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www. epa. gov/iris
f/EPA
TOXICOLOGICAL REVIEW
OF
THALLIUM and COMPOUNDS
(CAS No. 7440-28-0)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
January 2008
NOTICE
This document is an External Review draft. This information is distributed solely for the
purpose of pre-dissemination peer review under applicable information quality guidelines. It has
not been formally disseminated by EPA. It does not represent and should not be construed to
represent any Agency determination or policy. It is being circulated for review of its technical
accuracy and science policy implications.
U.S. Environmental Protection Agency
Washington, DC
-------
DISCLAIMER
This document is a preliminary review draft for review purposes only. This information
is distributed solely for the purpose of pre-dissemination peer review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not
represent and should not be construed to represent any Agency determination or policy. Mention
of trade names or commercial products does not constitute endorsement or recommendation for
use.
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CONTENTS—TOXICOLOGICAL REVIEW OF THALLIUM AND COMPOUNDS
(CAS No. 7440-28-0)
LIST OF TABLES v
LIST OF ACRONYMS AND ABBREVIATIONS vi
FOREWORD viii
AUTHORS, CONTRIBUTORS, AND REVIEWERS ix
1. INTRODUCTION 1
2. CHEMICAL AND PHYSICAL INFORMATION 3
3. TOXICOKINETICS 5
3.1. ABSORPTION 5
3.2. DISTRIBUTION 5
3.3. METABOLISM 6
3.4. ELIMINATION 6
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS 7
4. HAZARD IDENTIFICATION 8
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS 8
4.1.1. Incident/Case Reports 8
4.1.2. Population Surveys 14
4.1.3. Occupational Exposure 15
4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIO AS SAYS
IN ANIMALS—ORAL AND INHALATION 17
4.2.1. Oral Exposure 17
4.2.2. Inhalation Exposure 24
4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES 24
4.4. OTHER ENDPOINT-SPECIFIC STUDIES 31
4.4.1. Liver and Kidney Toxicity 31
4.4.2. Cardiotoxicity 38
4.4.3. Neurotoxicity 38
4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE
OF ACTION 42
4.5.1. Interference with Potassium Transport 43
4.5.2. Disturbance of Mitochondrial Function and Induction of Oxidative Stress 43
4.5.3. Reaction with Thiol Groups 44
4.5.4. Other Endpoint-specific Mechanistic Data 44
4.5.5. Genotoxicity 47
4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS 48
4.6.1. Oral 48
4.6.2. Inhalation 50
4.6.3. Mode of Action Information 50
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4.7. EVALUATION OF CARCINOGENICITY 51
4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES 52
4.8.1. Possible Childhood Susceptibility 52
4.8.2. Possible Gender Differences 52
5. DOSE-RESPONSE ASSESSMENTS 53
5.1. ORAL REFERENCE DOSE (RfD) 53
5.1.1. Choice of Principal Study and Critical Effect—with Rationale and
Justification 53
5.1.2. Methods of Analysis 55
5.1.3. RfD Derivation—Including Application of Uncertainty Factors
(UFs) 56
5.1.4. Previous RfD Assessment 60
5.1.5. Uncertainties in the Oral Reference Dose (RfD) 61
5.2. INHALATION REFERENCE CONCENTRATION (RfC) 63
5.3. CANCER ASSESSMENT 63
6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF_HAZARD AND DOSE
RESPONSE 64
6.1. HUMAN HAZARD POTENTIAL 64
6.2. DOSE RESPONSE 66
7. REFERENCES 68
APPENDIX A. Summary of External Peer Review and Public Comments and Disposition A-l
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LIST OF TABLES
Table 1. Chemical and physical properties of thallium and selected thallium salts 4
Table 2. Thallium toxicity in humans, following oral exposure 9
Table 3. Selected blood chemistry values 19
Table 4. Incidence of alopecia in rats exposed to thallium sulfate for 90 days 20
Table 5. Thallium toxicity in animals, following oral exposure 26
Table 6. Thallium toxicity in animals via injection 34
Table 7. Reference doses for soluble thallium salts 58
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LIST OF ACRONYMS AND ABBREVIATIONS
AchE Acetyl cholinesterase
ALA Aminolevulinic acid
ALT Alanine aminotransferase
ARDS Adult respiratory distress syndrome
AST Aspartate aminotransferase
BMD Benchmark dose
BUN Blood urea nitrogen
CASRN Chemical Abstracts Service Registry Number
ChAT Choline acetyltransferase
CHO Chinese hamster ovary
EPA Environmental Protection Agency
F Female
GI Gastrointestinal
GLPs Good Laboratory Practices
GSH Glutathione
5-HT 5-Hydroxytryptamine
i.p. Intraperitoneal
i.v. Intravenous
IRIS Integrated Risk Information System
LD50 Median lethal dose
LDH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
M Male
MAO Monoamine oxidase
MDA Malondialdehyde
MED Minimum effective dose
MEPP Miniature endplate potential
NA Nucleus accumbens
NOAEL No-observed-adverse-effect level
PAD peripheral arterial disease
RfC Inhalation reference concentration
RfD Oral reference dose
s.c. subcutaneous
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SCE Sister chromatid exchange
SCOT Serum glutamic oxaloacetic transferase (now termed AST)
SGPT Serum glutamate pyruvate transaminase (now termed ALT)
SOD Superoxide dismutase
Tl Thallium
UF Uncertainty factor
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FOREWORD
The purpose of this Toxicological Review is to provide scientific support and rationale
for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to thallium
and compounds. It is not intended to be a comprehensive treatise on the chemical or
toxicological nature of thallium and compounds.
The intent of Section 6, Major Conclusions in the Characterization of Hazard and Dose
Response, is to present the major conclusions reached in the derivation of the reference dose,
reference concentration, and cancer assessment, where applicable, and to characterize the overall
confidence in the quantitative and qualitative aspects of hazard and dose response by addressing
the quality of the data and related uncertainties. The discussion is intended to convey the
limitations of the assessment and to aid and guide the risk assessor in the ensuing steps of the
risk assessment process.
For other general information about this assessment or other questions relating to IRIS,
the reader is referred to EPA's IRIS Hotline at (202) 566-1676 (phone), (202) 566-1749 (fax), or
hotline.iris@epa.gov (email address).
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER/AUTHORS
Octavia Conerly, M.S.P.H. (Chemical Manager)
Office of Water
U.S. Environmental Protection Agency
Washington, DC
Robyn B. Blain, Ph.D.
ICF Consulting
Fairfax, VA
REVIEWERS
This document and the accompanying IRIS Summary have been peer reviewed by EPA
scientists and independent scientists external to EPA. Comments from all peer reviewers were
evaluated carefully and considered by the Agency during the finalization of this assessment.
INTERNAL EPA REVIEWERS
Joyce Donohue, Ph.D.
Office of Water
Elizabeth Doyle, Ph.D.
Office of Water
Steven Kueberuwa, Ph.D.
Office of Water
Mike Hughes, Ph.D.
Office of Research and Development
Amal Mahfouz, Ph.D.
Office of Water
Susan Rieth, MPH
Office of Research and Development
David Thomas, Ph.D.
Office of Research and Development
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EXTERNAL PEER REVIEWERS
Name
Affiliation
Summaries of the external peer reviewers' comments and the disposition of their
recommendations are in Appendix A.
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1. INTRODUCTION
This document presents background information and justification for the Integrated Risk
Information System (IRIS) Summary of the hazard and dose-response assessment of thallium
and compounds. IRIS Summaries may include oral reference dose (RfD) and inhalation
reference concentration (RfC) values for chronic and other exposure durations, and a
carcinogenicity assessment.
The RfD and RfC, if derived, provide quantitative information for use in risk assessments
for health effects known or assumed to be produced through a nonlinear (presumed threshold)
mode of action. The RfD (expressed in units of mg/kg-day) is defined as an estimate (with
uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without an appreciable risk of
deleterious effects during a lifetime. The inhalation RfC (expressed in units of mg/m3) is
analogous to the oral RfD, but provides a continuous inhalation exposure estimate. The
inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for
effects peripheral to the respiratory system (extrarespiratory or systemic effects). Reference
values are generally derived for chronic exposures (up to a lifetime), but may also be derived for
acute (<24 hours), short-term (>24 hours up to 30 days), and subchronic (>30 days up to 10% of
lifetime) exposure durations, all of which are derived based on an assumption of continuous
exposure throughout the duration specified. Unless specified otherwise, the RfD and RfC are
derived for chronic exposure duration.
The carcinogenicity assessment provides information on the carcinogenic hazard
potential of the substance in question and quantitative estimates of risk from oral and inhalation
exposure may be derived. The information includes a weight-of-evidence judgment of the
likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic
effects may be expressed. Quantitative risk estimates may be derived from the application of a
low-dose extrapolation procedure. If derived, the oral slope factor is an upper bound on the
estimate of risk per mg/kg-day of oral exposure. Similarly, a unit risk is an upper bound on the
estimate of risk per |ig/m3 air breathed.
Development of these hazard identification and dose-response assessments for thallium
and compounds has followed the general guidelines for risk assessment as set forth by the
National Research Council (1983). EPA guidelines and Risk Assessment Forum Technical
Panel reports that may have been used in the development of this assessment include the
following: Guidelines for the Health Risk Assessment of Chemical Mixtures (U.S. EPA, 1986a),
Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Guidelines for Developmental
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Toxicity Risk Assessment (U.S. EPA, 199 la), Guidelines for Reproductive Toxicity Risk
Assessment (U.S. EPA, 1996), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998a),
Guidelines for Carcinogen Assessment (U.S. EPA, 2005a), Supplemental Guidance for Assessing
Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA., 2005b), Recommendations
for and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988),
(proposed) Interim Policy for Particle Size and Limit Concentration Issues in Inhalation Toxicity
(U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry (U.S. EPA, 1994b), Use of the Benchmark Dose Approach
in Health Risk Assessment (U.S. EPA, 1995), Science Policy Council Handbook: Peer Review
(U.S. EPA, 1998b, 2000a, 2006), Science Policy Council Handbook: Risk Characterization (U.S.
EPA, 2000b), Benchmark Dose Technical Guidance Document (U.S. EPA, 2000c),
Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S.
EPA, 2000d), and A Review of the Reference Dose and Reference Concentration Processes (U.S.
EPA, 2002).
The literature search strategy employed for this compound was based on the Chemical
Abstracts Service Registry Number (CASRN) and at least one common name. Any pertinent
scientific information submitted by the public to the IRIS Submission Desk was also considered
in the development of this document. The relevant literature was reviewed through August 2007.
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2. CHEMICAL AND PHYSICAL INFORMATION
Thallium occurs naturally in the earth's crust. Metallic thallium (Tl) is bluish-white or
grey, very soft, malleable, and insoluble in water. Thallium is a Group IIIA metal, one whose
salts do not hydrolyze at pH > 7 to form insoluble hydroxides. According to Mulkey and Oehme
(1993), this is a physical property that contributes to thallium's marked toxicity. Thallium exists
in monovalent [thallous; thallium (I); Tl+1] and trivalent [thallic; thallium (III); Tl+3] states.
Monovalent thallium is favored in the standard potential of Tl+3/Tl+1 coupling with a redox
potential of+1.25V (Tl+3 + 2e" goes to Tl+1). According to Pearson (1963), monovalent thallium
is a Lewis acid (electron pair receiver) that prefers to interact with inorganic and organic sulfur,
carbon, phosphorous and arsenic moieties as the electron pair donor (Lewis base). Monovalent
thallium ions also are more stable in aqueous solution, but trivalent thallium (Tl+3) can be
stabilized by complexing agents (Sabbioni et al., 1980a). Trivalent thallium forms more stable
organic compounds than monovalent thallium.
Monovalent thallium is similar to potassium (K+) in ionic radius and electrical charge,
which contribute to its toxic nature. Many of the thallium salts are soluble in water with the
exception of thallium (III) oxide, which is insoluble. Thallium compounds and their chemical
and physical properties are listed in Table 1.
According to IPCS (1996), thallium is used only in small amounts by industry, and thus
worldwide production of pure thallium is low. Sources for the production of thallium are zinc,
lead and sometimes copper or iron smelters and sulfuric acid plants. In 1981 the production of
thallium in the United States was discontinued. Thallium is released to the environment through
the combustion of fossil fuels (in particular coal-fired power-generating plants), refinement of oil
fractions, the smelting of ferrous and non-ferrous ores (including lead, copper and zinc), and by
some other industrial processes such as cement production and brick works (IPCS, 1996).
Due to its ability to remove hair, thallium (I) sulfate was used in the past as a depilatory
agent. Thallium (I) sulfate was once used in medicine to treat infections such as venereal
diseases, ringworm of the scalp, typhus, tuberculosis and malaria. It was also used in the past as
a pesticide for various rodents and insects but has been banned for this use in the United States
since 1972. Currently thallium is still used in the semiconductor industry and the manufacture of
optic lenses. When thallium is alloyed with mercury, it is used on switches and closures, which
can operate at subzero temperatures. Thallium compounds are also used to manufacture low-
melting glass, low-temperature thermometers, alloys, electronic devices, mercury lamps,
fireworks, and imitation gems. Thallium radioisotopes are used in medicine for scintigraphy of
certain tissues and the diagnosis of melanoma (Ibrahim et al., 2006; NLM, 1998; IPCS, 1996;
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ATSDR, 1992; U.S. EPA, 1991b).
Table 1. Chemical and physical properties of thallium and selected thallium
compounds
Name
Metallic
thallium
Thallium (I)
acetate
Thallium (I)
carbonate
Thallium (I)
chloride
Thallium (I)
nitrate
Thallium (III)
oxide
Thallium (I)
selenite
Thallium (I)
sulfate
CASRN
7440-28-0
563-68-8
6533-73-9
7791-12-0
10102-45-1
1314-32-5
12039-52-0
7446-18-6
Chemical
formula
Tl
T1C2H3O2
T12CO3
T1C1
T1NO3
T12O3
Tl2SeO3
T12S04
Molecular
weight
204.38
263.43
468.78
239.84
266.39
456.76
535.72
504.82
Melting point
(°C)
303.5
131
273
430
206
717
no data
632
Boiling point
(°C)
1457
no data
no data
720
430
875
no data
decomposes
Solubility in
water (g/L)
insoluble
very soluble
40.3 (15.5°C)
very soluble
(20°C)
95.5 (20°C)
insoluble
no data
48.7 (20°C)
Sources: IPCS (1996); ATSDR (1992).
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3. TOXICOKINETICS
3.1. ABSORPTION
Studies in humans and animals indicate that thallium compounds are readily absorbed
through various routes of exposure, but few studies provide quantitative measures of absorption.
Mulkey and Oehme (1993) reported that water soluble salts are rapidly and completely absorbed
from the respiratory tract, gastrointestinal (GI) tract, or skin but did not provide data or cite
references to support this conclusion. Thallium ions have been detected in the urine of exposed
humans (Ludolph et al, 1986; Davis et al, 1981; Schaller et al, 1980; Cavanagh et al., 1974;
Gefel et al., 1970) and animals (Thomas and McKeever, 1993; Waters et al., 1992; Leloux et al.,
1987; Talas and Wellhoner, 1983), which implies absorption from environmental sources.
Shaw (1933) determined that 61.6% of an oral dose of thallium (I) sulfate (25 mg Tl/kg)
was absorbed by a dog. Lie et al. (1960) determined that thallium was completely absorbed via
the GI tract, following oral administration of 767 jig 204Tl/kg, as thallium (I) nitrate. This was
based on observations in male Wistar-derived rats where the body burden decreased
exponentially and extrapolated to 100% absorption. The same results were obtained when
thallium (as thallium nitrate) was administered by other routes of exposure (intravenous [i.v.],
38 |ig/kg; intramuscular, 96 |ig/kg; subcutaneous, 96 |ig/kg; intratracheal, 123 |ig/kg; and
intraperitoneal [i.p.], 146 |ig/kg). Eighty percent of a single dose of 10 nmol of thallium, as
thallium (I) sulfate, was absorbed within one hour from tied-off jejunal segments in anesthetized
rats (Forth and Rummel, 1975; Leopold et al., 1968).
No information was found regarding the absorption of thallium salts via inhalation.
There are a few case reports (Hirata et al., 1998; Ludolph et al., 1986) in which occupational
exposure has been associated with toxicity, but it could not be determined if exposure occurred
via inhalation or another route (e.g., oral or dermal).
The use of thallium salts in the past as depilatory agents, as a treatment for ringworm of
the scalp, and as treatment for night sweats associated with tuberculosis suggests dermal
absorption (Leonard and Gerber, 1997; Reed et al., 1963; Lie et al., 1960).
3.2. DISTRIBUTION
Thallium ions are rapidly distributed (as early as 1 hour after exposure) throughout the
body in both experimental animals (Careaga-Olivares and Gonzalez-Ramirez, 1995; Galvan-
Arzate and Rios, 1994; Aoyama, 1989; Rios et al., 1989; Talas and Wellhoner, 1983; Sabbioni et
al., 1980a, b; Lameijer and van Zwieten, 1977; Andre et al., 1960; Downs et al., 1960; Lie et al.,
1960; Lund, 1956) and humans (Talas et al., 1983; Davis et al., 1981; Cavanagh et al., 1974;
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Barclay et al, 1953), regardless of the route of exposure, dose, length of exposure, type of
thallium compound, or valence state (Sabbioni et al., 1980a, b; Lameijer and van Zwieten, 1977).
The highest thallium concentrations have typically been found in the kidney and the lowest
concentrations in the brain, with none being detected in fat tissue. Thallium also has been
demonstrated to cross the placenta in humans (Hoffman, 2000) and experimental animals
(Gibson and Becker, 1970).
The distribution of thallium in newborn Wistar rats differed from that in adult Wistar rats.
Newborns administered an i.p. dose of 16 mg/kg thallium (I) acetate (12.4 mg Tl/kg) had the
highest levels of thallium in the testis, heart, and kidneys, in that order, 24 hours after
administration (Galvan-Arzate and Rios, 1994). Levels in the liver and brain were
approximately three- to fourfold lower. In adult rats, the level of thallium in the kidney 24 hours
after an i.p. dose of 16 mg/kg thallium (I) sulfate was approximately twofold higher than the
level present in the testis (Rios et al., 1989). Galvan-Arzate and Rios (1994) also demonstrated
age-related differences in the regional distribution of thallium in the brain. Twenty-four hours
after i.p. injection of 16 mg/kg thallium (I) acetate, the thallium content among all regions of the
brain of newborn rats was homogeneous, whereas the thallium content in the brain of rats 5 to 20
days old showed a region-dependent distribution, with thallium levels in the cortex significantly
lower than levels in the hypothalamus.
3.3. METABOLISM
Because thallium is an element, it is not metabolized. It is not known if thallium is
transformed from one valence state to another in vivo.
3.4. ELIMINATION
Thallium salts are eliminated mainly via urine and feces, but the amount excreted via
each route varies depending on the species. Thallium also has been found to be excreted in
breast milk, sweat, saliva, and tears (IPCS, 1996). Thallium deposition into hair and nails also is
considered an important route of elimination.
In a survey of 776 members of the general population (>40 years of age) that participated
in the 1999-2000 National Health and Nutrition Examination Survey (NHANES 1999-2000), the
geometric mean level of thallium in the urine was 0.16 |ig/L, with a maximum of 0.86 |ig/L
(Navas-Acien et al., 2005).
A study of a human cancer patient orally administered thallium (I) sulfate and
radiolabeled thallium (I) nitrate (204T1NO3) demonstrated that thallium was mainly excreted in
the urine; 15.3% of the thallium salts were recovered in the urine over 5.5 days with 0.4%
recovered in the feces over 3 days (Barclay et al., 1953). Shaw (1933) demonstrated that 32 and
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61.6% of a single oral dose of 25 mg Tl/kg as thallium (I) sulfate administered to a dog was
excreted in the urine at 3 and 36 days after dosing, respectively; however, fecal excretion was not
measured.
Thallium is excreted to a greater extent in the feces than in the urine of rats and rabbits.
Lund (1956) determined that after 26 days, 51.4% of an i.p. dose of 10 mg thallium (I) sulfate/kg
in the rat was eliminated via the feces, while 26.4% was excreted in the urine. Talas and
Wellhoner (1983) demonstrated that thallium (I) acetate administered to rabbits via i.v. injection
(as a radioactive tracer) was excreted mainly in the feces. Both studies found that, although the
feces was the major route of excretion in the rat and rabbit, neither species had high levels in the
bile, suggesting that excretion via the liver was relatively low. Lund (1956) determined that
thallium was mainly excreted in the feces through gastric and intestinal secretions, which is
likely associated with potassium excretion. Lund (1956) demonstrated that rabbits excreted
thallium through the kidneys by glomerular filtration, but approximately one-half the dose
filtered was reabsorbed in the tubuli. In Syrian golden hamsters, thallium (I) sulfate was mainly
excreted in the feces after i.p. administration but was excreted at an equal rate in the feces and
urine after an oral dose (Aoyama, 1989).
Sabbioni et al. (1980b) determined that thallium (I) sulfate administered at doses of
0.00004 to 2000 jig/rat was persistent in the kidneys for 8 days (192 hours) after dosing with
2.5% of the dose still present at that time. The biological half-life of thallium in rats has been
estimated to range from 3-8 days (Lehmann and Favari, 1985; Lie et al., 1960). The biological
half-life in humans has been estimated to be approximately 10 days, with values up to 30 days
reported (IPCS, 1996).
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
There are no physiologically based toxicokinetic models for soluble thallium salts.
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4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
Studies of thallium toxicity in humans are comprised of clinical reports, case studies, and
medical surveys. Because case reports largely involved accidental ingestion, intentional
poisoning, or suicide attempts, they do not provide useful information on thallium toxicity
associated with chronic exposure. Available epidemiology studies involving long-term exposure
to thallium are limited by small study populations and insufficient characterization of long-term
exposure. Health effects information was based on self-reporting (via questionnaire) or medical
histories/physical examinations of uncertain scope. Table 2 summarizes the individual case
reports of human exposure to thallium.
In adults, the average lethal oral dose has been estimated to range from 10 to 15 mg/kg
(Schoer, 1984; Gosselin et al, 1984). Without treatment, death typically follows in about 10-12
days, but death as soon as 8-10 hours also has been documented (IPCS, 1996).
4.1.1. Incident/Case Reports
As indicated by case reports, the acute toxicity of thallium is characterized by alopecia
(hair loss), severe pain in the extremities, lethargy, ataxia, abdominal pain or vomiting, back
pain, abnormal reflexes, neuropathy, muscle weakness, coma, convulsion, other neurological
symptoms (i.e., mental abnormalities, tremors, abnormal movements, abnormal vision, and
headache), and death (Lu et al., 2007; Tsai et al., 2005; Saha et al., 2004: Sharma et al., 2004;
Rusyniak et al., 2002; Atsmon et al., 2000; Hirata et al., 1998; Feldman and Levisohn, 1993;
Yokoyama et al., 1990; Heyl and Barlow, 1989; Roby et al., 1984; Limos et al., 1982; Davis et
al., 1981; Cavanagh et al., 1974; Gefel et al., 1970; Reed et al., 1963). Symptoms were
observable within 14 hours after a high dose (i.e., 5-10 g of thallium (I) nitrate), with death
occurring 8 days later (Davis et al., 1981). The lowest known single dose of thallium associated
with adverse effects was reported to be 0.31 g of thallium (I) acetate (3.4 mg Tl/kg assuming a
70 kg body weight). This dose caused paresthesia, pain, weakness, vomiting, and alopecia in a
26-year-old male. Approximately 1 month after the onset of symptoms, complete recovery
occurred following treatment. In adults, doses ranging from 6 to 40 mg/kg have been reported to
be lethal (IPCS, 1996). Table 2 summarizes the individual case reports.
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Table 2. Thallium toxicity in humans, following oral exposure
Reference
Sex
Age
Dose
Symptoms
Final outcome
Males — adult
Gefeletal., 1970
Cavanaghetal., 1974
Cavanaghetal., 1974
Cavanaghetal., 1974
Davis etal., 1981
Limosetal., 1982
Limosetal., 1982
Robyetal., 1984
Male
Male
Male
Male
Male
Male
Male
Male
41 years
60 years
56 years
26 years
19 years
56 years
26 years
45 years
Unknown but
chronic;
urine thallium
0.15mg/100mL
0.93 g thallium (I)
acetate in 2 divided
doses
0.93 g thallium (I)
acetate in 3 divided
doses
0.3 Ig thallium (I)
acetate
5-10 g thallium (I)
nitrate
Unknown
Unknown
Unknown;
urine thallium:
2000 ug/L
High blood pressure; lower back pain; vomiting;
severe pain in the feet; weakness of the calf muscle;
alopecia; slurred speech; atrophic lower limbs;
limited vision
Diarrhea; vomiting; dizziness; back pain; paresthesia
of the feet and lower legs; high blood pressure; facial
weakness; dysphagia; difficulty breathing
Abdominal pain; diarrhea; vomiting; paresthesia;
photophobia, nystagmus, visual impairment; facial
weakness; bilateral ptosis
Paresthesia in both feet; chest pain; tenderness over
the sternum; vomiting, weakness, pain in the knees
and ankles that inhibited walking; alopecia
Nausea; vomiting; slurred speech; paresthesia of
hands and feet; respiratory weakness
Visual disturbances; alopecia; elevated AST and
ALT; high blood glucose and creatine kinase;
decreased myelinated fibers; denervated Schwann
cell clusters
Visual disturbances; alopecia; elevated AST and
ALT; high blood glucose and creatine kinase;
decreased myelinated fibers; denervated Schwann
cell clusters
Burning pain in feet; inability to walk; alopecia;
acute fibrillation
Death
Death within a week of
symptoms
Death within 3 weeks of
symptoms
Recovery
Death
Bedridden; could not
speak
Residual tremors of the
extremities and muscle
weakness of the lower
limbs
Continued neurological
dysfunction
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Table 2. Thallium toxicity in humans, following oral exposure
Reference
Heyl and Barlow, 1989
Yokoyama et al., 1990
Hantsonetal., 1997
Hirata et al., 1998
Atsmon et al., 2000
Sharma et al., 2004
Sex
Male
Male
Male
Male
Male
Male
Age
"5 young men"
3 1 years
48 years
29 years
40 years
48 years
Dose
Unknown
Unknown;
urine thallium:
3.5 mg/L
200 mg thallium (I)
sulfate
Unknown; hair
thallium: 20 ng/g
(32 months after
possible exposure)
Unknown;
urine thallium: 7 mg
Unknown;
serum thallium:
870 ug/100 ml
urine thallium:
5000 ug/ml
Symptoms
Follicular plugging of the skin (nose, cheeks, and
nasolabial folds) by keratinous material; crusted
eczematous lesions and acneiform eruptions on the
face; dry scaling on palms and soles; and alopecia
(scalp, eyelashes, lateral eyebrows, arms and legs).
Skin biopsies (scalp and cheek): disintegrating
hairshafts, gross follicular plugging, and eosinophilic
keratohyaline granules in the epidermis; necrotic
sebaceous glands; (pustular lesions on the face):
folliculitis and necrosis of the follicles; (feet) marked
hyperkeratosis and hypergranulosis.
Nausea, vomiting; leg pain; alopecia; abnormal
behavior; decreased conduction velocity of fast
nerve fibers
No overt symptoms within 24 hours; increase in
binucleated cells with micronuclei 15 days after
exposure
Alopecia; abdominal pain; diarrhea; tingling in
extremities; neuropathy
Weakness of the limbs; vomiting; severe
neurological symptoms; alopecia; high blood
pressure; increased ALT and AST; Mees lines;
decreased visual acuity; bilateral foot-drop
Painful peripheral neuropathy, decreased
consciousness
Final outcome
4/5 recovered; 1/5
experienced permanent
neurological damage
Recovery
Recovery
Recovery
Recovery
Death
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Table 2. Thallium toxicity in humans, following oral exposure
Reference
Sex
Age
Dose
Symptoms
Final outcome
Females — adult
Robyetal., 1984
Robyetal., 1984
Robyetal., 1984
Hoffman, 2000
Saha et al., 2003
Female
Female
Female
Female
Female
5 1 years
61 years
80 years
Pregnant; ages
not specified
26 years
Unknown;
serum thallium:
50 ug/100 mL;
urine thallium:
5000 ug/L
Unknown;
serum thallium:
740 ug/100 mL
Unknown;
serum thallium:
422 ug/100 mL;
urine thallium:
21,600 ug/L
150-1350 mg
thallium (I) sulfate
Unknown;
Serum thallium: 12
ug/100 ml
Numbness and weakness of the legs and hands;
alopecia; fluctuating pulse and blood pressure;
bradycardia; hypotension
Burning chest pain; paresthesia; difficulty speaking
and swallowing; inability to walk; hypotension;
Acute Respiratory Distress Syndrome (ARDS)
ARDS
Paresthesia; abdominal pain; muscle weakness;
lethargy; alopecia; Mees lines
Headache, lethargy, abdominal pain, muscle cramps,
joint pain, backache, numbness of fingers, alopecia,
erosion of nails
Persistent ventricular
ectopy and neurological
dysfunction
necessitating placement
at a nursing home
Death
Death
None specified
Not specified
Both sexes - adult
Brockhausetal., 1981
Schoer, 1984; Gosselin
etal., 1984
Rusyniaketal.,2002
Both
Both
Both
Not reported
Adult
Various
Unknown
10-15 mg/kg
thallium
Unknown; various
levels were detected
in urine
Sleep disorders; tiredness; weakness; nervousness;
headache; other psychic alterations; neurological and
muscular symptoms
None specified
Myalgia; arthralgia; paresthesia; dysesthesia; joint
stiffness; insomnia; alopecia; abdominal pain
Not reported
Death (average lethal
dose)
Recovery in 7; 5 had
ongoing psychiatric
problems
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Table 2. Thallium toxicity in humans, following oral exposure
Reference
Tsai et al., 2006
Lu et al., 2007; Kuo et
al., 2005
Sex
Both
Both
Age
48-yr old
female; 52-year
old male
48 and 52 years
Dose
1.5-2 .4 g
1.5 and 2. 3 g/person
(estimated);
Serum thallium:
950-2056 ug/L
Urine thallium:
1 1,325-14,520 ug/L
Symptoms
Confusion, disorientation, hallucination, anxiety,
depression, memory impairment, peripheral
neuropathy, erythematous skin rashes, diarrhea,
tachycardia, alopecia
Nausea, vomiting; general aching muscle pain;
numbness of tongue and mouth within a few hours;
severe paresthesia and dysesthesis in hands and feet
(one day post-exposure); erythematous rash;
diarrhea; urine retention; hyporeflexia; muscle
weakness; hypoesthesia; acneiform eruptions;
alopecia (1-3 weeks); mees lines (2-3 months).
Skin biopsy: parakeratosis; dilated hair follicles
filled with keratin and necrotic sebaceous materials;
mild epidermal atrophy; vacuolar degeneration of the
basal layer.
Cutaneous nerve biopsy: axonal degeneration; loss
of epidermal nerves indicating involvement of the
small sensory nerves (2 months).
Final outcome
Impairment of memory
and verbal fluency
remained at 6 moths;
neuropsychological
impairment persisted at
9 months
At one-year follow-up,
persistent paresthesia,
dysesthesia, and
impairment of small
sensory nerve fibers in
skin
Children
Reedetal, 1963
Feldman and Levisohn,
1993
Hoffman, 2000
Both
Male
Both
1-11 years
10 years
Transplacental
Unknown
Unknown;
serum thallium:
296 jig/L;
urine thallium:
322 ug/24 hours
Unknown
Alopecia; lethargy; ataxia; abdominal pain;
vomiting; abnormal reflexes; neuropathy; muscle
weakness; coma; convulsion
Alopecia; leg paresthesia; abdominal pain; seizures
Premature birth; low birth weight; alopecia
Neurological
abnormalities;
retardation; psychosis;
death
Recovery
None specified
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High blood pressure or fluctuating blood pressure was noted upon hospital admission in
several cases (Roby et al, 1984; Cavanagh et al, 1974; Gefel et al, 1970). Elevated serum
aspartate aminotransferase (AST, formerly referred to as SGOT) and serum alanine
aminotransferase (ALT, formerly referred to as SGPT), high blood glucose, and creatine kinase
values also have been noted in case reports of thallium exposure (Atsmon et al., 2000; Limos et
al., 1982). The same symptoms were noted across age and sex groupings. Retardation and
psychosis were the most common findings in children (1 to 11 years old) after nonlethal thallium
exposure. Several cases were so severe that institutionalization was necessary (Reed et al.,
1963). Thallium significantly decreased the conduction velocities of faster nerve fibers in a 31-
year-old male, who ingested a thallium-containing rodenticide, compared with baseline levels
recorded following recovery.
In most case-study reports, thallium was detectable in the urine or tissues. In some cases,
thallium could not be definitively associated with the symptoms because other heavy metals
were also found in the blood or urine of the subject.
Hantson et al. (1997) evaluated cytogenetic changes in blood from a 48-year-old man
who accidentally ingested 200 mg of thallium (I) sulfate intended for rodenticide use. Despite
the lack of overt symptoms 24 hours after ingesting the thallium, the man was admitted to the
emergency room and Prussian blue treatments were commenced. Blood samples were obtained
on days 1 and 15 for cytogenetic analysis. Slight increases in mean sister chromatid exchange
(SCE) numbers on days 1 and 15 were not considered related to thallium exposure. A 3.5-fold
increase in binucleated cells with micronuclei (35% versus 10% in the historical controls) was
noted on day 15. The thallium level was determined to be 14.4 |ig/dL in blood at the time of
hospital admission, and the concentration in urine was 3804 jig Tl/g creatinine (reference value,
<1 ,ig Tl/g).
Fifty-one case histories of women treated for thallium poisoning following external
application of a 3 to 8% thallium (I) acetate ointment were reviewed for signs of possible
thallium intoxication (Munch, 1934). Neurological and GI symptoms were observed in 29 cases
after an unspecified number of applications with 2 to 24 ounces of the ointment. This was
approximately equivalent to a dose of 53 to 636 mg Tl/kg per application using a 5.5% ointment
on a 50-kg woman. Alopecia followed several weeks after beginning treatment.
Hoffman (2000) provided case reports and a comprehensive literature review of thallium
poisoning that occurred during pregnancy. Exposures were primarily oral, but some of the cases
involved dermal exposure. The majority of the doses were unreported, but those doses that were
documented ranged from 150 mg to 1350 mg thallium (I) sulfate. Of the 18 cases that met
Hoffman's criteria (cases were excluded if maternal or fetal outcomes were not provided), 5
women were exposed during the first trimester and 5 during the second trimester; the remaining
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8 were exposed during the third trimester. The ages of the women were not reported. While the
mothers developed the classic symptoms of thallium poisoning, including paresthesia, abdominal
pain, muscle weakness, lethargy, alopecia, and Mees lines (single transverse white bands
occurring on the nails), the only consistent finding in their offspring was a trend toward
prematurity and low birth weight. Several of the children had alopecia, particularly those
exposed during the third trimester.
4.1.2. Population Surveys
Several published studies have surveyed populations living near a cement plant in
Lengerich, a small city in northwest Germany. These populations were studied because of their
potential to experience exposure to thallium as a result of its presence as an impurity in pyrite
and its release during the roasting of pyrite for use in making some types of cement. Thallium
was discharged to outdoor air, deposited in soils, and was taken up by local crops and indigenous
plants. People who lived near the plant and consumed large quantities of home-grown foods thus
were exposed to thallium through their diets. Prior to 1979, the concentration of thallium in the
pyrite was 400 ppm. After 1979, a pyrite with lower levels of thallium (2 ppm) was used.
Brockhaus et al. (1981) conducted an epidemiological study of a group of 1200 people
living near the cement plant in Lengerich. Urinary thallium data were also collected from two
reference populations without increased thallium intake—one group consisting of 31 persons
living in a small (rural) city in northwest Germany, and a second group consisting of 10 persons
living in an urban area in Dusseldorf, Germany. The study investigators did not perform specific
tests for toxicity but surveyed for the presence of certain symptoms by using questionnaires.
Thallium exposure was assessed by measurements in urine and hair. The thallium body burden
of the study population was increased over the reference populations, as indicated by a mean
urinary thallium level of 5.2 ± 8.3 |ig/L (range: <0.1 to 76.5 |ig/L) in the study population
compared to the reference population means of 0.4 ± 0.2 |ig/L (rural) and 0.3 ± 0.2 (urban) |ig/L
(range: 0.1 to 1.2 |ig/L). The predominant contributing factor to the thallium burden was
consumption of homegrown fruits and vegetables. When the consumption of homegrown foods
was restricted, thallium exposure was reduced, as indicated by decreased thallium in the urine.
No correlation between dermal or gastrointestinal symptoms and thallium level was observed.
There was a negative correlation between thallium and hair loss (13.6% with urine levels
<2 |ig/L, 6.6% with urine levels 2-20 |ig/L, and 5.9% with urine levels >20 |ig/L; 10.7% with
hair levels <10 ng/g, 9.6% with hair levels 10-50 ng/g, and 2.3% with hair levels >50 ng/g).
These data appear to conflict with other reports that indicate hair loss increases with increasing
thallium exposure. A positive association was observed among thallium levels in urine or hair
and the following self-reported symptoms: sleep disorders, tiredness, weakness, nervousness,
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headache, other psychic alterations, and neurological and muscular symptoms (Brockhaus et al,
1981).
Dolgner et al. (1983) examined the potential developmental effects of thallium in this
same German population. Of 300 births registered in Lengerich between January 1, 1978, and
August 31, 1979, questionnaires on health status and maternal risk factors were completed by the
mothers of 297 infants. One hundred fifty-four urine and 164 hair samples were analyzed for
thallium content. All children with suspected congenital malformations or other abnormalities
were examined physically and medical histories of mothers were taken. Eleven out of the 297
births were identified as exhibiting congenital malformations or abnormalities (confirmed by a
pediatrician) with five major malformations noted. Two of the five major malformations in the
study population were determined by the authors to likely be due to hereditary factors.
The observed rate of congenital malformations in the study population (5 out of 297) was
compared to the expected rate of 0.8 per 297 births based on annual statistics from the North
Rhine-Westphalia region of Germany for 1974-1978. Congenital malformations in the reference
population were thought to be underreported because reporting of birth defects is not required on
birth certificates in that area of Germany. The study authors noted that other investigations
reported an incidence of 2-3% birth defects among live births, a value that is consistent with
1.7% incidence of birth defects in the study population (5/297 for major malformations) and
3.7% (11/297) for all malformations. The study authors concluded that a causal relationship
between thallium exposure and congenital malformations in this population was unlikely.
However, study deficiencies, including lack of information on exposure to thallium at the time of
pregnancy, limit the strength of this study.
Navas-Acien et al. (2005) examined the association between urinary levels of various
metals, including thallium, with peripheral arterial disease (PAD) in a cross-sectional analysis of
790 participants in NHANES 1999-2000. Thallium was not associated with PAD in this sample
of the U.S. population.
4.1.3. Occupational Exposure
Schaller et al. (1980) examined 128 men (ages 16-62 years) who were exposed to
thallium for 1 to 42 years in three cement manufacturing plants in the Franconia region of
Germany. Health effects were determined through medical histories and a physical examination
for symptoms. Information on the scope of the physical examinations was not provided.
Analyses of roasted pyrites and electro-filter dust confirmed the presence of thallium in various
production areas in the plants. The median concentration of thallium in the urine in exposed
workers was 0.8 jig Tl/g creatinine with a range of <0.3 to 6.3 jig Tl/g creatinine. The range in
20 individuals without known occupational exposure was <0.3 to 1.1 jig Tl/g creatinine (median
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concentration not reported). Medical histories and physical examinations did not indicate
thallium poisoning. The health status of exposed workers, however, was not compared with an
unexposed reference population, and a single measurement of urinary thallium did not provide a
measure of past exposures.
Thirty-six cement plant workers (presumably in Germany) were examined for clinical
and electrophysiological parameters (Ludolph et al, 1986). Thallium levels were found to be
elevated in the blood of 16 workers, urine of 5 workers, and hair of 5 workers. It was not noted
if these were all separate cases or if elevations in all three parameters occurred in the same
individuals. The study determined that 28-39% of the individuals had some form of peripheral
and central motor and sensory impairment. The neurological impairments could not
conclusively be attributed to thallium exposure because half the patients suffered from
concurrent diseases (including peptic ulcer, diabetes, disorders of joints and connective tissue,
and hypertensive vascular disease), which could possibly cause neuromuscular impairment. No
controls were employed, and no correlations were made with the levels of thallium in individuals
and their disease states.
In another occupational study, Marcus (1985) examined medical records for 86 workers
(sex not reported) occupationally exposed to thallium at a magnesium seawater battery factory.
Exposure was determined by measuring thallium in urine samples. Marcus also examined the
records of 79 unexposed workers matched for age, length of employment, shift pattern, and type
of work. Exposed workers did not have an increase in incidence of benign neoplasms or any
other clinical diagnoses when compared with unexposed workers. This study is limited by lack
of exposure quantitation, the size of the cohort, and unknown length of follow-up.
Although there are many case reports of thallium poisoning in the literature, the doses
were largely unknown because ingestion was accidental or occurred through criminal poisoning.
Given the severity of reported symptoms, most of the exposures were likely to have been
relatively large. The few epidemiology studies that looked at populations surrounding a cement
factory that released thallium only attempted to compare thallium exposure with congenital
malformations or surveyed symptoms. None of the studies specifically studied cancer as an
endpoint. Overall, the available epidemiology literature is considered limited and inconclusive.
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4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
4.2.1. Oral Exposure
4.2.1.1. Acute and Subchronic Studies
Rats
In a study performed by Midwest Research Institute (MRI, 1988) for EPA's Office of
Solid Waste, male and female Sprague-Dawley rats (45 days old, 20/sex/group) were
administered 0 (untreated and vehicle controls), 0.01, 0.05, or 0.25 mg/kg-day of an aqueous
solution of thallium (I) sulfate (approximately 0, 0.008, 0.04, or 0.20 mg Tl/kg-day) by gavage
for 90 days. The study was conducted in compliance with EPA Good Laboratory Practices
(GLPs). MRI (1988) study is an unpublished study; accordingly, it was externally peer reviewed
by EPA in November 2006. Body weight, food consumption, hematologic and clinical
chemistry parameters, ophthalmic examinations, gross pathologic observations, and organ
weights (liver, kidneys, brain, gonads, spleen, heart, and adrenals) were recorded for all animals.
Neurotoxicological examinations (3 times/week) were performed on 6 rats/sex/group; these
examinations were apparently observational (further details were not provided in the study
report). Tissues from 3 rats/sex/group were prepared for neuropathological examination.
Complete histopathological examinations (including neuropathological examinations) were
conducted for the vehicle control and 0.2 mg Tl/kg-day groups only; for the other three groups,
only the livers, lungs, kidneys and gross lesions were examined histopathologically.
Neuropathological examinations included the following: dorsal and ventral root fibers of the
spinal nerves, dorsal root ganglia, spinal cord at C3-C6 and L1-L4, and six sections of the brain.
There were no statistically significant differences in body weight, food consumption, or
absolute and relative organ weights among control groups and groups receiving thallium (I)
sulfate. Ophthalmology examinations did not indicate any treatment-related effects. The study
authors concluded that the histopathological examination did not reveal any treatment-related
effects.
Lacrimation (secretion of tears) and exophthalmos (abnormal protrusion of the eyeball)
were observed at higher incidences in the treated rats compared with both controls. The
incidence of lacrimation in males (M) and females (F) was as follows: untreated control—1/20
(M), 7/20 (F); vehicle control—6/20 (M), 6/20 (F); 0.008 mg Tl/kg-day—19/20 (M), 20/20 (F);
and 0.04 and 0.2 mg Tl/kg-day—20/20 (M and F). The incidence of exophthalmos was as
follows: untreated control—1/20 (M), 5/20 (F); vehicle control—5/20 (M), 6/20 (F); 0.008 mg
Tl/kg-day—12/20 (M), 19/20 (F); and 0.04 and 0.2 mg Tl/kg-day—20/20 (M and F).
Ophthalmic examination and gross and histopathological examination of the eyes, however,
revealed no treatment-related abnormalities.
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Subtle but statistically significant changes were observed in several blood chemistry
parameters that the investigators considered probably treatment related. Specifically, dose-
related increases in serum glutamic oxaloacetic transferase (AST), lactate dehydrogenase (LDH),
and sodium levels and decreases in blood sugar levels were detected in male and female rats after
30 and 90 days of exposure. Reported values for the selected blood chemistry parameters are
summarized in Table 3. Other changes in blood chemistry parameters were less consistent
across species, dose groups, and exposure durations.
At 90 days, changes in AST, LDH, sodium, and blood sugar levels in dosed male and
female rats were no greater than 31%, 38%, 4%, and 82%, respectively, of the vehicle control
group values. The investigators observed that the increases in AST and LDH levels could
indicate a possible effect of treatment on cardiac function, that increases in LDH coupled with
subtle changes in electrolytes could indicate an effect on renal function, and that, in rare
instances, a decrease in blood sugar coupled with an increase in sodium occurs as a defense
mechanism for maintaining cellular integrity. The investigators concluded that none of the
changes observed in the blood chemistries of males or females during the study were of
sufficient magnitude to significantly affect the health status of the animals. Further,
histopathological evaluation did not confirm any cellular damage suggested by the clinical
chemistry findings.
Clinical observations revealed an increased incidence of alopecia, particularly in female
rats at the high dose (see Table 4). Based on a statistical analysis performed by the U.S. EPA1,
the incidence of alopecia (total number of cases in each dose group) was statistically
significantly elevated relative to controls in mid-dose males and mid- and high-dose females.
Most instances of alopecia in females were attributed to barbering behavior (where fur was
present but cropped short). Of the twelve high-dose females with alopecia, five instances were
not totally attributed to barbering behavior. Histopathological examination revealed atrophy of
the hair follicles in two high-dose female rats. This lesion was not found in other dose groups or
the control, but the skin was examined for histopathological changes only in the vehicle control
and high-dose groups. The two high-dose females with atrophy of the hair follicles also had
alopecia; whether the hair follicle atrophy and alopecia occurred at the same location on the rats
could not be determined from the study report. The authors noted that the cases of alopecia that
were not totally attributed to barbering behavior occurred in various anatomical locations,
thereby lessening the likelihood of chemical effect. They further observed that based on
microscopic evaluation, the alopecia was attributable to the cyclic pattern of hair growth in
1 A statistical analysis of the incidence of alopecia (based on the total number of cases of alopecia in each dose
group) was performed by the U.S. EPA using Fisher's exact text. Incidence in the treated groups was compared to
incidence in the untreated control, vehicle control, and pooled control.
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rodents. Consequently, the authors did not consider these findings to be biologically significant
and identified the highest dose, 0.25 mg/kg-day thallium (I) sulfate (0.20 mg Tl/kg-day), as the
no-observed-adverse-effect level (NOAEL). Upon further analysis of the MRI (1988) findings
as part of this health assessment, a different determination was reached regarding the NOAEL
and LOAEL; see the discussion in Section 5.1.1.
Table 3. Selected blood chemistry values
Blood
chemistry
parameter
Study day
Untreated
control
Vehicle control
0.008 mg/kg-
day
0.04 mg/kg-
day
0.2 mg/kg-day
Males"
AST
(I.U.)
LDH
(I.U.)
Na
(meq/L)
Blood sugar
(mg/100 mL)
30
90
30
90
30
90
30
90
91 ±26.5
77 ±19.7
795 ± 322
587 ± 305
148 ±1.3
144 ±1.6
100 ±22.1
158 ±15.6
108 ±18.6
87 ±17.8
1206 ± 424b
856 ± 385
149 ±2.4
147 ± 2.0b
97 ±18.1
138±16.8b
128 ± 24.5b
99 ± 20.4
1333±340b
1003 ± 363b
152 ± 4.0b
147±1.9b
93 ± 10.0
131±17.6b
134 ± 29.0b'c
113±27.0b'c
1396 ± 407b
1071±507b
154 ± 2.5b'c
149 ± 2.0b'c
90 ± 18.3
121 ± 15.7b
152±20.1b'c
114±31.1b'c
1802±341b'c
1119±477b
153±2.1b'c
151±2.2b'c
62 ± 14.8b'c
113±22.4b'c
Females3
AST
(I.U.)
LDH
(I.U.)
Na
(meq/L)
Blood sugar
(mg/100 mL)
30
90
30
90
30
90
30
90
95 ± 22.8
77 ±19.2
1047 ±335
745 ± 320
148 ±1.7
146 ±1.8
103 ±23.9
110 ±28.7
115 ±30.3
90 ±19.1
1277 ± 495
881 ±273
150 ±1.9
146 ±1.0
80±13.3b
89 ±15.9
127 ± 27.8b
93 ±33.1
1402 ±501
823 ± 354
153±4.1b'c
148±1.8b'c
80 ± 9.0b
103 ± 19.9
149 ± 26.8b'c
lll±30.7b
1763 ± 370b'c
1044 ± 436
154 ± 2.8b'c
150 ± 2.0b'c
67 ± 20.0b
88 ± 20.4
154 ± 18.2b'c
112±31.0b
1764±361b'c
1219±338b
155±2.5b'c
152±1.0b'c
50±11.8b'c
70 ± 18.0b
"Mean ±SD of 7 to 10 rats.
bSignificantly different (p<0.05) from the untreated control group.
Significantly different (p<0.05) from the vehicle control group.
Source: MRI (1988).
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Table 4. Incidence of alopecia in rats
Dose
(mg Tl/kg-day)
0 (untreated control)
0 (vehicle control)
0.008
0.04
0.2
Males
Alopecia3' b
2/20
1/20
4/20
9/20e
4/20
Hair follicle
atrophy0
d
0/20
d
d
0/20
Females
Alopecia3' b
4/20
1/20
4/20
9/20f
12/20e
Hair follicle
atrophy0
d
0/20
d
d
2/20
"Number of animals with alopecia at least once during the 90-day study based on clinical observations.
b Of the animals with alopecia, the following are the numbers of cases in each dose group that the study
authors stated were "not totally attributed to barbering behavior":
Males: untreated control - 1; vehicle control - 0; 0.008 mg/kg-d - 2; 0.04 mg/kg-d - 4; 0.2 mg/kg-d - 1.
Females: untreated control - 0; vehicle control - 0; 0.008 mg/kg-d - 1; 0.04 mg/kg-d - 3; 0.2 mg/kg-d - 5.
0 Based on histopathological observation.
d Skin was not examined for histopathological lesions.
e Incidence of alopecia (total number of cases) was statistically significantly elevated (p<0.05) relative to
incidence in vehicle control, incidence in untreated control, and pooled incidence of vehicle and untreated
control, based on Fisher's exact test performed by the U.S. EPA.
Incidence of alopecia (total number of cases) was statistically significantly elevated (p<0.05) relative to
incidence in vehicle control and pooled incidence of vehicle and untreated control, based on Fisher's exact
test performed by the U.S. EPA.
Source: MRI (1988)
Manzo et al. (1983) administered drinking water containing thallium (I) sulfate at a
concentration of 10 mg Tl/L (approximately equivalent to a dose of 1.4 mg Tl/kg-day based on
reported thallium intakes and an assumption that the rats weighed 200 g) to 80 female Sprague-
Dawley rats for 36 weeks. Mortality was 15 and 21% after 40 and 240 days of treatment,
respectively. After 4+ weeks (32 days) of treatment, hair loss appeared and involved about 20%
of the animals thereafter. Functional and histopathological changes were observed in the
peripheral nerves, including changes in motor and sensory action potentials and histopathological
changes in the sciatic myelin sheath and axonal destruction characterized by Wallerian
degeneration (degeneration of the axon and its myelin sheath distal to a site of injury),
mitochondrial degeneration, neurofilamentous clustering, and elevated lysozomal activity.
Ten adult male albino rats were administered 0.8 mg/kg (l/20th of the LDso) of thallium
(I) sulfate orally (presumably via gavage) for 3 months (El-Garawany et al., 1990). Blood
samples were obtained initially and at monthly intervals. At all three monthly intervals, the
treated group had statistically significantly (p<0.001) increased levels of blood urea, serum
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creatinine, serum bilirubin, and serum ALT. The largest increase (<90%) in these parameters
occurred in the first month with smaller increases (>15%) occurring for each additional month.
Mourelle et al. (1988) examined the effects of silymarin, an antioxidant, on various
biochemical indicators of liver damage in male Wistar rats (200-250 g) induced by oral (gavage)
administration of thallium (I) sulfate (10 mg/kg) dissolved in water. The controls were given
vehicle only. Ten rats per group were sacrificed at 0, 24, 48, 72, and 96 hours and 5, 10, and 20
days after treatment. Without silymarin administration, thallium administration produced a
statistically significant (p<0.05) decrease in the content of glycogen and reduced glutathione and
a statistically significant (p<0.05) increase in malondialdehyde (MDA) production and
triglycerides in the liver 48 hours after treatment. (Malondialdehyde production and reduced
glutathione content in the liver served as indicators of lipid peroxidation.) Levels of serum
alkaline phosphatase were increased and liver cell membrane alkaline phosphatase activity was
decreased after 24 hours and remained unchanged for 5 days. Further, Na+/K+-ATPase activity
in the liver cell membranes was rapidly reduced within 24 hours of thallium treatment; the
decrease persisted through day 5 and began to rebound by day 10 with values similar to the
control by day 20. Serum and liver cell membrane gamma-glutamyl transpeptidase and serum
ALT were significantly (p<0.001) elevated by 24 hours and remained elevated through day 5.
Administration of silymarin (100 mg/kg i.p.) completely prevented these biochemical changes.
The authors suggested that silymarin acted by stabilizing membranes via some antioxidant
property. During the 20 days, none of the rats treated with thallium alone died, but the rats
exhibited signs of toxicity that included hypomotility and piloerection.
Downs et al. (1960) fed groups of Wistar-derived albino rats (5/sex/dose) diets containing
nominal concentrations of 0, 5, 15, or 50 mg thallium (I) acetate/kg (or ppm) in the diet
(corresponding to approximately 0, 0.4, 1.2, and 3.9 mg Tl/kg body weight-day for 100 g rats,
assuming food consumption of 10 g/day). Animals were allowed ad libitum access to these diets
for 15 weeks. At the 50 ppm dose level, mortality was 100% by week 5 in males and by week
13 in females. By week 15, 4/10 control animals died (2/sex), making interpretation of survival
in the remaining dose groups difficult (15 ppm, 3/5 males and 1/5 females died; 5 ppm, 2/6
males and 0/4 females died). An additional treatment group (30 ppm) and control group
(corresponding to 0 and 2.4 mg Tl/kg body weight-day) were added 6 weeks after the study had
been initiated and were maintained on the diet for 9 weeks. At the end of the 9 weeks, 2/5 male
and 1/5 female controls were dead and 4/5 males and 3/5 females at 30 ppm were dead. At
termination, the only gross finding was alopecia in the 15 and 30 ppm groups. The alopecia was
noted beginning 2 weeks after commencement of the diet, with the rats nearly free of hair at
termination. The authors reported a slight increase in kidney weight (doses not specified, data
not shown). The authors also reported that histopathologic evaluations did not indicate
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treatment-related pathology, but they did not prepare skin sections. The study findings for
alopecia suggest aNOAEL and lowest-observed-adverse-effect level (LOAEL) of 0.4 mg Tl/kg-
day and 1.2 mg Tl/kg-day, respectively, for this endpoint. Because mortality occurred in rats in
both the control and treated groups, it is not possible to determine whether the deaths in low-dose
(5 ppm) male rats were related to thallium exposure. Therefore, a NOAEL and LOAEL cannot
be reliably established for this study.
Downs et al. (1960) also examined the effects of thallium (III) oxide on weanling Wistar-
derived albino rats (5 rats/sex/treatment). Rats received 0, 20, 35, 50, 100, or 500 mg thallium
(III) oxide/kg (or ppm) in the diet for 15 weeks. This was equivalent to doses of 0, 1.8, 3.1, 4.5,
9.0, or 44.8 mg Tl/kg body weight-day, respectively. All rats (males and females) treated with
50 ppm and greater in the diet died before 8 weeks. The mortality rates in the remaining groups
at 15 weeks were as follows: 1/5 control males, 0/5 males treated with 20 ppm, and 4/5 males
treated with 35 ppm; 0/5 control females, 2/5 females treated with 20 ppm, and 2/5 females
treated with 35 ppm. Thallium (III) oxide caused a dose-related decrease in body weight at 15
weeks. Body weight reductions relative to the control were 50 and 180 grams in males treated
with 20 and 35 ppm dietary doses, respectively, and 50 grams in females treated with 35 ppm in
the diet. Males treated with either 20 or 35 ppm in the diet had marked hair loss beginning
around 4 weeks, with near complete hair loss after 6 weeks; females were less affected.
There was a statistically significant (p<0.05) increase in absolute kidney weights in males
and females treated with 20 ppm and females treated with 35 ppm and a dose-response trend in
kidney to body weight ratio. Histopathological examination did not reveal any alterations in the
kidney related to thallium treatment. Histopathological evaluation of the skin revealed a
decrease in the number of hair follicles and hair shafts, atrophy of the remaining follicles,
decrease in the size of the sebaceous glands, and hyperkeratinized epidermis. However, the
incidence by dose was not presented. The lowest level tested, 1.8 mg Tl/kg-day (20 ppm
thallium (III) oxide in the diet), is considered to be a LOAEL based upon findings of alopecia
and significant elevations in kidney weights for male and female rats. A NOAEL was not
identified for this study.
Leloux et al. (1987) investigated the acute toxicity of oral exposure to thallium (I) nitrate
in the adult Wistar rat. In the first experiment, a single dose of 20 mg/kg thallium (I) nitrate was
administered via gavage to male and female rats (3 per sex); all males and females were found
dead within 40 and 54 hours post-dosing, respectively. Increases in absolute kidney (36%,
females; 61%, males) and adrenal (47%, females; 100%, males) weights were observed
following the single exposure. The second experiment involved administering four daily gavage
doses of 1 mg/kg-day thallium (I) nitrate to 20 animals of each sex. Male rats treated with 4
doses began to lose their hair 96 hours after the first exposure. All treated animals had diarrhea.
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Two of the 20 males and 2/20 females died after the fourth gavage dose. Two more females died
within 126 hours, and 11 females and 15 males died within 168 hours. Three rats of each sex
were sacrificed at 126 hours post-dosing for gross pathological examination and organ weight
changes. The remaining two females were sacrificed at 192 hours post-dosing. Treated animals
weighed less than the untreated controls. The tissues did not demonstrate any macroscopic
degenerative changes, but there was an increase in the absolute weights of the kidneys (33%,
females; 48%, males) and eyes (54%, females; 34%, males). Histopathology was not performed.
Dogs
Reports of thallium toxicity in dogs are limited to a few cases in the literature of
accidental exposure. A nine-month-old Doberman pinscher accidentally consumed mole bait
containing 1% thallium (Waters et al, 1992). Two days later the dog was lethargic, vomited
blood, and had bloody feces. The dog had moderate hypoproteinemia and a slight prolonged
activated clotting time. The dog's condition was improved by the third day following supportive
care, including treatment with activated charcoal.
Thomas and McKeever (1993) reported a case of a one-year-old neutered male miniature
schnauzer that had ingested an unknown amount of bread soaked in thallium (the level in one
piece of bread was 1.6 ppm). Beginning symptoms were lethargy followed two weeks later by
severe, rapidly progressing alopecia. No abnormalities were found in a CBC count, serum
chemistry profile, urinalysis, or abdominal radiographs. Diphenylthiocarbazone treatments (40
mg/kg three times daily) were started upon establishing thallium toxicity. On the second day of
veterinary treatment, the dog showed signs of respiratory distress and was euthanized due to its
poor condition. An autopsy revealed severely congested and edematous lungs, congestion of the
liver and kidneys, and areas of congestion and hemorrhage in the pancreas. Histological
evaluations demonstrated abnormalities in the lungs, kidneys, liver, and pancreas. Thallium was
detected in the liver (11 ppm), kidneys (12 ppm), and spleen (7 ppm).
Histopathology of the skin from 13 cases of thallium poisoning in dogs revealed
dyskeratotic and necrolytic changes in the skin and hair follicles (Schwartzman and Kirschbaum,
1961). The most prominent features were massive parakeratosis, spongiform abscess formation
and induction of telogen follicles.
4.2.1.2. Chronic Studies and Cancer Bioassays
There are no chronic animal studies or cancer bioassays for thallium reported in the
literature.
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4.2.2. Inhalation Exposure
No studies were identified that examined the effects of inhaled thallium in animal
models.
4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES
Reproductive Toxicity
Effects of thallium on male reproduction have been investigated in rats (Formigli et al,
1986; Gregotti et al., 1985; Zasukhina et al., 1983) and mice (Wei, 1987). These studies suggest
that thallium exposure can produce effects on the testes and sperm. None of the available
reproductive toxicity studies, however, used standard protocols for evaluating reproductive
endpoints. No studies of the potential reproductive toxicity of thallium in female experimental
animals were identified.
Male Wistar rats (10/group) were administered drinking water containing 10 ppm
thallium (I) sulfate (approximately 0.7 mg Tl/kg-day based on reported daily thallium
consumption [270 jig Tl/rat] and initial body weights [350-380 g]) (Formigli et al., 1986). The
compound was administered for 30 and 60 days. Although the study authors stated that the
controls were pair-fed, they also stated that food was available ad libitum, and that thallium did
not affect food consumption. No abnormalities were observed after 30 days of treatment.
However, after 60 days of treatment, the following testicular effects were observed:
disarrangement of the tubular epithelium, cytoplasmic vacuolation and distention of smooth
endoplasmic reticulum of the Sertoli cells, reduced testicular B-glucuronidase activities (an
enzyme primarily located in the Sertoli cell and spermatogonia), high concentrations of thallium
in the testes, and reduced sperm motility. Plasma testosterone levels were within normal limits.
B-Glucuronidase activity was also affected after 60 days of treatment and ultrastructural changes
were observed in the Sertoli cells. From these results, a LOAEL of 0.7 mg Tl/kg-day (10 mg/L)
was identified.
Gregotti et al. (1985) also reported B-glucuronidase activity and ultrastructural changes in
the Sertoli cells after 60 days of treatment. Gregotti et al. (1992) further examined this effect in
vitro and demonstrated that thallium (even at the lowest Tl concentration) causes a dose- and
time-dependent detachment of germ cells from Sertoli cells when testicular cells were treated
with thallium concentrations corresponding to 1.4, 7, and 35 jig Tl/g testis, estimated from
protein content of cultures.
Zasukhina et al. (1983) performed a dominant lethal test with male rats that were given
daily oral doses of thallium (I) carbonate (0.005, 0.05, and 0.5 |ig/kg-day) for 8 months and
subsequently mated with untreated females. The authors reported a treatment-related
enhancement of embryonic mortality. Confidence in the reported findings is low, however,
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because of inadequate reporting (e.g., the paper did not report the number of male rats exposed
or the rat strain), the relatively small number of pregnant females (16-18 per group), and lack of
statistical analysis. Further, the low and mid doses used in this study are smaller than the
average daily intake for the general population (7 ng/day for a 70-kg adult or 0.1 jig/kg-day)
(ATSDR, 1992).
Wei (1987) administered 0, 0.001, 0.01, 0.1, 1.0, or 10.0 mg/L thallium (I) carbonate in
drinking water for 6 months to groups of male Kunming mice (10-20/group) weighing 15-20
grams at study initiation. At the end of the exposure period, half of the males were sacrificed for
epididymal sperm examination, and half were mated with untreated females. Water intake, body
weights, behavior, and animal health were reportedly assessed; however, this information was
not provided in the study report, and numbers of animals examined for sperm and reproductive
endpoints were ambiguously reported. The author reported that sperm motility (rapid speed,
sperm immobility) was affected at the lowest dose (0.001 mg/L) tested. Effects were shown to
increase with increasing dose, thus indicating a dose-response relationship. At 0.01 mg/L and
higher, the number of dead sperm significantly increased and the number of dead fetuses in
females mated to treated male mice increased. Sperm counts were significantly reduced and the
percent of deformed sperm increased at doses of 0.1 mg/L and higher. The author indicated that
there was an adverse effect on sperm quality (motility) at low doses, but as the dose increased
there was an accompanying decrease in sperm count in addition to the motility change.
However, the reproductive index (number of pregnant female mice/number of mating female
mice) and the number of implantations were not statistically different between treated and
control animals. Reported results suggest that the lowest dose tested (0.001 mg/L thallium (I)
carbonate) was a LOAEL. Failure to report age of the mice at study initiation, water
consumption, and terminal body weight data, and use of a nonstandard strain of mice limit the
utility of this study for dose-response assessment.
Table 5 summarizes thallium toxicity in animals following oral exposure.
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Table 5. Thallium toxicity in animals, following oral exposure
Reference
Species
Age
Sex
Route
Dose and duration
NOAEL
LOAEL
Effect
Acute studies
Leloux et al,
1987
Leloux et al.,
1987
Mourelle et
al., 1988
Rat
n=3/sex
Rat
n=10/sex/
group
Rat
n =
10/group
Adult
Adult
NSb
Both
Both
Male
Oral
(gavage)
Oral
(gavage)
Oral
(gavage)
20 mg/kg thallium
(I) nitrate; single
dose
0, 1 mg/kg thallium
(I) nitrate; once daily
for 4 days
0,10 mg/kg thallium
(I) sulfate; single
dose. Sacrificed at
24 hours to 2 days
after dosing
NIa
NI
NI
15 mg/kg Tl
0.77 mg/kg Tl
8.1 mg/kg Tl
Difficulty breathing; rough coat; increased
absolute kidney, adrenal weights; death
Alopecia; diarrhea; increased absolute
kidney, eye weights; death
Liver changes: increased triglycerides and
lipid peroxidation; decreased glutathione and
glycogen; increased alkaline phosphatase in
serum and liver cell membranes
Subchronic studies
Downs et al.,
1960
Rat/
n=5/sex/
group
NS
Both
Oral
(feed)
0, 5, 15, or 50 ppm
thallium (I) acetate
(corresponding to 0,
0.4, 1.2, or 3.9 mg
Tl/kg-day); 15
weeks
0 or 30 ppm
(corresponding to 0
or 2.4 mg Tl/kg-
day) ; 9 weeks
0.4 mg
Tl/kg-day*
1. 2 mg Tl/kg-
day*
Alopecia; increased kidney weight; mortality
in treated and control groups
*The NOAEL and LOAEL are for alopecia.
Because of reported mortality in the control
and treated groups, a study NOAEL and
LOAEL cannot be reliably determined.
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Table 5. Thallium toxicity in animals, following oral exposure
Reference
Downs et al,
1960
El-Garawany
etal, 1990
Manzo et al.,
1983
MRI, 1988
Species
Rat
n=5/sex/
group
Rat
n=10
Rat
n=80
Rat
n=20/sex/
group
Age
Weanling
NS
NS
45 days
Sex
Both
Male
Female
Both
Route
Oral
(feed)
Oralc
Oral
(DWd)
Oral
(gavage)
Dose and duration
0,20,35,50, 100,
and 500 ppm
thallium (III) oxide
(corresponding to 0,
1.8, 3.1,4.5,9.0, and
44.8mgTl/kg-day);
15 weeks
0.8 mg/kg thallium
(I) sulfate; 90 days
lOmgTl/Las
thallium (I) sulfate;
36 weeks
0,0.01, 0.05, or 0.25
mg thallium (I)
sulfate/kg; 90 days
NOAEL
NI
NI
NI
0.04 mg
Tl/kg-daye
LOAEL
1.8mgTl/kg-
day (20 ppm)
0.65 mg
Tl/kg-day
1.4 mg Tl/kg-
day
0.20 mg
Tl/kg-daye
Effect
Reduced body weight; alopecia; increased
mortality; increased absolute and relative
kidney weights
Increased blood urea; serum creatinine;
serum bilirubin; serum ALT
Nerve histopathology; alopecia; mortality
Increased incidence of alopecia, lacrimation,
and exophthalmos; statistically significant
increases in AST, LDH, and sodium levels;
decreased blood sugar levels.
The study authors identified 0.2 mg Tl/kg-
day as the NOAEL.
Reproductive toxicity
Formigli et
al., 1986
Rat
n=10/
group
Adult
Male
Oral
(DW)
0,10 ppm thallium
(I) sulfate; 30 or 60
days
NI
0.7 mg Tl/kg-
day
Testicular effects: tubular epithelium
disarrangement; cytoplasmic vacuolation;
reduced sperm motility; distention of smooth
endoplasmic reticulum of Sertoli cells;
reduced (3-glucuronidase activity
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Table 5. Thallium toxicity in animals, following oral exposure
Reference
Wei, 1987
Rossi et al,
1988
Species
Mouse
Rats
Age
NS
Fetus -
60 days
Sex
Male
Both
Route
Oral
(DW)
Mother's
DW then
dam's
(DW)
Dose and duration
0,0.001,0.01,0.1,
1.0, and lOmg/L
thallium (I)
carbonate; 6 months
0, 1 mg/dL of
thallium (I) sulfate
Day 1 of gestation to
weaning then thru 60
days
NOAEL
NI
LOAEL
Cannot be
calculated
due to non-
reporting of
water intake,
body weights
within dose
groups
NI
Effect
Decreased sperm motility and counts;
increase in deformed sperm; decrease in live
fetuses
Prenatal and postnatal exposure caused a
delay in the development of the pilus
apparatus by 50 days; reduction of the a- and
(3-adrenergic and muscarinic vasomotor
reactivity noted.
aNI = not identified.
bNS = not specified.
Presumably via gavage.
dDW = drinking water.
eSee discussion of the NOAEL and LOAEL determination in Section 5.1.1.
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Developmental Toxicity
Developmental toxicity studies in the rat (Rossi et al, 1988; Gibson and Becker, 1970;
Barroso-Moguel et al., 1992) and chicken embryo (Hall 1972, 1985; Karnofsky et al., 1950)
provide evidence that thallium exposure during development can produce abnormalities
(including effects on the developing vascular autonomic nervous system and bones) and reduced
fetal body weight. Of the studies in rats, only one involved oral drinking water exposure to
thallium (Rossi et al., 1988); in other developmental rat studies, dams were exposed by i.p.
injection.
A group of NOS albino male and female rats was administered 1 mg/dL of thallium (I)
sulfate from day 1 of gestation to weaning (22 days after birth) via the dam's drinking water,
then through their own drinking water until 60 days of age (Rossi et al., 1988). These rats were
considered prenatally exposed. Another set of NOS albino male and female rats were exposed to
1 mg/dL of thallium (I) sulfate via the dam's drinking water from birth until weaning (22 days
after birth) then through their own drinking water until 60 days of age. These rats were
considered postnatally exposed. Both situations (pre- and postnatal exposure) caused a delay in
the development of the pilus apparatus by 50 days. A reduction of the a- and B-adrenergic and
muscarinic vasomotor reactivity also was noted. Authors noted that this reduction may be due to
one of the following mechanisms: probable reduction in the number and/or sensitivity of both •«-
and •«-adrenergic and muscarinic receptors or a change of cell membrane in relation to a possible
modification of potassium cell concentration.
Gibson and Becker (1970) administered thallium (I) sulfate (i.p.) to pregnant Simonsen
Sprague-Dawley rats during early (2.5 mg/kg on days 8, 9, and 10) or late (2.5 or 10 mg/kg on
days 12, 13, and 14) gestation. Fetuses were examined for abnormalities. All three thallium
treatments caused a statistically significant (p<0.05) reduction in fetal body weight. Thallium
treatment (2.5 mg/kg) during early gestation caused a slight (not statistically significant) increase
in the incidence of hydronephrosis (29% in treated versus 16% in control) and missing or non-
ossified vertebral bodies (36% in treated versus 17% in controls). The 2.5 mg/kg thallium (I)
sulfate treatment administered during late gestation caused a statistically significant (p<0.05)
increase in the incidence of hydronephrosis (47% in treated versus 16% in control) and missing
or non-ossified vertebral bodies (60% in treated versus 17% in controls). Increasing the dose to
10 mg/kg thallium (I) sulfate during late gestation did not increase the incidence of
developmental abnormalities. In fact, 10 mg/kg thallium (I) sulfate administered during late
gestation had no effect on the incidence of hydronephrosis and was comparable to the 2.5 mg/kg
dose administered during late gestation in the induction of missing or non-ossified vertebral
bodies (i.e., 60% in treated versus 17% in controls). Maternal toxicity (diarrhea, lethargy,
irritability, poor hair luster, and hair loss) was noted.
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Barroso-Moguel et al. (1992) administered a single i.p. injection of 32 mg/kg aqueous
thallium (I) acetate to 20 newborn (24-hour-old) Wistar rats. Results were compared with those
of five vehicle controls. Rats (four treated and one control per time point) were sacrificed at 24,
48, and 72 hours and at 7 and 50 days. Cartilaginous and osseous tissue alterations were noted.
Diarrhea was observed through 72 hours post-injection. Two rats surviving to 50 days
postinjection had persisting alopecia (one irreversible and one with discrete recovery). Although
skeletal images of 72-hour-old animals did not show any differences when compared with the
control, microscopic images of the distal third of the tibia showed disorganization and edema of
the fibroblasts of the fibrous layer. By day 7, delays in ossification in the right forelimb were
noted. Microscopic examination demonstrated a majority of pycnotic chondrocytes and the lack
of bone trabeculae calcification. Profound skeletal alterations were noticeable 50 days after
injection. Many of the cartilaginous cells were altered or dead, leading to a decrease of the
growth cartilage, scanty bone trabeculae with few osteoblasts. The bone marrow also had few
myeloblasts and megakaryocytes.
Hall (1972) incubated chick embryos in a forced-draft Humidaire incubator and injected
0.6 mg thallium (I) sulfate/0.5 mL saline into each embryo via the chorioallantoic membrane at 7
days of incubation. This dose caused a minimal lethal effect with survival varying from 94 to
100%. Treated embryos were smaller than controls from 10 days of incubation onward and by
18 days were 26% smaller than controls. Treated embryos failed to commence ossification or
had not progressed to similar developmental stages observed in the control. The long bones of
treated embryos were smaller (the tibia to a greater degree than the femur), contained less
organic material, and contained more water (as a percent of dry weight) than the untreated
control embryos. An abnormal distribution of the acid mucopolysaccharides and necrotic areas
in maturing hypertrophic chondrocytes were detected histologically. In addition, biochemical
assays verified the reduced acid mucopolysaccharide activity. Hall (1985) further demonstrated
that the critical period of susceptibility ended at 8b days of incubation. Tibial growth was
inhibited by thallium sulfate in 8-day-old embryos but not in 9-day-old embryos.
Achondroplasia (a birth defect characterized by imperfect bone formation) also was
induced in embryonic chicks via in vitro cultures (Hall, 1985) with injection into the
chorioallantoic membrane (Hall, 1972) or injection into the yolk sac (Karnofsky et al., 1950).
Karnofsky et al. (1950) determined that thallium (I) sulfate was lethal to two-day embryos at a
dose lower than would be necessary to induce achondroplasia. Treatment of 4-day-old chick
embryos with 0.2, 0.5, 1.0, or 2.0 mg/egg induced 0, 45, 92, and 100% incidence of
achondroplasia, respectively. Although the data were not presented, the study authors reported
that thallium (I) nitrate produced achondroplasia at similar doses.
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4.4. OTHER ENDPOINT-SPECIFIC STUDIES
A number of investigators have specifically examined the effect of thallium compounds
administered to experimental animals by injection (subcutaneous, i.p., or i.v.), and reported
effects on the liver, kidneys, heart, and nervous system.
4.4.1. Liver and Kidney Toxicity
Liver and kidney were among the organs affected when male and female Sprague-
Dawley rats were given subcutaneous injection of thallium (I) acetate as acute (single dose of 20-
50 mg/kg), subacute (2-3 weekly injections of 10-15 mg/kg), or chronic (10-20 mg/kg, followed
by weekly injections of 5 mg/kg or occasionally 2.5 mg/kg for up to 26 weeks) exposures.
Toxicity was observed in all treatment groups (Herman and Bensch, 1967). Animals dosed
acutely displayed the symptoms earlier than those on subacute or chronic dosing schedules.
Animals were sacrificed when signs of toxicity became apparent.
Acutely exposed animals had the following changes observed via light microscopy:
eosinophilic granular casts in 50-75% of the renal proximal and distal tubules, mild to moderate
enteritis, moderate to severe colitis, and dense infiltration of polymorphonuclear leukocytes and
lymphocytes that extended through all layers of the wall of the large intestine. Electron
microscopy revealed severe degenerative changes in the mitochondria of the renal tubules and
hepatocytes. The subacutely treated rats had eosinophilic granular casts were in one-third of the
proximal and distal tubules. Electron microscopy revealed moderately prominent mitochondrial
granules in the kidney, dense bodies in the cytoplasm of the cells in the loops of Henle, and distal
convoluted tubules. Mitochondrial granules of hepatocytes were slightly enlarged and lacked
electron-lucent cores.
In the chronically exposed rats, electron microscopy revealed increased size of
mitochondrial granules in the proximal convoluted and an increase in cup-shaped mitochondria
in the distal convoluted tubules. Hepatocytes had increased numbers of large complex residual
bodies and lipid droplets, and the mitochondria were swollen with enlargement of mitochondrial
granules.
Yoshida et al. (1997) administered a single i.p. injection of thallium (I) sulfate (25
mg/kg) to ICR mice (30-35 g). As was observed in Mourelle et al. (1988) after a single oral
dose of thallium (I) sulfate (10 mg/kg) to Wistar rats, liver Na+/K+-ATPase was statistically
significantly decreased by 12 hours. However, the rebound occurred by 24 hours instead of the 5
days observed in the Mourelle et al. (1988) study. While the Na+/K+-ATPase activity was
decreased, the ATP levels were increased and returned to control values by 12 hours post-dosing.
The effects were slightly different in the kidney. At 6 hours Na+/K+-ATPase activity was
statistically significantly decreased but had rebounded by 12 hours. The ATP levels were
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significantly (p<0.01) increased through 12 hours, then decreased to levels significantly
(p<0.01) lower than controls by 24 hours; ATP levels did not rebound until 240 hours after
thallium administration.
Male albino rats (210-260 g) receiving a single i.p. injection of 30, 60, or 120 mg/kg
thallium (I) sulfate had statistically significant (p<0.05) increased levels of AST and ALT above
controls (0.5 mL of 0.9% saline) 16 hours after treatment, regardless of dose (Leung and Ooi,
2000). There was a dose-dependent increase in ALT and AST between 30 and 60 mg/kg, but the
levels did not increase between 60 and 120 mg/kg. Some 30-mg/kg animals exhibited weakness,
sluggishness, loss of hair, ptosis of the eyelids, diarrhea, and respiratory difficulty; they were
sacrificed 4 days post-dosing. The ALT and AST levels in these animals were still elevated over
the controls by a factor of 2-2.5. Serum creatinine levels also were elevated by approximately
2.5 times over the control (0.5 mg/dL control versus 1.33 mg/dL treated). Histological
evaluation confirmed damage to both the kidney and the liver. The damage in the liver consisted
of necrosis and swollen and vacuolated cells, which appeared to reduce the sinusoidal space.
Kidney tubules were atrophied and vacuolated with cell outlines less distinct and cells containing
many pyknotic nuclei. Amorphous material was apparent in the lumen of the proximal tubules,
and the brush borders were disorganized.
Appenroth et al. (1995) examined the effects of a single i.p. dose of thallium (I) sulfate
(5, 10, 15, or 20 mg/kg) on renal function and morphology in adult female Wistar rats. Low
doses (i.e., 5 and 10 mg/kg) of thallium (I) sulfate increased the volume of urine (measured on
day 2) but did not affect the protein level. Higher doses (i.e., 15 and 20 mg/kg) caused a
reduction in urinary volume along with an increase in the urinary protein concentration. The
glomerular filtration rate was statistically significantly (p<0.05) reduced at 2 days after treatment
with 20 mg/kg but had returned to control levels by day 10. Blood urea nitrogen (BUN) levels
were significantly (p<0.05) increased 2 days after treatment but had returned to normal values by
day 10. Histopathology showed a thickening of ascending limb of the loop of Henle notable on
day 2 after treatment and resolved by day 10. Na+/K+-ATPase activity was significantly
(p<0.05) increased in the medulla on day 2 but was significantly (p<0.05) reduced by day 5. No
changes in Na+/K+-ATPase activity were noted in the cortex.
In follow-up studies, Appenroth et al. (1996) and Fleck and Appenroth (1996) examined
the age-related nephrotoxicity of thallium (I) sulfate. Both studies demonstrated that
nephrotoxicity was more severe in the adult rat (Wistar) than in young rat (10 or 20 days old)
after a single i.p. injection of 20 mg/kg thallium (I) sulfate. Appenroth et al. (1996) determined
that there were several biochemical differences in kidney function between 10- and 20-day-old
rats (Wistar) administered 20 mg/kg thallium (I) sulfate, but there were no structural changes
indicating kidney damage in either group of young rats. In comparison, the thick ascending limb
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of loop of Henle in 55-day-old rats showed damage. Thallium did not affect the glomerular
filtration rate in either 10- or 20-day-old rats but caused a significant reduction in the rate in 55-
day-old rats (Appenroth et al, 1996; Fleck and Appenroth, 1996). Thallium caused a statistically
significant (p<0.05) increase in the fractional excretion of a few amino acids (i.e., B-alanine,
taurine, and 1-methylhistidine), a statistically significant (p<0.05) decrease in the fractional
excretion of glycine in 10-day-old rats, and a statistically significant (p<0.05) increase in the
fractional excretion of 13 amino acids in 55-day-old rats. Fleck and Appenroth (1996)
determined that thallium affects renal tubular amino acid resorption and causes kidney damage
only when mature kidney function is present.
Woods and Fowler (1986) examined the effects of a single i.p. dose of thallium (III)
chloride (TICL?) at doses of 50, 100, or 200 mg/kg on liver structure and function in male
Sprague-Dawley rats (CD strain; 150-200 g) 16 hours after treatment. They determined a dose-
related effect on the volume density of mitochondria (increased), rough endoplasmic reticulum
(increased), lysosomes (increased), and cytoplasm (decreased). The surface densities of the
inner cristae of mitochondria and the rough endoplasmic reticulum also were determined to
increase in a dose-dependent manner. Statistically significant (p<0.05) increases occurred in
monoamine oxidase (100 and 200 mg/kg) and ferrochelatase (50, 100, and 200 mg/kg).
Statistically significant (p<0.05) decreases occurred in aminolevulinic acid (ALA) synthetase
(50, 100, and 200 mg/kg), aminopyrine demethylase (200 mg/kg), aniline hydroxylase (50, 100,
and 200 mg/kg), and NADPH cytochrome c (P450) reductase (50, 100, and 200 mg/kg). In
addition, in vitro studies using 50, 100, or 200 |ig/mL TICL? demonstrated a significant (p<0.05)
reduction in ALA synthetase, ferrochelatase, aniline hydroxylase, ALA dehydratase, and
NADPH cytochrome c (P450) reductase for all dose concentrations. A dose-related loss of
ribosomes from the smooth endoplasmic reticulum and proliferation of the rough endoplasmic
reticulum were observed through ultrastructural examination. Also observed were generalized
mitochondrial swelling and increased numbers of electron-dense autophagic lysosomes.
Table 6 summarizes toxicity data from animal studies involving i.p. or i.v. injection.
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Table 6. Thallium toxicity in animals via injection
Reference
Species
Age or
weight
Sex
Route/exposure
period
Doses
NOAEL/LOAEL
Study type/effect
Acute studies (single dose)
All etal., 1990
Appenroth et al,
1995
Barroso-Moguel
etal., 1990
Barroso-Moguel
etal., 1992
Barroso-Moguel
etal., 1996
Kuperberg et al.,
1998
Rat
Rat
Rat
Rat
Rat
Rat
Adult
Adult
Newborn
Newborn
Newborn
250-300
g
Male
Female
Both
Both
Both
Male
i.p./single injection
i.p./single injection
i.p./single injection
i.p./single injection
i.p./single injection
i.p./single injection
20 mg Tl/kg as
thallium (I) acetate
5, 10, 15, and 20
mg/kg thallium (I)
sulfate
32 mg/kg thallium
(I) acetate
32 mg/kg thallium
(I) acetate
16 mg/kg thallium
(I) acetate
25 mg/kg thallium
(I) acetate
LOAEL=20 mg Tl/kg
LOAEL=12mgTl/kg
LOAEL=25 mg Tl/kg
LOAEL=25 mg Tl/kg
LOAEL=12mgTl/kg
LOAEL=19mgTl/kg
Neurological toxicity:
neurochemical changes in the
brain that were resolved within 24
hrs
Kidney toxicity: decreased urine
volume: increased urine protein:
thickened ascending limb of the
loop of Henle: changes in brain
Na+/K+-ATPase
Neurological toxicity: neuronal
and vascular damage in the brain
Developmental toxicity: diarrhea;
alopecia; cartilaginous and osseous
tissue alterations; profound
skeletal alterations
Developmental toxicity: diarrhea;
muscle atrophy; small size;
alopecia; death; interstitial edema
between myelin sheaths; thinner
muscle fibers; nerve fiber damage
Bladder and neurological toxicity:
distended bladder; reduced AchE
activity in the brain and bladder;
increased ChAT activity in the
brain and bladder
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Table 6. Thallium toxicity in animals via injection
Reference
Lameijer and
van Zwieten,
1976
Leung and Ooi,
2000
Osorio-Rico et
al, 1995
Woods and
Fowler, 1986
Species
Rat
Rat
Rat
Rat
Age or
weight
Young
adult
210-260
g
200-250
g
Young
adult
Sex
Male
Male
Male
Male
Route/exposure
period
i.v./single injection
i.p./single injection
i.p./single injection
i.p./single injection
Doses
3-100 mg/kg
thallium (I) sulfate
30,60, 120 mg/kg
thallium (I) sulfate
30 or 50 mg/kg
thallium (I) acetate
50, 100, and 200
mg/kg thallium
(III) chloride
NOAEL/LOAEL
LOAEL=24 mg Tl/kg
(30 mg/kg thallium (I)
sulfate)
LOAEL=24 mg Tl/kg
LOAEL=23 mg Tl/kg
LOAEL=42 mg Tl/kg
Study type/effect
Cardiotoxicity: hypertension
General toxicity: increased AST
and ALT; weakness; sluggishness;
alopecia; ptosis of the eyelids;
diarrhea; respiratory difficulty;
liver necrosis; kidney damage
Neurological toxicity: increase in
MAO and 5-HT in the brain
Liver toxicity: increased volume
density of mitochondria,
lysosomes, and rough endoplasmic
reticulum of the liver; decreased
cytoplasm in the liver; increased
MAO and ferrochelatase; changes
in several liver enzymes
Acute studies (3-10 doses)
Brown et al.,
1985
Gibson and
Becker, 1970
Rat
Rat
250 g
Fetus; 8,
9, and 10
or 12, 13,
and 14
days of
gestation
Male
Both
i.p./6 days
Transplacental via
i.p. injection to
dam/3 days
4 or 8 mg/kg-day
thallium (I) acetate
2.5 or 10 mg/kg-
day thallium (I)
sulfate
LOAEL=3.1 mg
Tl/kg-day
LOAEL=1.9mg
Tl/kg-day
Neurological toxicity: increased
lipid peroxidation in the brain;
increased (3-galactosidase activity
in the brain; behavioral changes
Developmental toxicity: reduced
fetal body weight; increase in
hydronephrosis; increase in
missing or non-ossified vertebral
bodies
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Table 6. Thallium toxicity in animals via injection
Reference
Gibson and
Becker, 1970
Hasan et al,
1977
Hasan et al.,
1978
Hasan and All,
1981
Hasan and
Haider, 1989
Species
Rat
Rat
Rat
Rat
Rat
Age or
weight
Pregnant
-150 g
-150 g
-150 g
-150 g
Sex
Female
Male
Male
Male
Male
Route/exposure
period
i.p./3 days
i.p./7 days
i.p./7 days
i.p./7 days
i.p./6 days
Doses
2.5 or 10 mg/kg-
day thallium (I)
sulfate
5 mg/kg thallium
(I) acetate
5 mg/kg thallium
(I) acetate
5 mg/kg thallium
(I) acetate
5 mg/kg thallium
(I) acetate
NOAEL/LOAEL
LOAEL=1.9mg
Tl/kg-day
LOAEL=3.9 mg
Tl/kg-day
LOAEL=3.9 mg
Tl/kg-day
LOAEL=3.9 mg
Tl/kg-day
LOAEL=3.9 mg
Tl/kg-day
Study type/effect
General toxicity: diarrhea;
lethargy; irritability; poor hair
luster; alopecia
General toxicity: anorexia; poor
hair luster; diarrhea; difficulty
walking; abnormal head rotation;
lethargy; death; changes in Golgi
complexes and smooth cisternae/
vesicles of hypothalamic neurons;
decreased succinic dehydrogenase
and guanine deaminase activities
in the brain
Neurological toxicity: decreased
dopamine, norepinephrine, and 5-
HT in the brain
General toxicity: anorexia; poor
hair luster; diarrhea; difficulty
walking; abnormal head rotation;
lethargy; increased lipid
peroxidation; aggregation of
lipofuscin granules in the
perikarya of cerebellar neurons
Neurological toxicity: reduced
glutathione
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Table 6. Thallium toxicity in animals via injection
Reference
Kuperberg et al,
1998
Species
Rat
Age or
weight
250-300
g
Sex
Male
Route/exposure
period
i.p./5 days
Doses
0,0.1, 1.0, or 5.0
mg/kg thallium (I)
acetate
NOAEL/LOAEL
LOAEL= 0.08 mg
Tl/kg-day
Study type/effect
Neurological toxicity: difficulty
walking and maintaining pressure
on the hind paws; loss of
coordination in motor activity;
lethargy; reduced food
consumption; distended bladder;
decreased AchE activity in the
bladder
Subchronic study
Galvan-Arzate
etal.,2000
Rat
200-250
g
Male
i.p./30 days
0.8 or 1.6mg/kg-
day thallium (I)
acetate
LOAEL=0.6 mg
Tl/kg-day
Neurological toxicity: increased
lipid peroxidation in the brain
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4.4.2. Cardiotoxicity
Male Wistar rats (180 to 220 g) injected i.v. with 3 to 100 mg/kg thallium (I) sulfate,
while under pentobarbital anesthesia, rapidly developed hypotension with the lowest blood
pressures reached within 3 to 5 minutes (Lameijer and van Zwieten, 1976). Blood pressures
dropped in a dose-dependent manner with doses of 30 to 100 mg/kg causing a drop of 20 to 40%
from initial values and a maximum effect achieved in the 50 to 100 mg/kg range. Thallium had a
greater effect on the diastolic pressure. After 10 minutes, animals injected with doses ranging
from 3 to 40 mg/kg had blood pressures resembling those prior to thallium injection. The higher
doses had a more permanent effect on the blood pressure. In addition to lower blood pressure,
the rats had a dose-dependent decrease in heart rate with no maximum achieved. Rats treated
with 100 mg/kg had heart rates that were one-third their pre-injection rates. The same effects
were observed in anesthetized cats when injected i.v. with monovalent thallium but not when the
thallium was infused into the left vertebral artery (Lameijer and van Zwieten, 1976).
4.4.3. Neurotoxicity
No studies of thallium neurotoxicity following exposures by the oral, inhalation or
dermal routes of exposure were identified. All studies reported in this section used
intraperitoneal (i.p.), subcutaneous (s.c.) or intravenous (i.v.) routes of exposure.
A single i.p. injection of 20 mg/kg thallium (I) acetate in 8-12 (exact number per group
not specified) adult male Sprague-Dawley rats (-300 g) resulted in a statistically significant
(p<0.02) decrease in aspartate and taurine in the hippocampus 6 hours after treatment that was
resolved by 24 hours (Ali et al, 1990). The frontal cortex had a statistically significant (p<0.05)
increase in glutamine and taurine at 6 hours. While the glutamine returned to control levels by
24 hours, the taurine was still significantly elevated. A dose-dependent decrease in dopamine
and muscarinic cholinergic receptor binding in caudate nucleus was not reported in these treated
rats but was observed in caudate nucleus incubated in vitro with thallium. The study report
indicated that the effect was not observed 24 hours after the last subacute dose (5 mg/kg daily for
10 days, i.p.) of thallium (I) acetate in a separate study, but the results were not presented. The
subacute study demonstrated a statistically significant (p<0.05) increase in dopamine, 3,4-
dihydroxyphenylacetic acid, and 5-hydroxytryptamine (5-HT; serotonin) levels in the amygdala
nucleus, as well as an increase in 5-HT in the hypothalamus. Dopamine, 3,4-
dihydroxyphenylacetic acid, and 5-HT remained similar to control concentrations in the caudate
nucleus, frontal cortex, and hippocampus.
A set of companion studies in newborn Wistar rats (Barroso-Moguel et al., 1996, 1990)
demonstrated severe and progressive lesions in nerve fibers following i.p. administration of
thallium (I) acetate. In the first study (Barroso-Moguel et al., 1990), 32 mg/kg thallium (I)
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acetate was given to 15 newborn Wistar rats. Equal numbers were sacrificed at 24, 48, and 72
hours and on days 7 and 51 (3 rats/time point). Alterations in the capillary vessel walls of the
brain, observed within the first hours after thallium injection, progressed to irregular thickened
walls and fibrotic sclerosis, which obstructed the lumen by 51 days postexposure. Other changes
in the brain began in a diffuse manner with all sections affected. Cortical neurons developed the
first and most intense lesions; by 51 days, the cortical neurons had mostly disappeared and
lesions were apparent in the central grey nuclei.
In a follow-up study (Barroso-Moguel et al., 1996), 16 mg/kg thallium (I) acetate was
administered via i.p. injection to 20 newborn Wistar rats (10 each sacrificed at 8 and 50 days of
age). General toxicity was manifested through diarrhea, progressive muscular atrophy, small
body size, and persistent alopecia. Eight of the 20 thallium-treated rats died during the study.
By 8 days of age, thallium-treated rats had interstitial edema between the myelin sheaths
(causing separation of the nerve fibers), edema around some axons and within the myelin, and, in
some cases, initial damage and degeneration of the myelin sheaths. In addition, muscle fibers
were thinner and showed signs of beginning progressive muscular atrophy. Hemorrhage,
necrosis, and destruction of the striation were present in some areas of the muscle. By 50 days of
age, the rats developed nerve damage with progressive disappearance of nerve fibers and
granular, filiform, and amorphous inclusions in abnormal axons and collapsing myelin sheaths.
At this time, the muscle fibers lost their transverse striation. Other muscle fibers were observed
to be atrophic, fragmented, and exhibiting hyaline degeneration and initial fibroblast reaction;
further, some were infiltrated with phagocytic macrophages.
Osorio-Rico et al. (1995) measured monoamine oxidase (MAO) activity and 5-HT
turnover rates in different regions of the brain in 127 male Wistar rats (200-250 g) 24 hours after
an i.p. administration of 30 or 50 mg/kg aqueous thallium (I) acetate. Results demonstrated
MAO was significantly (/K0.05) increased at 30 mg/kg in the midbrain (27.7% over controls)
and pons (37% over controls) sections. MAO increases also were observed at 50 mg/kg in the
midbrain (48% over controls) and pons (47%). 5-HT turnover was significantly increased in the
pons (172% over controls; p<0.001) after 30 mg/kg treatment and in the pons (166.7% over
controls; p<0.001) and midbrain (56% over controls; p<0.01) after 50 mg/kg treatment. No
significant changes were observed in the dopamine turnover rate.
Subcutaneous injection of thallium (I) acetate as acute (single dose of 20-50 mg/kg),
subacute (2-3 weekly injections of 10-15 mg/kg), or chronic (10-20 mg/kg, followed by weekly
injections of 5 mg/kg or occasionally 2.5 mg/kg for up to 26 weeks) doses to male and female
Sprague-Dawley rats (250-500 g) caused toxicity in all treatment groups (Herman and Bensch,
1967). Symptoms reported in all groups included diarrhea, marked weight loss, anorexia, and
lethargy. Animals dosed acutely displayed the symptoms earlier than those on subacute or
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chronic dosing schedules. Chronically exposed animals also had hair loss (maximal at 2-4
weeks after initial injection), irritability, and dragging of the hind limbs. Animals were
sacrificed when signs of toxicity became apparent.
In acutely exposed animals, the mitochondria of the brain were frequently filled with an
overabundance of stacked mitochondrial cristae. Three of four animals administered thallium (I)
acetate subacutely had changes in the brain including occasional foci of perivascular cuffing with
lymphocytes and hemosiderin-filled macrophage, acute necrosis, and swollen histiocyte-like
cells. Peripheral nerves had occasional dense bodies in an unmyelinated nerve plexus. Brain
neurons had numerous lipofuscin bodies as did the neurons of the chronically exposed animals.
Twenty-four hours after a single dose of 25 mg/kg thallium (I) acetate, acetyl
cholinesterase (AchE) activity was reduced in the hypothalamus and nucleus accumbens (NA)
regions of the brain and the activity of choline acetyltransferase (ChAT) activity was
significantly (p< 0.05) increased (Kuperberg et al, 1998). At 48 hours, the AchE in the
hypothalamus was still significantly (p< 0.05) reduced, the AchE in the NA region of the brain
was back to control levels. AchE activity also was reduced in the duodenum, and the spincter-
trigon region of the bladder following this single high dose while choline acetyltransferase
(ChAT) activity was significantly (p< 0.05) increased in the ileum, duodenum, and both regions
of the bladder. After 48 hours, the AchE levels in the duodenum and the spincter-trigon and
detrusor regions of the bladder were still significantly (p< 0.05) reduced.
Adult male Sprague-Dawley rats (250-300 g) administered 0.1, 1.0, or 5.0 mg/kg
thallium (I) acetate (i.p.) daily for 5 days exhibited difficulty walking and maintaining pressure
on their hind paws, loss of coordination in motor activity, lethargy, and reduced food
consumption (Kuperberg et al., 1998). Most of the rats (6 of 8) treated at the high dose died by
48 hours post-treatment. The only significant changes observed 24 hours after the last dose were
a reduction of AchE levels in the NA region of the brain with the 1.0 mg/kg dose, and an
increase in the AchE levels in the striatum and midbrain of rats treated with 5 mg/kg. There was
a decrease in AchE activity in the sphincter-trigon region of the bladder at 24 hours in all of the
repeat-dose groups (i.e., 0.1, 1.0, and 5.0), which had returned to control values by 48 hours.
Decreased bladder AchE levels were also observed in the detrusor region of the bladder 24 hours
after 1.0 or 5.0 mg/kg doses and 48 hours after the 0.1 mg/kg dose. The bladders of these rats
were distended and contained twice the amount of urine seen in the controls.
Brown et al. (1985) examined lipid peroxidation in the brain after thallium exposure. In
this study, groups of male Sprague-Dawley rats (250 g) were administered daily i.p. injections of
4 or 8 mg/kg thallium (I) acetate in water for 6 days. Controls received saline. Twenty-four
hours after the final injection behavioral analysis was performed and the following morning, rats
were sacrificed. A dose-dependent increase in lipid peroxidation was observed in the
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cerebellum, brain stem, and striatum but not in the midbrain and hippocampus. The 8-mg/kg
dose also caused a statistically significant (p<0.05) increase in the lipid peroxidation of the
cortex. Beta-galactosidase activity followed a dose-dependent increase in the cerebellum, brain
stem, and cortex. The 8-mg/kg dose also caused a statistically significant (p<0.05) increase in
beta-galactosidase activity in the midbrain and hippocampus. The beta-galactosidase activity in
the striatum was not statistically significantly changed by either dose. In general, thallium
decreased the frequency of grooming behavior while the frequency of exploratory and attention
behaviors was increased. However, the changes were not dose dependent.
Male Charles Foster rats (approximately 150 g) injected with 5 mg/kg thallium (I) acetate
daily for 7 days were anorexic, failed to gain weight, had poor hair luster and diarrhea, dragged
their hindlimbs, and had fits of abnormal rotation of the head and neck (Hasan and Ali, 1981).
All rats were lethargic after 4-5 days of treatment. Rats were sacrificed the day after the final
dose (day 8) and their brains were removed and separated into sections. A statistically
significant (p<0.001) increase in lipid peroxidation was reported in the cerebral hemisphere,
cerebellum, and brain stem by 49, 142, and 116%, respectively. Electron microscopy
demonstrated prominent aggregation of lipofuscin granules in the perikarya cerebellar neurons
(cell body of neurons in the brain) in thallium-treated rats that were hardly discernible in control
rats. Comparisons made with nickel- and cobalt-treated rats demonstrated differences in the
areas of increased lipid peroxidation. Nickel and cobalt both had the greatest impact on the brain
stem, whereas thallium had a greater effect on the cerebellum. Although Hasan and Ali (1981)
could not relate this to the differences in behavioral observations, they did note that nickel- and
cobalt-treated rats were irritable and restless; these symptoms were not observed in the thallium-
treated rats.
Using a similar protocol to Hasan and Ali (1981), Hasan et al. (1977) administered 5
mg/kg thallium (I) acetate i.p. for 7 days to albino male rats (weighing approximately 150 g).
Controls received sodium acetate solution in equal volumes with the same molar concentration.
Clinical symptoms were similar to those reported above by Hasan and Ali (1981) with 8/55
treated rats dying by day 7. Electron microscopy showed an increased incidence of well-
developed Golgi complexes and curved conformation of smooth cisternae and vesicles of the
neurons in the hypothalamus. More significantly, there was a peculiar isolation of axonal
endings of the anterior hypothalamus by membranous circumferential lamellae, which appeared
to have arisen from the neighboring astrocytic processes. In addition, the succinic
dehydrogenase and guanine deaminase activities in the cerebrum were significantly decreased in
thallium-treated rats. Protein levels, monoamine oxidase, adenosine triphosphate, and protease
levels in the cerebrum were unaffected. Mitochondrial succinic dehydrogenase also was
decreased in the cerebrum of thallium-treated rats.
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Hasan and colleagues also examined the effects of thallium (I) acetate on
neurotransmitter levels and sulfhydryl groups in the brain. Charles Foster rats (approximately
150 g) were administered 5 mg/kg thallium (I) acetate i.p. for 6 (Hasan and Haider, 1989) or 7
(Hasan et al, 1978) days. Dopamine, norepinephrine and 5-HT were reduced in the four
sections of the brain examined (hypothalamus and limbic area, corpus striatum, cerebellum, and
brain stem), but not all reductions were statistically significant. Dopamine was significantly
reduced in the hypothalamus and limbic area (50%;/?<0.05) and corpus striatum (64%;/?<0.01).
Norepinephrine was reduced by 9-33% depending on the brain region, but none of these
reductions were statistically significant. 5-HT was significantly reduced in the corpus striatum
(53%;/K0.001), cerebellum (36%;/K0.05), and brain stem (66%;/K0.001) (Hasan et al.,
1978). Glutathione was significantly (p<0.001) reduced in the cerebrum (56%), cerebellum
(62%), and brain stem (74%), and sulfhydryl radicals were significantly (p<0.05) reduced in the
cerebellum (25%) and brain stem (32%) (Hasan and Haider, 1989).
Galvan-Arzate et al. (2000) administered 0.8 mg/kg (considered 1/40 of the median lethal
dose [LD50]) or 1.6 mg/kg (considered 1/20 of the LD50) thallium (I) acetate in deionized water
via i.p. injection for 30 days to male Wistar rats (200-250 g). Three days after treatments ended,
rats were sacrificed and their brains were dissected into 5 different regions (hypothalamus,
cerebellum, frontal cortex, hippocampus, and corpus striatum). In each region, with the
exception of the cerebellum, significant (p<0.01) increases in thallium content were observed
after administration of 1.6 mg/kg compared to administration of 0.8 mg/kg. There were no
statistically significant differences in the deposition of thallium within each region of the brain
for each dose. The rate of lipid peroxidation, a marker of oxidative stress, was increased
significantly (p<0.01) in the corpus striatum (182%) and cerebellum (130%) after treatment with
0.8 mg/kg. At 1.6 mg/kg, all 5 regions exhibited statistically significant increases in lipid
peroxidation over controls (corpus striatum, 161% increase, p<0.05; hippocampus, 114%
increase, p<0.01; hypothalamus, 100% increase, p<0.01; cerebellum, 81% increase, p<0.01; and
frontal cortex, 80% increase, p<0.05). The two regions affected at 0.8 mg/kg (i.e., corpus
striatum and cerebellum) were not affected to a greater extent at the higher dose. Lipid
peroxidation was measured to determine if oxidative stress plays a role in thallium's toxicity.
The study authors concluded that additional studies need to be performed to establish the precise
mechanism of neurotoxicity.
4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF
ACTION
Several, possibly related, mechanisms have been postulated for the toxic action of
thallium; however, the exact mechanism(s) of toxicity is unknown.
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4.5.1. Interference with Potassium Transport
Monovalent thallium is similar to potassium (K+) in ionic radius and electrical charge,
which may contribute to its toxic properties.
Monovalent thallium has been demonstrated to have a 10-fold higher affinity for rabbit
kidney Na+/K+-ATPase than does potassium (Britten and Blank, 1968). Barrera and Gomez-
Puyou (1975) reported that monovalent thallium also inhibits the influx and efflux of potassium
in rat liver mitochondria at concentrations (10 to 15 nmol bound monovalent thallium per mg of
mitochondrial protein) that do not affect oxidative phosphorylation. This inhibitory effect of
thallium seemed to be specific for potassium since it did not affect the movement of sodium.
Monovalent thallium was completely equilibrated by human red blood cells in 30 minutes
in a high (140.5 mM)-sodium (Na+) medium (Cavieres and Ellory, 1974) but was equilibrated
even faster when the medium contained a low concentration (5 mM Na+). In the high-Na+
medium containing 1 mM external potassium, monovalent thallium caused a dose-dependent
decrease in the ouabain-sensitive potassium influx. Monovalent thallium had a different effect in
a medium containing 0.17 mM potassium; low (0.2 mM or less) monovalent thallium ion
concentrations stimulated the ouabain-sensitive potassium influx but inhibited it at higher
concentrations. Monovalent thallium also had an inhibitory effect on the ouabain-sensitive
sodium efflux. It was suggested that the effects on ouabain-sensitive sodium efflux and
potassium influx are related to thallium's high-affinity substitution of potassium at the external
potassium sites of the sodium pump, which is actively transporting monovalent thallium ions in
while pumping sodium ions out.
4.5.2. Disturbance of Mitochondrial Function and Induction of Oxidative Stress
Thallium may exert toxicity by disturbing mitochondrial function. Thallium (I) acetate
caused an uncoupling of oxidative phosphorylation and swelling of isolated mitochondria, and
induced an increase in oxygen consumption and lactic acid production in ascite tumor cells in
vitro (IPCS, 1996).
Other research suggests that thallium may trigger toxicity through induction of oxidative
stress. Hanzel et al. (2005) investigated effects of thallium (III) hydroxide on metabolism of
glutathione (GSH), which plays a key role in the regulation of cell redox state, in an in vitro
system using rat brain cytosolic fractions. Thallium hydroxide decreased the content of reduced
glutathione and inhibited glutathione peroxidase and glutathione reductase activity, suggesting
that thallium impairs the glutathione-dependent antioxidant defense system. Using rat
pheochromocytoma (PI2) cells in vitro incubated with both thallium (I) nitrate and thallium (III)
nitrate, Hanzel and Verstraeten (2006) found a concentration- and time-dependent decrease in
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cell viability, decreased mitochrondrial membrane potential, increased steady-state levels of
mitochondrial hydrogen peroxide (H2O2, a product of partial reduction of molecular oxygen
whose generation is enhanced when electron transport is impaired), and reduced glutathione
content. These investigators postulated that both ionic species of thallium enhance reactive
oxygen species production in the cell, decreasing mitochondrial functionality and cell viability.
Galvan-Arzate et al. (2005) investigated the effects of a single dose (8 or 16 mg/kg, i.p.)
of thallium acetate on lipid peroxidation in different brain regions of Wistar rats (as an indicator
of oxidative damage) and alterations in endogenous antioxidant systems. Lipid peroxidation was
increased in three of five brain regions at day 7 post-exposure (but not at days 1 and 3) and at the
16 mg/kg; antioxidants GSH and superoxide dismutase (SOD) showed only a modest depletion
in only one or two brain regions.
4.5.3. Reaction with Thiol Groups
The capacity of thallium to react with thiol groups, thereby interfering with a variety of
processes, is postulated as another mechanism of toxicity, although interference with the
metabolism of sulfur-containing amino acids does not seem to be directly involved in toxicity
(IPCS, 1996). Thallium (I) chloride formed complexes with a number of sulphur-containing
amino acids (i.e., L-cysteine, DL-penicillamine, N-acetyl-L-cysteine, and N-acetyl-DL-
penicillamine) in aqueous solution (Bugarin et al., 1989). Because the thallium (I) complexes
formed were weaker than those formed using dimethylthallium (III), the study authors concluded
that this was unlikely to be the major mechanism of toxicity.
4.5.4. Other Endpoint-specific Mechanistic Data
Cardiotoxicity
Monovalent thallium ions caused a dose-dependent decrease in the heart rate and
contractile force of spontaneously beating atria of guinea pigs (Lameijer and van Zwieten, 1976).
At a concentration of 10"3 M, monovalent thallium reduced the heart rate by approximately 60%.
When the isolated atria were electrically driven, monovalent thallium ions at doses up to 10"3 M
were not able to significantly decrease the amplitude of contraction. Neither potassium (ranging
from 0.0024 M to 0.0094 M) nor cocaine (10"6 or 10"5 M) were able to influence the reduction in
heart rate or contractile force of spontaneously beating guinea pig atria caused by monovalent
thallium ions (0.0005 M) (Lameijer and van Zwieten, 1976).
Isolated rat heart (from albino rats of both sexes) perfused with a nitrate-Krebs solution
containing monovalent thallium ions (as thallium (I) nitrate) in place of potassium had a rapid
decrease in beat frequency (Hughes et al., 1978). The heart stopped completely in an average of
7 minutes. Placing the hearts in normal or nitrate-Krebs saline allowed for some recovery in
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approximately 10 minutes. The monovalent thallium ions were still present in the heart tissue
(9 mmol Tl+/kg wet tissue) after 30 minutes in thallium-free solution; this residual thallium
caused the heartbeat frequency and amplitude to remain low. When only a portion of the
potassium was replaced with monovalent thallium ions, there was a concentration ratio and time
dependency on the reduction of the heart rate. In a separate experiment, it was noted that
injecting thallium (I) nitrate into the perfusion stream close to the heart caused an initial
acceleration of the heartbeat followed by a reduction in amplitude until at certain concentrations
the heart stopped. The heartbeat could recover somewhat following nitrate-Krebs perfusion, but
the heartbeat frequency and amplitude did not return to initial values and were instead
comparable to those values noted prior to the heart stopping. There was a dose-dependent effect
on the length of the cardiac paralysis (5-25 jimol monovalent thallium ions injected). The use of
potassium nitrate instead of thallium (I) nitrate also caused a dose-dependent increase in the
length of cardiac paralysis, but the length of paralysis was shorter than that with thallium (I)
nitrate. Further, potassium nitrate-treated hearts recovered completely when washed with
nitrate-Krebs solution (Hughes et al, 1978).
Neurotoxicity
Wiegand et al. (1984) recorded the frequencies (reflects presynaptic processes) and
amplitudes (reflects postsynaptic processes) of miniature endplate potentials (MEPPs) from
neuromuscular junctions of rat (strain not specified) phrenic nerve (of the diaphragm)
preparations. Investigators reported a gradual increase in the frequency of MEPPs by a factor of
10 within 30 and 180 minutes at doses of 1 x 10"3 and 5 x 10"4 mol/L thallium (I) acetate,
respectively, which was reversible. The amplitude was unchanged. Therefore, it was concluded
that thallium interferes presynaptically with spontaneous transmitter release. A follow-up
experiment using triangularis sterni muscles of adult mice (strain not specified) demonstrated
that although thallium disturbed the presynaptic transmission in a manner similar to divalent
metal cations, thallium (monovalent; compound used not specified) acted via a different
mechanism than either divalent cobalt or cadmium (Wiegand et al., 1990). This study also
demonstrated that thallium did not influence the presynaptic potassium or calcium channels.
Hippocampal slices from adult guinea pigs or rats (strain not specified) were used to
examine the effects of thallium on central neuronal activity (Lohmann et al., 1989). The study
authors did not note any differences between the guinea pig and rat results and appear to have
combined the results. Light microscopy did not show any morphological changes in thallium-
treated hippocampal slices even with a high concentration (1-1.2 mM) for 6 hours. Thallium
was determined to reversibly reduce the amplitudes of the compound action potential of CA1
pyramidal cells in a dose- and time-related manner. Thallium did not alter intracellular response
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parameters, indicating that membrane potential and input resistance were not affected, but
postsynaptic potentials were inhibited. The study authors concluded that in the hippocampal
slices thallium reacts mainly with postsynaptic target sites and exerts an unknown influence on
intracellular metabolism of CA1 pyramidal cells (Lohmann and Wiegand, 1996; Lohmann et al,
1989).
Diaphragms from male and female albino rats perfused with a nitrate-Krebs solution
containing monovalent thallium (as thallium (I) nitrate) in place of potassium (K+) had an initial
(1-2 minute) increase in the contraction amplitude, followed by a steady decline in response
(Hughes et al., 1978). Four experiments were performed with the sequence taking 20-40
minutes to block indirect (nerve) stimulation and 70-100 minutes to block direct (muscle)
stimulation. After returning the diaphragms to normal nitrate-saline, the block in response was
reversed, but contraction amplitudes were 30% of the original response for both nerve and
muscle after a 75-minute perfusion. The presence of monovalent thallium in the solution,
whether as a replacement or an addition to potassium, caused a dose dependency to the response.
Diaz and Monreal (1994) examined the effects of thallium compounds [thallium (III)
chloride, thallium (III) nitrate, and thallium (I) acetate] on proton and chloride permeabilities
through myelin lipid biolayers using an in vitro system of lipo somes prepared with lipids from
brain myelin. Trivalent thallium, but not monovalent thallium, mediated a rapid
chloride/hydroxyl ion exchange through the lipid bilayers. Trivalent thallium in the presence of
reducing agents did not have the same reaction. The ion exchange was faster with trivalent
thallium than with mercury (Hg+2). In addition, the reaction occurred with a 10-fold lower
concentration of trivalent thallium than of mercury.
Dermal Toxicity
Arbiser et al. (1997) examined the effects of thallium acetate on three types of skin cells,
human keratinocytes, primary endothelial cells, and melanoma cells, to determine whether
thallium affected cell growth and differentiation in vitro. Inhibition of proliferation of all three
cell types was observed. In melanoma cells, thallium caused dose-dependent decreases in cell
dendricity and shape, but not cellular motility. In normal human keratinocytes, thallium
appeared to interfere with the normal program of cutaneous keratinization. In an in vivo study
by the same investigators using piebald LPJ mice with both melanin rich and poor areas in the
same animal, one week administration of thallium acetate (5 mg/kg daily) by i.p. injection
produced evidence of lipid peroxidation in skin in a perifollicular distribution (Arbiser et al.,
1997). [The investigators noted that lipid peroxidation in vivo results in oxidation of lipid
membranes, resulting in increased concentrations of aldehydes, which can react with the Schiff
reagent thereby producing a colored product.] It was suggested that lipid peroxidation may
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result in cell death due to membrane damage, and may partly account for thallium-induced
alopecia.
4.5.5. Genotoxicity
Positive results were obtained for thallium (I) nitrate (0.001 M) in the recombination-
repair (Rec) assay using Bacillus subtilis strains H17 and M45; whether or not hepatic
homogenates were used was not specified (Kada et al, 1980; Kanematsu et al, 1980). These
positive results were obtained using "cold incubation," which increases the sensitivity of the
assay by 20-50 times for many drugs. In this test, plates containing the bacteria with a 10-mm
filter paper disk containing the metal solution (0.05 mL) were incubated at 4°C for 24 hours prior
to being incubated at 37°C overnight. The differences in the inhibition of growth between the
Rec+ strain and the Rec" strain were measured. Thallium (I) nitrate was not mutagenic in
reverse mutation assays using Salmonella typhimwium strains TA98, TA100, TA1535, TA1537,
and TA1538 (histidine reversions) and Escherichia coli strains B/r WP2 tr~and WP2 her" tr~;
whether or not hepatic homogenates were used was not specified (Kanematsu et al., 1980).
Negative results were obtained in a screening assay for the induction of mitogenic gene
conversion and reverse mutation in the yeast, Saccharomyces cerevisiae, at a 0.1 M
concentration of thallium (I) nitrate (Singh, 1983).
Thallium (I) nitrate did not affect cell division in S. cerevisiae (isolated from baker's
yeast) and E. coli (strain B) but proved toxic to the aerobic growth processes of S. cerevisiae
(Loveless et al., 1954). A dose of 250 |ig/mL thallium (I) nitrate caused a 50% reduction in
aerobic growth processes. The report did not identify specific doses of thallium (I) nitrate tested.
The organisms were treated under conditions of logarithmic phase growth. S. cerevisiae was
incubated for 4 hours with thallium (I) nitrate, and E. coli was incubated for 1.5 hours. The
study authors noted that several of the other compounds tested (e.g., iodoacetamide) that were
specific inhibitors of sulfhydryl groups also reduced the growth processes with no effect on
cellular division.
A concentration of 1000 |ig/mL thallium (I) acetate reduced viability of Chinese hamster
ovary (CHO) cells in culture to 20% with a concomitant decrease in DNA synthesis (i.e., 1% of
control values) (Garrett and Lewtas, 1983). The ECso values (concentration necessary to
produce a 50% response) were 307 |ig/mL for viability and 18 |ig/mL for DNA synthesis.
Thallium acetate also depressed ATP and protein synthesis in culture.
Single-strand DNA breaks occurred in cell cultures of C57BL/6 mouse and rat embryo
fibroblasts exposed to thallium (I) carbonate at both concentrations tested in mouse fibroblasts
(i.e., 10"5 and 10"4M) and all three concentrations tested in rat fibroblasts (i.e., 10"6, 10"5, and 10"4
M) (Zasukhina et al., 1983). However, thallium (I) carbonate did not induce single-strand DNA
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breaks in CBA mouse fibroblasts after treatment with 10"4-10"6M concentrations.
Zasukhina et al. (1983) performed a dominant lethal test on male white rats that received
daily oral doses of thallium (I) carbonate (0.005-0.5 jig/kg-day) for eight months and were
subsequently mated with untreated females. Female rats were sacrificed on day 20, and
mutagenic potential was evaluated based on evidence of embryotoxicity. The investigators
reported an increase in embryonic death, suggestive of a dominant lethal effect. As reported
previously (Section 4.3), however, confidence in this study is low. The number of resorptions
was highest in the control group. In addition, methods were not adequately reported and results
were not analyzed statistically.
4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS
4.6.1. Oral
Thallium is readily absorbed through the GI tract and distributed throughout the organs
and tissues of the body. Although thallium is not metabolized, it occurs in two valence states. If
or how the body modifies the valence state of thallium is unknown, but orally administered
monovalent thallium and trivalent thallium appear to be distributed in a similar manner
throughout the body (Sabbioni et al., 1980a, b). Once thallium is distributed, elimination occurs
mainly in the urine and feces with the amounts in each varying by species.
Most of the available human case reports are the results of poisonings, suicide attempts,
or accidental ingestion of rodenticides. The lowest known dose to cause symptoms is a single
dose of 0.31 g; the patient recovered after treatment (Cavanagh et al., 1974). The only studies of
repeated oral exposure to thallium were two surveys of populations exposed to thallium through
contaminated homegrown foods (Dolgner et al., 1983; Brockhaus et al., 1981). Limitations in
these epidemiology studies included the lack of objective tests for toxicity, reliance on the
incidence of symptoms obtained from questionnaires, and characterization of chronic thallium
exposure by measuring the levels in urine and hair at a single point in time. Three studies of
occupationally exposed populations (Ludolph et al., 1986; Marcus, 1985; Schaller et al., 1980)
did not conclusively establish an association between thallium exposure and impaired health
status; however, all three studies were limited in terms of size of the study population and study
design.
Symptoms of thallium toxicity are diverse in both humans and animals. The triad of
gastroenteritis, polyneuropathy, and alopecia has been regarded as the classic syndrome of
thallium poisoning (IPCS, 1996), although not all three of these effects are observed in all
poisoning cases, and other symptoms develop in varying sequence depending on the magnitude
and duration of thallium exposure.
The nervous system as a target organ of thallium is supported by observations from
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human case reports and animal studies. Relatively high doses of thallium cause neurological
symptoms in humans (e.g., paresthesia of the hands and feet, weakness, tremors, coma, and
convulsions). Some of these neurological symptoms (e.g., paresthesia and weakness) were
reversible, although recovery was slow. Other effects, including mental and/or psychological
problems, were more persistent. Neurological symptoms have also been associated with chronic
exposure to thallium in humans. These symptoms include sleep disorders, tiredness, weakness,
nervousness, headache, other psychic alterations, and neurological and muscular problems. In
experimental animal studies, thallium exposure has been associated with biochemical changes,
lipid peroxidation, and histopathological changes in the brain and functional and
histopathological changes in peripheral nerves. The areas affected in the brain differ with the
age of the treated animal; nevertheless, all measured endpoints (symptoms, biochemical
measurements, and histopathology) indicate that high doses (close to lethal doses) of thallium
induce significant degradation of the nervous system. Results from in vitro studies further
confirm these observations.
Although paresthesia of the hands and feet are trademark symptoms of thallium toxicity,
it is generally alopecia that leads to a diagnosis of thallium poisoning in humans. Alopecia
occurs about 2 weeks after exposure and is reversible after exposure to thallium is discontinued.
Alopecia has also been repeatedly observed in experimental animals exposed to thallium
compounds.
Thallium exposure in humans has been associated with respiratory effects and
gastrointestinal effects, including diarrhea and vomiting. Other toxic effects associated with oral
thallium exposure in humans and animals are changes in blood pressure (high, low, and
fluctuating values have all been noted) and liver and kidney damage (kidney damage is age
dependent and occurs only in mature kidneys), all of which appear to be reversible with the
removal of thallium exposure. Doses that do not affect survival have been shown to affect
clinical chemistry parameters such as ALT, AST, BUN, blood glucose, and blood sodium levels,
indicating liver and kidney damage with subchronic exposures (Leung and Ooi, 2000; Fleck and
Appenroth, 1996; Appenroth et al, 1996, 1995; El-Garawany et al, 1990; Mourelle et al, 1988).
Thallium salts have been shown to affect reproductive function. A dose as low as 0.7 mg
Tl/kg-day (10 ppm of thallium (I) sulfate) resulted in testicular damage and reduced sperm
motility in male Wistar rats within 60 days (Formigli et al., 1986). Wei (1987) reported that
doses as low as 0.001 mg/L in the drinking water for 6 months in Kunming mice reduced sperm
motility (rapid speed only), and 0.01 mg/L reduced overall sperm motility and sperm counts and
caused a reduction of live offspring while also increasing the number of dead offspring.
Confidence in this study is low, however, due to the non-reporting of water consumption and
body weights within dose groups.
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Limited data in humans and experimental animals suggest that thallium may produce
developmental toxicity. A review of case studies of women exposed orally to high levels
(approximately 120 to 1100 mg) of thallium during pregnancy suggested a trend toward
premature and low-birth-weight infants, especially if exposure took place in the last trimester; no
other developmental abnormalities were identified (Hoffman, 2000). Dolgner et al. (1983)
examined birth defects in a German population living near a cement plant emitting thallium dusts
during the mid-1970s and found a higher incidence of congenital malformations than the
incidence documented in the government birth records from the area. The association between
the number of birth defects and thallium exposure was weak, however, because two of the
malformations were considered hereditary and the incidence for birth defects, although greater
than that determined from civil records, was consistent with that reported in the literature.
Confidence in this study was limited by lack of exposure data during pregnancy and possible
underreporting in controls. In vivo data in rats support an association between intraperitoneal
thallium exposure and low birth weight, although such an association has not been reported with
orally administered thallium. In vitro data demonstrated an increase in bone malformations in
both rat and chick embryos.
4.6.2. Inhalation
There are currently no studies that examine the effects of inhaled thallium. A few case
reports (Hirata et al., 1998; Ludolph et al., 1986) suggest an association between occupational
exposure and toxicity (including alopecia, gastrointestinal symptoms, and neuropathy), but the
route or routes of exposure in these workplace setting could not be established. A study of a
population living near a cement factory emitting thallium (Dolgner et al., 1983) determined that
thallium exposure occurred via consumption of plants grown in thallium-contaminated soil to a
greater extent than via inhalation.
4.6.3. Mode of Action Information
The precise mechanism of thallium toxicity is unknown. Both potassium and thallium
are monovalent cations with similar atomic radii (Tl+: 1.50 A, and K+: 1.38 A) (Ibrahim et al.,
2006). Thallium has been shown to replace potassium in the reaction of Na+/K+-ATPase (Barrera
and Gomez-Puyou, 1975; Britten and Blank, 1968) and to mimic the biological actions of
potassium. Monovalent thallium has been shown to have a 10-fold higher affinity than
potassium for Na+/K+-ATPase and thus replaces potassium as a substrate for this enzyme
(Barrera and Gomez-Puyou, 1975; Britten and Blank, 1968). In other studies it caused a
decrease in Na+/K+-ATPase activity in the liver and kidney (Yoshida et al., 1997; Mourelle et al.,
1988). After a single oral or intraperitoneal dose of thallium (10 mg/kg orally or 25 mg/kg i.p.),
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the disruption of Na+/K+-ATPase activity was found to be reversible.
Thallium's activity as a Lewis acid with an affinity for organosulfur compounds (Lewis
bases) may account for its adverse effect on hair production. Keratin is the primary protein
found in hair. It is rich in the amino acid cysteine and its low solubility is, in large part, the
product of the formation of inter-polypeptide cysteine-cysteine crosslinks during post-
translational modification of the nascent polypeptides. Thallium prevents keratinization of hair
proteins by binding with cysteine and preventing the formation of the crosslinking bonds
(Mulkey and Oehme, 1993), a property that may be related to the alopecia observed in humans
and animals following thallium exposure. Binding to cysteine may also account for inhibition of
enzymes with active site cysteine residues and increases oxidative stress as a result of GSH
modification (Mulkey and Oehme, 1993).
4.7. EVALUATION OF CARCINOGENICITY
Under EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), there is
"inadequate information to assess the carcinogenic potential" for thallium and thallium
compounds. There are presently no studies that evaluate the carcinogenic potential of thallium in
animals and no adequate studies of humans chronically exposed to thallium.
Two studies of chronic health effects in workers exposed to thallium are available
(Marcus, 1985; Schaller et al., 1980), but these studies are inadequate for the assessment of
carcinogenicity. The study by Marcus (1985) is limited by the examination of medical records
only, lack of exposure quantitation, small cohort size, and the unknown length of observation.
Schaller et al. (1980) identified health effects in a worker population at a single time point
through medical histories and physical examinations for unspecified symptoms. Worker
exposures to thallium were limited to a single measure of urinary thallium, which would not
provide an adequate measure of past exposure. This health evaluation was not adequate to detect
any carcinogenic response.
Relatively few studies have examined the genotoxicity of thallium compounds; these
studies provide inconsistent evidence for genotoxicity. Positive results were obtained at 0.001M
for thallium (I) nitrate in the Rec assay using B. subtilis strains HI7 and M45 (Kanematsu et al.,
1980). However, negative results were obtained in reverse mutation assays using several S.
typhimurium and E. coll strains and mitogenic gene conversion and reverse mutation tests in
yeast. Cytotoxic levels (1000 jig/mL) of thallium (I) acetate caused depressed DNA synthesis in
CHO cells (Garrett and Lewtas, 1983). Single-strand DNA breaks occurred in C57B1/6 mouse
and rat embryo fibroblasts exposed to thallium carbonate but not in similarly exposed CBA
mouse fibroblasts (Zasukhina et al., 1983). A dose of 200 mg thallium sulfate caused a slight
increase in SCEs in peripheral blood lymphocytes taken from a 48-year-old man on day 1 and
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day 15 postexposure and caused a 3.5-fold increase in binucleated cells with micronuclei
(Hantson et al, 1997).
4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES
There are little or no data available to establish a particular subpopulation as being
particularly susceptible to the toxic effects of thallium salts.
4.8.1. Possible Childhood Susceptibility
Exposures in human case reports generally are poorly characterized. Therefore, no
comparison can be made between children and adults with regard to susceptibility. In rats, doses
of thallium that caused maternal toxicity have been demonstrated to affect the developing fetus
(Gibson and Becker, 1970). The only studies that examined the toxic effects of thallium at
different ages were those of Appenroth et al. (1996) and Fleck and Appenroth (1996), which
focused on the age-related effects on nephrotoxicity. In these studies, mature rats were
determined to be more susceptible to kidney damage than young (10 or 20 days old) rats, as
mature kidney function appeared necessary for thallium to adversely affect the kidney.
4.8.2. Possible Gender Differences
Leloux et al. (1987), MRI (1988), and Downs et al. (1960) are the only available toxicity
studies of thallium compounds using both male and female rats. LeLoux et al. (1987)
administered only a single lethal dose of thallium (I) nitrate to rats and thus did not provide
findings useful for discerning possible gender differences. Downs et al. (1960) reported slight
differences in thallium (III) oxide toxicity between the sexes, with males dying earlier, exhibiting
greater and more severe alopecia, and having more profound decreases in body weight than
females. No sex-related differences in response were noted in rats treated with thallium (I)
acetate (Downs et al., 19960). No marked differences in response were noted in male and female
rats after exposure to thallium (I) sulfate (MRI, 1988); however high-dose female rats exhibited a
higher incidence of alopecia than males, and hair follicle atrophy was observed in females only.
Overall, the limited data do not identify any consistent pattern of gender-related differences in
response to thallium exposure.
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5. DOSE-RESPONSE ASSESSMENTS
5.1. ORAL REFERENCE DOSE (RfD)
5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification
As discussed in Section 4.6.1., most information on thallium toxicity in humans comes
from poisonings, suicide attempts, or accidental exposures, and epidemiological studies of the
general population or occupationally-exposed populations are limited in terms of study design
and insufficient exposure characterization. Thus, available human study findings do not provide
data useful for dose-response analysis.
There are only three repeat-dose oral studies of thallium compound toxicity that used
more than one dose level: Downs et al. (1960), Wei (1987), and MRI (1988). Other repeat-dose
studies of thallium oral toxicity used study designs not appropriate for dose-response analysis,
including single-dose only studies (El-Garawany et al., 1990; Rossi et al., 1988; Formigli et al.,
1986; Gregotti et al., 1985; Manzo et al., 1983) or studies that suffered from critical reporting
deficiencies (Zasukhina et al., 1983; see Section 4.3). In the Downs et al. (1960) study of
thallium (I) acetate, mortality in two control groups was 30-40%, complicating interpretation of
the findings in treated rats (mortality and alopecia). A study of thallium (III) oxide by the same
investigators (Downs et al., 1960) failed to identify a NOAEL. Further, death in 2 of 5 female
rats at the lowest dose tested in this study was observed and may have been treatment related.
Wei (1987) reported effects on sperm count, motility, and viability in Kunming mice exposed to
relatively low concentrations of thallium (I) carbonate in drinking water; however, the
reproductive index and number of implantations in the dosed mice were not affected by
treatment. Doses associated with drinking water levels were not reported by the study authors,
and water consumption and terminal body weight data for the mice from which dose estimates
could be derived were not provided by the study authors. Further, the mouse strain used in this
study was a nonstandard strain. For these reasons, the study data in Wei (1987) were considered
to be of low confidence and not appropriate for dose-response analysis. The subchronic (90-day)
toxicity study of thallium (I) sulfate in Sprague-Dawley rats (MRI, 1988) is the most
comprehensive study of thallium toxicity and was conducted according to EPA GLPs. This
study examined sensitive measures of thallium toxicity and identified the lowest NOAEL among
subchronic toxicity studies. Accordingly, this study was selected as the principal study for
derivation of the RfD.
In the MRI (1988) study, rats (20/sex/group) were treated by gavage daily for 90
consecutive days with 0, 0.01, 0.05, or 0.25 mg/kg-day of an aqueous solution of thallium (I)
sulfate (approximately 0, 0.008, 0.04, or 0.20 mg Tl/kg-day). There were no differences
observed among control groups and groups receiving thallium sulfate for body weight, body
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weight gains, food consumption, or absolute and relative organ weights. In male rats, the
incidence of alopecia was increased over the controls, although the increase was not dose related
(i.e., 10, 5, 20, 45, and 20% for the untreated control, vehicle control, 0.008, 0.04, and 0.2 mg
Tl/kg-day, respectively). In females, a dose-related increase in the incidence of alopecia was
observed (i.e., 20, 5, 20, 45, and 60% for the untreated control, vehicle control, 0.008, 0.04, and
0.2 mg Tl/kg-day, respectively). The study authors related the occurrence of alopecia to cyclic
patterns of hair growth and concluded that the results were not biologically significant. The
study authors also characterized some of the cases of alopecia as "not totally attributed to
barbering behavior." The incidence of cases of alopecia in females not totally attributed to
barbering behavior showed a dose-related increase (0, 0, 5, 15, 25% for the untreated control,
vehicle control, 0.008, 0.04, and 0.2 mg Tl/kg-day, respectively). The study authors identified
the highest dose (0.20 mg Tl/kg-day) as a NOAEL based upon a lack of biological significance
for the observed effects (alopecia in females).
At the high dose, however, histologic examination of skin samples from two high-dose
females showed atrophy of hair follicles. These two animals also exhibited alopecia. Hair loss
(alopecia) is characteristic of thallium poisoning in humans and experimental animals (Ibrahim et
al, 2006; Galvan-Arzate and Santamaria, 1998), and typically occurs in humans within two
weeks of exposure. It is hypothesized that thallium's affinity for sulfhydryl groups may be
responsible for alopecia; thallium prevents keratinization of hair proteins by binding with
cysteine. Skin biopsies have been taken from a limited number of patients with alopecia and
other symptoms of thallium poisoning; these biopsies have revealed atrophic and necrotic
changes of the skin (Lu et al., 2007; Heyl and Barlow, 1989; Saddique and Peterson, 1983). For
example, skin biopsy findings from two patients who ingested water that contained thallium
included parakeratosis, dilated hair follicles filled with keratin and necrotic sebaceous materials,
mild epidermal atrophy, and vacuolar degeneration of the basal layer (Lu et al., 2007).
In summary, female rats exhibited a dose-related increase in alopecia, an effect
characteristic of thallium toxicity. Although alopecia was observed in controls as well as
thallium-exposed rats, females exhibited a dose-related increase in alopecia that was statistically
significantly elevated over controls at the mid- and high-doses, and also exhibited a dose-related
increase in the incidence of alopecia that could not be totally attributed to barbering behavior
(see Table 4). The finding of two cases of atrophy of the hair follicles in high-dose female rats
with alopecia is consistent with the atrophic changes observed in cases of human thallium
poisoning, and provides additional support that alopecia at the high-dose (0.2 mg Tl/kg-day) is
likely related to thallium exposure. Whether alopecia is itself an adverse effect merits
consideration. In humans, alopecia is generally reversible upon cessation of thallium exposure.
Alopecia, however, appears to be a part of a continuum of dermal changes observed following
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thallium exposure, as well as one of a spectrum of effects on target organs that include the
nervous and gastrointestinal systems. For these reasons, alopecia supported by two cases of hair
follicle atrophy is considered adverse. Accordingly, the high dose, 0.25 mg/kg-day thallium (I)
sulfate, is considered to be the LOAEL, and the mid dose, 0.05 mg/kg-day thallium (I) sulfate,
the NOAEL. The equivalent NOAEL and LOAEL for thallium only are 0.04 and 0.2 mg Tl/kg-
day, respectively.
Review of the LOAELs from studies of subchronic exposure duration (see Table 5)
shows the LOAEL of 0.2 mg Tl/kg-day from MRI (1988) to be generally consistent with the
LOAELs from other experimental animal studies (0.7 to 1.8 mg Tl/kg-day). A comparison of
LOAELs across subchronic studies suggests that the nature of response to thallium (I) salts may
sharply increase in severity with increasing dose. For example, treatment-related mortality (15-
21%), as well as alopecia and nerve histopathology, were observed following a 36-week
exposure to 1.4 mg Tl/kg-day (Manzo et al, 1983), a dose only sevenfold higher than the
LOAEL of 0.2 mg Tl/kg-day for alopecia alone from MRI (1988). By way of comparison, the
lowest exposure associated with acute thallium-related toxicity in humans is approximately
4 mg/kg (Cavanagh et al., 1974)2 - a dose 20-fold higher than the repeat-dose LOAEL from MRI
(1988), and exposures reported to be lethal to humans are as low as 6 mg/kg (IPCS, 1996) - a
dose 30-fold higher than the LOAEL from MRI (1988).
5.1.2. Methods of Analysis
The NOAEL-LOAEL approach was used to derive an RfD for thallium salts. A
benchmark dose (BMD) analysis was not conducted because the incidence of
histopathologically-determined hair follicle atrophy was not considered amenable to BMD
methods. There were only two groups to consider, with histopathological examination of the
skin performed for high-dose and vehicle control groups only. Two of 20 female rats in the
high-dose group (10%) had hair follicle atrophy and alopecia that was consistent with thallium
toxicity in both animals and humans and was thus characterized as treatment-related. The
majority of cases of alopecia in the control and dosed groups was attributed to barbering
behavior or normal cyclic hair growth patterns. Given the background occurrence of alopecia in
study animals and the potential for misclassification, there is some uncertainty about the
incidence of possibly treatment-related alopecia in treated animals.
Thus, the NOAEL of 0.04 mg Tl/kg-day from MRI (1988) was used as the point of
departure for developing the RfD.
2 Based on a toxic dose of 0.31 g/person and assuming a body weight of 70kg.
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5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs)
Soluble Thallium Salts: Acetate, Carbonate, Chloride, Nitrate, andSulfate
The principal study used to derive the RfD (MRI, 1988) involved administration of
thallium (I) sulfate. There are no studies of thallium (I) acetate, thallium (I) carbonate, thallium
(I) chloride, or thallium (I) nitrate that are appropriate as the basis for an RfD. For the following
reasons, it was considered appropriate to treat these monovalent thallium salts as toxicologically
equivalent to thallium (I) sulfate when expressed in terms of thallium. It is likely that the
mechanism of toxicity is the same for these salts due to the fact that they all contain monovalent
thallium ions and are water soluble. There are only small differences in the toxicity of various
water-soluble thallium (I) salts in mice, rats, rabbits, and dogs. In general, for most laboratory
species at an observation period of approximately 1-2 weeks, the LDso or minimum effective
dose (MED) values range between 10 and 30 mg/kg body weight for thallium (I) salts,
independent of the exposure route (IPCS, 1996). Therefore the use of thallium (I) sulfate as a
surrogate for the other thallium salts is appropriate.
The RfD for thallium is derived using the NOAEL of 0.04 mg Tl/kg-day and applying a
total uncertainty factor of 3000 (10 for interspecies extrapolation, 10 for intraspecies
extrapolation, 3 for extrapolation from a subchronic to chronic study, and 10 for database
deficiencies).
• A default interspecies uncertainty factor of 10 was applied for extrapolation from
laboratory animals to humans. No information was available to characterize the
toxicokinetic or toxicodynamic differences between experimental animals and
humans.
• A default intraspecies uncertainty factor of 10 was applied to account for variation in
human susceptibility in the absence of information on the variability of response to
thallium in the human population.
• Because no chronic toxicity studies for thallium are available, an uncertainty factor of
3 was applied to account for extrapolation from subchronic to chronic exposure
duration. Oral toxicity data for thallium suggests that a full default uncertainty factor
of 10 would overestimate the difference in response following subchronic and chronic
oral exposures. Alopecia, the critical effect used to derive the RfD, occurs within
weeks of exposure to thallium (i.e., this sensitive effect does not require chronic
exposure in order to manifest), and once hair loss has occurred, the effect cannot
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change in nature or severity. Thus, for this particular endpoint, the uncertainty
associated with use of a subchronic study can reasonably be characterized as smaller
than the default factor of 10.
• An uncertainty factor for LOAEL to NOAEL extrapolation was not needed because
the principal study identified a NOAEL.
• The thallium database includes several subchronic oral toxicity studies in rats.
Studies of reproductive and developmental toxicity of thallium compounds in rats and
mice are available; however, these studies used nontraditional study designs that did
not provide adequate testing of reproductive or developmental endpoints. In
reproductive toxicity studies by Gregotti et al. (1985) and Formigli et al. (1986), male
rats only were exposed for periods up to 60 days and evaluation of reproductive
toxicity was limited to examination of male reproductive organs. In two other
reproductive toxicity studies, male rats (Zasukhina et al., 1983) or mice (Wei, 1987)
only were exposed to thallium compounds for 6 to 8 months and mated with untreated
females. Confidence in these latter two studies was low (see Section 4.3). No studies
of reproductive toxicity in exposed females and no multigeneration reproductive
toxicity study were identified. Developmental toxicity by the oral route was limited
to Rossi et al. (1988) in which rats were exposed to thallium sulfate from gestation
day 1 through 60 days of age or from birth through 60 days of age. No investigation
of developmental endpoints at the end of the gestation period was performed. Despite
the limitations in the available reproductive and developmental toxicity studies, the
available studies provide suggestive evidence that thallium compounds can adversely
affect male reproductive organs and the developing fetus and highlight the
deficiencies in the current thallium database. Limited neuropathological
examinations were included in the subchronic toxicity studies by MRI (1988) and
Manzo et al. (1993), but no neurobehavioral studies were identified. Because the
nervous system is a sensitive target of thallium toxicity, the limited investigation of
thallium neurotoxicity represents a data deficiency. Thus, a database uncertainty
factor of 10 was applied to account for a lack of adequate developmental toxicity
studies and a two-generation reproductive toxicity study, and additional uncertainty
associated with the limited data available on neurotoxicity in light of the potential for
neurotoxicity to represent a sensitive endpoint for thallium exposure.
Thus, the RfD for thallium (I) is calculated as:
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-5
0.04 mg Tl/kg-day •*• 3000 = 1 x 10s mg Tl/kg-day
RfD values for individual soluble thallium salts can be derived using the formula weight
ratio of the thallium salt to the thallium in the salt (molecular weight = 204) as follows:
• 0.04 mg Tl/kg-day x (molecular weight of the soluble salt divided by molecular
weight of thallium in the salt) = converted NOAEL for the specific thallium salt
• For example, the NOAEL for thallium (I) acetate (molecular weight = 263) is
estimated as 0.04 mg Tl/kg-day x 263/204 = 0.05 mg/kg-day
RfDs for soluble thallium salts based on the NOAEL for a given thallium salt and a total
uncertainty factor of 3000 are listed in Table 7.
Table 7. Reference doses for soluble thallium salts
Soluble thallium salt
Thallium (I) acetate
T1C2H302
Thallium (I) carbonate
T12C03
Thallium (I) chloride
T1C1
Thallium (I) nitrate
T1N03
Thallium (I) sulfate
T12S04
Molecular weight
263
469
240
266
505
Converted NOAEL
0.05 mg/kg-day
0.05 mg/kg-day
0.05 mg/kg-day
0.05 mg/kg-day
0.05 mg/kg-day
RfD
2 x 10~5 mg/kg-day
2 x!0~5 mg/kg-day
2 xlO~5 mg/kg-day
2x 10~5 mg/kg-day
2x 10~5 mg/kg-day
Insoluble Thallium Salts: Thallium (III) Oxide
There are no oral studies of thallium (III) oxide that are adequate to support derivation of
an RfD. Downs et al. (1960) administered thallium (III) oxide to Wistar-derived albino rats via
the diet for 15 weeks at exposure concentrations of 0, 20, 35, 50, 100, and 500 ppm. The study
reported only body weights, mortality, kidney weights, and limited histopathology. Because all
relevant endpoints were not evaluated, treatment group sizes were small (five per group per sex),
and few animals survived to termination, this study could not be used to derive an RfD.
Because of differences in the physical-chemical properties of thallium (I) sulfate and
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thallium (III) oxide, thallium (I) sulfate is not considered to be an appropriate surrogate. Unlike
thallium (I) sulfate, thallium (III) oxide is insoluble in water. Thallium (I) sulfate contains
monovalent thallium (Tl+1), while thallium (III) oxide contains trivalent thallium (Tl+3).
Although the gastric environment may increase the solubility of thallium (III) oxide, no studies
are available that examine the effects of the gastric pH and gastric environment on the valence
state of thallium (III) oxide.
Limited evidence from the toxicology literature suggests that distribution of thallium (I)
and thallium (III) compounds and lethality of these two compounds may be comparable.
Sabbioni et al. (1980a) determined that, following oral administration of either inorganic
monovalent thallium (Tl+1) as thallium (I) sulfate or trivalent thallium (Tl+3) as thallium (III)
chloride, there was a similar distribution of thallium in the tissues (valence state could not be
determined) at 16 hours and 8 days after administration, indicating that the valence state of
thallium did not affect tissue distribution (and presumably uptake). Downs et al. (1960)
demonstrated similar oral 7-day LDso values for thallium (I) acetate (32 mg Tl/kg) and thallium
(III) oxide (39 mg Tl/kg) in female rats, indicating that lethality may be independent of valence
state. However, other endpoints could respond differently to different valence states of thallium.
Monovalent thallium compounds have been determined to behave similarly to potassium (K+),
thus disrupting Na+-K+-ATPase and the systems dependent on this transporter (e.g., liver and
kidney). Trivalent thallium has not been demonstrated to behave in the same manner. A single
in vitro study of mono- and trivalent thallium compounds (Diaz and Monreal, 1994) suggested
that biological responses to thallium in the (I) and (III) valence states may differ. Using an in
vitro system with liposomes prepared with lipid from brain myelin, these investigators reported
that trivalent thallium, but not monovalent thallium, mediated a rapid chloride/hydroxyl ion
exchange through the lipid bilayers.
Given the lack of conclusive evidence that the valence state of thallium changes
following uptake, toxicity attributable to monovalent thallium may not apply to trivalent
thallium.
Thallium (I) Selenite
No toxicity studies of thallium selenite are available. Thallium (I) selenite contains
monovalent thallium as does thallium (I) sulfate. There is no information in the literature,
however, on the water solubility of thallium selenite. In the absence of solubility information, it
cannot be determined if thallium sulfate is an appropriate surrogate for thallium selenite.
Accordingly, the available data do not support derivation of an RfD for thallium selenite.
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5.1.4. Previous RfD Assessment
The previous IRIS RfD values for thallium (I) acetate, thallium (I) carbonate, thallium (I)
chloride, thallium (I) nitrate, and thallium (I) sulfate were posted to the IRIS database in
September 1988. These assessments were based on the same principal study by Midwest
Research Institute (MRI) as the current assessment. [The principal study was previously cited as
U.S. EPA (1986c). MRI subsequently issued a revised final report in 1988, which is the basis for
the current RfD. There are no substantive differences in the findings and conclusions between
the 1986 and 1988 versions of MRI report.] Previous RfD values (adjusted for differences in
molecular weight) ranged from 8 x 10"5 to 9 x 10"5 mg/kg-day. These RfD values were based on
a NOAEL of 0.25 mg/kg-day thallium sulfate, the highest dose tested by MRI (1988), and
application of a composite uncertainty factor of 3000 (10 to extrapolate from subchronic to
chronic data, 10 for intraspecies extrapolation, 10 to account for interspecies variability, and 3 to
account for lack of reproductive and chronic toxicity data). Although the same principal study is
used (MRI, 1988), the current oral RfD value for soluble thallium salts (acetate, carbonate,
chloride, nitrate, and sulfide) is based on a NOAEL of 0.05 mg/kg-day thallium sulfate. The
difference in the NOAEL between the 1988 and current assessment reflects an alternative
interpretation of the MRI (1988) findings (i.e., that the finding of two cases of alopecia in high-
dose [0.05 mg/kg-day thallium sulfate] female rats with atrophy of the hair follicles is an adverse
health effect and results in an RfD 4 to 4.5-fold lower than the RfDs posted to IRIS in 1988. The
total UF applied in the 1988 and current assessment is the same (i.e., 3000), although the
component UFs are different. The current assessment includes a UF for subchronic to chronic
extrapolation of 3 and a UF for incomplete database of 10, whereas the 1988 assessment applied
a UF of 10 for subchronic to chronic extrapolation and 3 for incomplete database. A reduction of
the subchronic to chronic UF from 10 to 3 reflects the revised interpretation of the alopecia
findings and the conclusion that application of a full default uncertainty factor of 10 would
overestimate the difference in response following subchronic and chronic oral exposures.
Alopecia is an effect that occurs within weeks of exposure to thallium (i.e., does not require
chronic exposure in order to manifest), and once manifested, does not change in nature or
severity. An increase in the database UF from 3 to 10 reflects a reconsideration of the
uncertainties associated with the current database (i.e., a lack of adequate developmental toxicity
studies and a two-generation reproductive toxicity study, and additional uncertainty associated
with the limited data available on neurotoxicity in light of the potential for neurotoxicity to
represent a sensitive endpoint for thallium exposure). See Section 5.1.3 for additional
justifications for the UFs used in the current assessment.
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The RfD values for thallium (I) selenite and thallium (III) oxide were withdrawn in 1993
and 1989, respectively. The absence of an RfD for these two thallium compounds in the current
assessment is in agreement with the previous IRIS file.
5.1.5. Uncertainties in the Oral Reference Dose (RfD)
Risk assessments need to describe associated uncertainty. The following discussion
identifies uncertainties associated with the RfD for thallium and compounds. As presented
earlier in this section (5.1.2 and 5.1.3), the uncertainty factor approach (U.S. EPA, 2002, 1994b,
1993) was used to derive the RfD for thallium. Using this approach, the point of departure
(POD) was divided by a set of factors to account for uncertainties in the RfD related to the
extrapolation from responses observed in animal bioassays to humans and from data from
subchronic exposure to chronic exposure, a diverse human population of varying susceptibilities,
and database deficiencies. Because of the limited chemical-specific information for thallium to
inform the various assumptions and extrapolations, default uncertainty factors were applied.
The available animal and human toxicity literature demonstrates that thallium adversely
affects a broad range of target organs (see Section 4), including the nervous, respiratory,
gastrointestinal, and reproductive systems, skin, liver, kidney, and possibly the developing
organism. Nevertheless, critical deficiencies in the thallium database have been identified;
uncertainties associated with these data deficiencies are discussed more fully below.
Selection of the critical effect for reference value determination. Alopecia (hair loss) in
rats (as identified in the 90-day MRI [1988] study) was identified as the critical effect for RfD
derivation. Numerous studies conducted in animals have documented alopecia as a sensitive
outcome of thallium exposure. Alopecia is also the best-known effect of thallium poisoning in
humans (Ibrahim et al., 2006; Galvan-Arzate and Santamaria, 1998). Hair loss usually occurs
within two weeks of exposure and is reversible after exposure to thallium is discontinued.
Population surveys and occupational epidemiological investigations do not provide similar
evidence for alopecia in thallium-exposed populations; however, it is not clear that any study
other than Brockhaus et al. (1981) specifically looked for hair loss in the study population. In a
survey of a population living near a cement plant in Lengerich, Germany, Brockhaus et al.
(1981) reported a negative correlation between thallium exposure (measured in urine or hair) and
hair loss, a finding inconsistent with the observation of alopecia consistently seen in reports of
poisonings.
Overall, the many observations of alopecia in animal studies and reports of human
poisonings lead to a relatively high degree of certainty that the selected critical effect is relevant
to human health assessment, although it is noted that alopecia has not been documented in
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population surveys or occupational epidemiological investigations at lower exposures.
Dose-response modeling. The RfD was derived using a NOAEL for the POD. A POD
based on a NOAEL or LOAEL is, in part, a reflection of the particular doses (and dose spacing)
selected in the principal study. The NOAEL or LOAEL lacks characterization of the dose-
response curve and for this reason is less informative than a POD obtained from benchmark dose
modeling.
Uncertainty is associated with the identification of the NOAEL from the MRI (1988)
study. The study investigators identified the highest dose (0.20 mg Tl/kg-day) as a NOAEL
based upon their interpretation of the observed effects (alopecia in females) as not biologically
significant. The U.S. EPA, however, interpreted the increasing trend of alopecia and the finding
of two cases of atrophy of the hair follicles in female rats to be consistent with evidence of
thallium-related toxicity (see Section 5.1.1). Accordingly, the U.S. EPA considered the high
dose (0.20 mg Tl/kg-day) to be the LOAEL, and the middle dose (0.04 mg Tl/kg-day) to be the
NOAEL. The difference in interpretation of the toxicological significance of alopecia in female
rats introduces uncertainty in the selection of the POD. The fact that male rats did not exhibit a
similar dose-related increase in alopecia introduces additional uncertainty. U.S. EPA's
interpretation of the study findings results in a POD fivefold lower than that of the study
investigators.
Animal to human extrapolation. Extrapolating dose-response data from animals to
humans is another source of uncertainty. The effect and the magnitude of the effect at the POD
in rodents is extrapolated to human response. Uncertainty in interspecies extrapolation can be
separated into two general areas—toxicokinetic and toxicodynamic. In the absence of
information to quantitatively assess either toxicokinetic or toxicodynamic differences between
animals and humans, a 10-fold UF was used to account for uncertainty in extrapolating from
laboratory animals to humans in the derivation of the RfD. Thallium-specific data to examine
the potential magnitude of over- or under-estimation of this UF is unavailable.
A PBPK model, which could reduce uncertainty in the pharmacokinetic portion of
interspecies extrapolation, is not available for thallium.
Intrahuman variability. Heterogeneity among humans is another source of uncertainty.
In the absence of thallium-specific data on human variation in response to thallium toxicity, a
default uncertainty factor of 10 was used to account for this area of uncertainty in the derivation
of the RfD. Human variation may be larger or smaller; however, thallium-specific data to
examine the potential magnitude of over- or under-estimation is unavailable.
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Subchronic to chronic exposure extrapolation. Because no chronic toxicity studies for
thallium are available, a UF of 3 was applied to extrapolate those data obtained from a study of
subchronic exposure to chronic exposure. Oral toxicity data for thallium suggests that a full
default uncertainty factor of 10 would overestimate the difference in response following
subchronic and chronic oral exposures. Alopecia occurs within weeks of exposure to thallium
(i.e., this sensitive effect does not require chronic exposure in order to manifest), and once hair
loss has occurred, the effect cannot change in nature or severity. Thus, for this particular
endpoint, the uncertainty associated with use of a subchronic study can reasonably be
characterized as smaller than the default factor of 10.
Data gaps. To the extent that the database for thallium is incomplete, it is possible that
certain endpoints of toxicity or certain sensitive lifestages have not been evaluated that could
result in PODs lower than those for which study data are available. The thallium database lacks
a chronic toxicity study and two-generation reproduction study. Several studies of reproductive
and developmental toxicity of thallium compounds in rats and mice are available; however, these
studies used nontraditional study designs that provided an incomplete evaluation of reproductive
and developmental toxicity endpoints, and in the case of two reproductive toxicity studies, low
confidence was assigned to the study findings. Of the available subchronic toxicity studies, only
the 90-day MRI (1988) study provided data adequate for dose-response analysis. Deficiencies in
the database related to neurotoxicity were also identified. A default uncertainty factor of 10 was
used to account for uncertainty associated with deficiencies in the thallium database. Thallium-
specific data to examine the potential magnitude of over- or under-estimation is unavailable.
5.2. INHALATION REFERENCE CONCENTRATION (RfC)
Information on the inhalation toxicity of thallium is insufficient to derive an inhalation
RfC. No studies of inhaled thallium in experimental animals were identified and occupational
epidemiology studies involving possible inhalation exposures to thallium were limited and
inconclusive.
5.3. CANCER ASSESSMENT
There are no human or animal studies available that are adequate to assess the
carcinogenic potential of thallium salts.
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6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF
HAZARD AND DOSE RESPONSE
6.1. HUMAN HAZARD POTENTIAL
Thallium is well absorbed from the gastrointestinal tract, skin, and respiratory tract and is
distributed throughout the body. Thallium, as an element, is not metabolized, but the extent to
which it may be converted from one valence state to another (i.e., Tl+1 and Tl+3) in the body is
not known. Excretion of thallium occurs mainly through the urine and feces, but the amounts are
species dependent. Humans mainly excrete thallium through the urine, but it also has been
detected in the hair, sweat, tears, and breast milk.
Thallium salts cause a wide spectrum of adverse effects in humans and animals.
Alopecia is an effect that is characteristic of thallium exposure. Alopecia generally occurs
within 2 weeks of exposure and is reversible when thallium exposure is removed. Only one
epidemiological study reported a negative correlation between thallium exposure and hair loss
(Brockhaus, 1981); however, this study lacked measures of chronic exposure to thallium and was
limited by reliance on questionnaires to determine symptomology in thallium-exposed
individuals.
Some study observations suggest that the nervous system may be the primary target
organ for thallium salt toxicity which has been observed after a single dose of 0.31 g thallium
acetate in an adult male or 1 mg/kg thallium (I) nitrate for 4 days in adult rats. A variety of
neurological effects have been reported in humans, including lethargy, back pain, paresthesia of
the hands and feet, weakness (including facial weakness), inability to walk, and prolonged
mental defects. Some of the effects are reversible depending on the severity, while others are
irreversible and may require long-term care. Animal studies support these findings in humans.
Kidney damage in humans has been noted by increases in BUN levels and serum
creatinine and is reversible with treatment and/or discontinued exposure to thallium. Data from
animal studies support those in humans with regard to kidney damage; thallium-related effects
include increased or decreased urine output (depending on dose), protein in the urine, and
changes in electrolyte balance. Histopathological examination of thallium-exposed animals
revealed changes in kidney morphology, including atrophied and vacuolated kidney tubules,
amorphous material in the lumen of the proximal tubules, disorganized brush borders, and
thickening ascending limb of the loop of Henle. Na+/K+-ATPase activity in the medulla also was
significantly reduced. None of these changes were dose related and were generally seen with
large doses of thallium. Animal studies also suggest that kidney toxicity requires mature kidney
function. The subchronic (90-day) toxicity study in rats used to derive the RfD showed moderate
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increases in AST and LDH, which are general indicators of tissue damage (MRI, 1988).
However, a specific relation to possible kidney damage was not indicated due to the lack of
changes in other clinical chemistry parameters (i.e., BUN and creatinine) and histopathological
changes in the kidney.
Cardiotoxicity findings in thallium-exposed humans are variable. Many case reports
indicate hypertension, while a few reported hypotension. Animal studies indicate that thallium
affects heart rate and causes a decrease in blood pressure, which also can be related to kidney
effects and is supported by in vitro results.
Many of the case reports in humans reported increased ALT and/or AST levels,
indicating liver toxicity. These effects returned to normal after patients received medical care for
thallium exposure. Various indicators of liver damage, including increases in ALT, AST, serum
bilirubin, lipid peroxidation, triglycerides, and serum alkaline phosphatase and decreases in
glycogen, glutathione, and liver Na+/K+-ATPase, have been reported in animal studies. In
addition, histopathology revealed swollen and vacuolated cells and swollen mitochondria. Many
of these effects were reversible in animals after a single dose of thallium. Statistically significant
increases in AST and LDH were observed in the MRI (1988) subchronic (90-day) toxicity study
in rats but were not associated with liver damage due to the lack of changes in other clinical
chemistry parameters (i.e., ALT) and histopathological changes in the liver.
Low birth weight is a likely adverse effect of thallium exposure in females (humans and
animals) exposed during pregnancy. Male mice exposed to thallium had low sperm counts, low
sperm motility, and increases in the number of deformed sperm. Testicular effects observed in
animals included disarrangement of the tubular epithelium, cytoplasmic vacuolation and
distention of smooth endoplasmic reticulum of the Sertoli cells, and reduced beta-glucuronidase
activities. Mating exposed male mice to unexposed female mice appeared to cause a decrease in
the number of live fetuses and an increase in the overall rate of dead fetuses; however, critical
information concerning the doses of thallium administered makes it difficult to assess these
results.
There are no human studies relating thallium exposure to developmental toxicity. A
literature review of pregnant women exposed to thallium during various stages of pregnancy
only related low birth weight with thallium exposure. A survey of children born near a cement
plant emitting thallium reported an increase in congenital malformations over those reported to
the government; however, the study authors did not consider these malformations to be
attributable to thallium exposure because two of the cases were considered hereditary and the
incidence was similar to that reported in the literature. Because of various study limitations, the
findings are considered inconclusive. In rats exposed transplacentally and/or via mother's milk,
then via the drinking water until 60 days of age, thallium (1 mg/dL in the drinking water of dams
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then offspring) affected bone development and vasomotor reactivity. Chick embryos exposed to
thallium developed achondroplasia; these data further support the potential role of thallium in the
disruption of bone development.
There are no studies available to determine the carcinogenic potential of thallium in
animals and no adequately conducted studies in humans. The limited number of studies of the
genotoxicity of thallium compounds provides inconsistent evidence of genotoxic potential.
Under EPA's guidelines for carcinogen risk assessment (U.S. EPA, 2005a), the Agency
concluded that there is "inadequate information to assess the carcinogenic potential."
6.2. DOSE RESPONSE
The 90-day gavage toxicity study of thallium (I) sulfate in Sprague-Dawley rats (MRI,
1988) was selected as the principal study. Alopecia was observed in all dose groups, including
the control, although the incidence increased in a dose-related pattern. Most, but not all, cases
were attributed to barbering behavior in the rats. Histopathological examination revealed
atrophy of the hair follicles in 2/20 high-dose female rats (0.25 mg/kg-day thallium sulfate or
0.20 mg Tl/kg-day) that also had alopecia. Because numerous animal studies and human case
studies have reported alopecia as an effect of thallium poisoning, the occurrence of alopecia with
hair follicle atrophy in high-dose females was considered to be lexicologically significant and
the high dose was identified as a LOAEL. The middle dose, 0.05 mg/kg-day thallium (I) sulfate
(0.04 mg Tl/kg-day), was considered a NOAEL. Other studies and endpoints were considered in
the selection of the critical effect. As shown in Table 5, alopecia was a particularly sensitive
endpoint of toxicity. Further, only three other datasets from subchronic studies of thallium
compounds included multiple doses that were amenable to dose-response analysis (Downs et al,
1960; Wei, 1987). In the Downs et al. (1960) study of thallium (I) acetate, mortality in two
control groups was 30-40%, complicating interpretation of the findings in treated rats (mortality
and alopecia). A study of thallium (III) oxide by the same investigators (Downs et al., 1960)
failed to identify a NOAEL. Wei (1987) reported effects on sperm count, motility, and viability
in mice exposed to relatively low concentrations of thallium (I) carbonate in drinking water;
however, study data were not amenable to dose-response quantification.
The NOAEL of 0.04 mg Tl/kg-day from MRI (1988) was used as the POD to derive the
RfD. A POD based on a NOAEL or LOAEL is, in part, a reflection of the particular doses (and
dose spacing) selected in the principal study. The NOAEL or LOAEL lacks characterization of
the dose-response curve and is thus less informative than a POD obtained from benchmark dose
modeling. A total uncertainty factor of 3000 (10 for interspecies extrapolation, 10 for
intraspecies extrapolation, 3 for extrapolation from a subchronic to chronic study, and 10 for
database deficiencies) was applied to the NOAEL to yield an RfD of 1 x 10"5 mg/kg-day for
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thallium sulfate. An RfD of 2 x 10"5 mg/kg-day for individual soluble thallium (I) salts
(specifically, the acetate, carbonate, chloride, nitrate, and sulfate), based on molar adjustment of
the NOAEL for thallium (I) sulfate to account for the different molecular weights of the different
thallium salts, was also presented. Information was unavailable to quantitatively assess
toxicokinetic or toxicodynamic differences between animals and humans and the potential
variability in human susceptibility to thallium toxicity; thus, default interspecies and intraspecies
UFs of 10 were applied. A UF of 3 was applied to address the uncertainty associated with
extrapolation of data obtained from a study of subchronic exposure to chronic exposure. A
default database UF of 10 was applied to account for deficiencies in the thallium toxicity
database, including lack of a two-generation reproductive toxicity study and studies of
cardiotoxicity, neurotoxicity, and immunotoxicity.
Confidence in the RfD for soluble thallium salts is low. Confidence in the principal
study, MRI (1988), is medium. This study was conducted in accordance with GLPs, and
included examination of sensitive measures of thallium toxicity, including dermal and neurologic
endpoints. Group sizes (20 animals/sex) were not particularly large and histopathological
examination of the skin was not conducted for all dose groups. Confidence in the identification
of the point of departure for the RfD based on MRI (1988) is low. A confidence ranking of low
for the point of departure reflects differences in the interpretation of the biological significance
of high-dose findings by EPA and the study investigators (and thus the designation of the
NOAEL and LOAEL from this study), the occurrence of hair follicle atrophy in female rats only,
and the background incidence of alopecia in control animals. Confidence in the database is low
to medium. The database includes numerous case reports of thallium poisonings, and several
limited studies of environmentally-exposed populations and worker populations. The reports of
human poisonings, in particular, provide considerable information on the target organs of
thallium in humans. Chronic studies of thallium toxicity in experimental animals have not been
performed, and of the thallium salts, only thallium (I) sulfate has been tested in an adequate
subchronic toxicity study. Developmental toxicity was investigated in two studies in rats, and
male reproductive toxicity in three studies, including a dominant lethal study. One of these
reproductive toxicity studies (Wei, 1987) provides evidence that male reproductive toxicity may
occur at relatively low drinking water concentrations; however, insufficient reporting precluded
dose-response analysis of the findings. Considering the confidence in the principal study, the
point of departure, and the database, the overall confidence in the RfD is low.
The available data are not adequate to derive an RfD for thallium (III) oxide or thallium
(I) selenite. Inhalation toxicity studies are not available to support derivation of RfCs for any
thallium compounds.
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.
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APPENDIX A
Summary of External Peer Review and Public Comments and Disposition
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