered in each weekly dose, and the difficulties in
extrapolating between subcutaneous and oral administration make this study
unsuitable for derivation of HA values.
In the two remaining studies, thallium toxicity was tested over a range
of doses via oral administration. Although both studies identify a NOAEL,
VIII-9
-------
tests for testlcular effects and neurotoxicity, which were observed in other
studies (Fornrigli et al., 1986; Herman and Bensch, 1967), were not conducted.
The study of Downs (1960) defines a LOAEL of 1.2 mg Tl/kg/day. Based on the
appearance of alopecia in Wistar rats maintained for up to 15 weeks on a
thallium-containing diet, the NOAEL was 0.4 mg Tl/kg/day. Stoltz et al.
(1986) reported moderate changes in blood chemistry in rats dosed, by gavage,
with 0.008 to 0.20 mg Tl/kg/day for 13 weeks. These changes included
increases in SCOT, LDH, and sodium levels. Although the enzymatic activities
were significantly elevated with respect to vehicle controls, it was not
possible to ascertain that the effects were dose related owing to the
scattering of data points. Furthermore, gross pathologic and light-
microscopic evaluation of organs and tissues did not reveal any significant
treatment -related effects. The only gross finding at necropsy thought to be
treatment related was alopecia; however, light-microscopic examination did not
reveal any histopathologic alteration that would indicate damage to hair
follicles. Based on the results of this study, in the absence of confirmatory
histological evidence, the dose of 0.20 mg Tl/kg/day is considered to be a
NOAEL. Based on this study, Longer-term HA values were derived as follows:
Longer-term HA^ - (0.20 ma n/ko/davl (10 kol -6,67 mg/L (7
(100) (3) (1 L/day)
where:
0.20 mg Tl/kg/day - NOAEL, based on the absence of gross or light-
microscopic histopathology in rats exposed to
thallous sulfate, by gavage, for 90 jiays.
100 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
3 » extra uncertainty factor to account for inadequate
testing of other species, endpoints and uncertainties
with the critical study.
10 kg - assumed weight of a child.
1 L/day « assumed water consumption of a 10-kg child.
V1II-10
-------
Longer-term HA,,,,,,, - fO.20 mo Tl/ka/dav) (70 kol - 0.023 mg/L (20 *g/L)
(100) (3) (2 L/day)
where:
0.20 rag Tl/kg/day - NOAEL, based on the absence of gross or light-
microscopic histopathology in rats exposed to
thallous sulfate, by gavage, for 90 days.
100 • uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
3 • extra uncertainty factor to account for inadequate
testing of other species, endpoints and uncertainties
with the critical study.
70 kg • assumed weight of an adult.
2 L/day - assumed water consumption of a 70-kg adult.
No existing guidelines or standards were located for longer term
(subchronic) exposure to thallium.
4. • Reference Dose and Drinking Water Equivalent Level
Table VIII-2 summarizes studies considered for derivation of the RfO and
DWEL for thallium.
Based on the rationale presented in the previous section (Section VIII.
B.3), the 90-day study with rats by Stoltz et al. (1986) has been selected for
calculation of the RfD and DWEL. A NOAEL of 0.2 mg Tl/kg/day was established,
based on the absence of gross and light-microscopic histopathological effects.
Although the study by Stoltz et al. (1986) revealed no histopathological
lesions at the light microscopic level, some uncertainty remains as to whether
any lesions would have been found at the electron microscopic level,
correlating with the blood chemistry changes that suggest some form of
extrahepatic damage. In fact, Herman and Bensch (1967) reported absence of
light-microscopic histopathology, in the presence of ultrastructural effects
in cells of kidney, liver, and brain of rats dosed with weekly intraperitoneal
VIII-11
-------
injections of 3.9 mg Tl/kg (approximately 0.6 mg Tl/kg/day) for at least 24
weeks.
Additional uncertainty is introduced into the NOAEL of 0.2 mg Tl/kg/day
defined by the study of Stoltz et al. (1986) by the observations of Formigli
et al. (1986). These authors reported that 0.74 mg Tl/kg/day administered in
the drinking water for 8 weeks produced reduced sperm motility and
vacuolization of Sertoli cells and increased the number of immature epididymal
sperm cells. Because the study of Formigli et al. (1986) was performed it
only one dose level and thus there is no dose-response curve, it is not
possible to rule out whether the testicular effects reported by Formigli et
al. (1986) would occur at or below the selected NOAEL value of 0.2 mg
Tl/kg/day, especially during long-term exposures.
Thus, in view of the uncertainty associated with the selected NOAEL value
of 0.2 mg Tl/kg/day, an uncertainty factor of 3 has been introduced into the
following calculations to account for inadequate testing of other endpoints of
toxicity. This factor of 3 is in addition to the factor of 1,000 for use with
an animal study of less-than-lifetime duration.
Using the study of Stoltz et al. (1986), the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - fO.25 ma TI.SOVkQ/davl » 0.08 »g TLSOykg/day
(l.pOtt) (3) ^
- 0.07 *g Tl/kg/day
where:
0.25 mg TlaSOykg/day - NOAEL, based on the absence of gross or light-
*' microscopic histopathology in rats exposed to
thallous sulfate, by gavage, for 90 days.
1,000 - uncertainty factor, chosen in accordance with
NAS/OOW guidelines for use with a NOAEL for an
animal study of less-than-lifetime duration.
VIII-12
-------
additional uncertainty factor to account for
inadequate testing of other species, endpoints of
toxicity, and uncertainties with the critical
study.
Step 2: Determination of the Drinking Water Equivalent Level (DUEL)
DWEL - fO.Q7 uo Tl/kQ/davl (70 kal
2 L/day
2.45 ,g T1/L (2-0 *g Tl/L)
where:
0.07 »g Tl/kg/day - RfD.
70 kg • assumed weight of an adult.
2 L/day - assumed water consumption of a 70-kg adult.
Thallium salts are designated as a hazardous substance under Section
311(b){2)(A} of the Federal Water Pollution Control Act and further regulated
by the Clean Water Act Amendments of 1977 and 1978. These regulations apply
to discharges of these substances (U.S. EPA, 19S6a).
The reportable quantity of thallium salts, when discharged into or upon
the navigable waters and adjoining shorelines of the United States, is 1,000
pounds (454 kg) (U.S. EPA, 1986b).
C. QUANTIFICATION OF CARCINOGENIC EFFECTS FOR THALLIUM
1. Characterization of Carcinogenic Potential
The carcinogenic potential of thallium has not been evaluated by the U.S.
EPA or the International Agency for Research on Cancer (IARC). Thallium has
been found to be genotoxic in IQ vitro assays with mammalian cells (see
Table V-2).
VIII-13
-------
2. Quantitative Carcinogenic Risk Estimates
No quantitative assessment of excess cancer risk has been reported.
D, SUMMARY
Table VIII-3 summarizes HA and DWEL values calculated on the basis of
noncarclnogenic endpolnts. No estimations of excess cancer risk were
performed.
VIII-14
-------
Table VIII-3. Summary of Quantification of lexicological Effects for Thallium
Value
Drinking water
concentration
Tl/L)
Reference
One-day HA for a 10-kg child — ' . --
Ten-day HA for a 10-kg child --• .--•-'. «-
Longer-term HA for
Longer-term HA for
DWEL (70-kg adult)
Excess cancer risk
a 10-kg child 7.0
a 70-kg adult 20.0
2.0
do-)
Stoltz et al. (1986)
Stoltz et al. (1986)
Stoltz et al. .(1986)
--
'The Longer-term HA for a 10-kg child is recommended as a conservative
estimate of the One-day and Ten-day HA values.
VIII-15
-------
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