EPA/635/R-08/001F 

 www.epa.gov/iris 

TOXICOLOGICAL REVIEW 

 

OF

THALLIUM AND COMPOUNDS 

(CAS No. 7440-28-0)

 

In Support of Summary Information on the 

Integrated Risk Information System (IRIS)

September 2009

 

U.S. Environmental Protection Agency 

 Washington, DC

 
DISCLAIMER

 This document has been reviewed in accordance with U.S. Environmental Protection 

Agency policy and approved for publication. Mention of trade names or commercial products 

does not constitute endorsement or recommendation for use. 

ii 
CONTENTS—TOXICOLOGICAL REVIEW OF THALLIUM AND COMPOUNDS 

(CAS No. 7440-28-0)

LIST OF TABLES .......................................................................................................................... v 

LIST OF FIGURES ...................................................................................................................... vii 

LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... viii 

FOREWORD ................................................................................................................................. ix 

AUTHORS, CONTRIBUTORS, AND REVIEWERS .................................................................. x 

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 ...................................... 8 

4. HAZARD IDENTIFICATION .................................................................................................. 9 

4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL 

CONTROLS ...................................................................................................................... 9 

4.1.1. Incident/Case Reports ............................................................................................. 9 

4.1.2. Population Surveys ............................................................................................... 16 

4.1.3. Occupational Exposure ......................................................................................... 17 

4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER 

BIOASSAYS IN ANIMALS—ORAL AND INHALATION ........................................ 18 

4.2.1. Oral Exposure ....................................................................................................... 18 

4.2.2. Inhalation Exposure .............................................................................................. 26 

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES ..................................................... 26 

4.3.1. Reproductive Toxicity .......................................................................................... 26 

4.3.2. Developmental Toxicity ....................................................................................... 31 

4.4. OTHER ENDPOINT-SPECIFIC STUDIES ................................................................... 32 

4.4.1. Liver and Kidney Toxicity ................................................................................... 33 

4.4.2. Cardiotoxicity ....................................................................................................... 40 

4.4.3. Neurotoxicity ........................................................................................................ 40 

4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE 

MODE OF ACTION ....................................................................................................... 45 

4.5.1. Interference with Potassium Transport ................................................................. 45 

4.5.2. Disturbance of Mitochondrial Function and Energy Generation ......................... 46 

4.5.3. Induction of Oxidative Stress ............................................................................... 46 

4.5.4. Reaction with Thiol Groups ................................................................................. 47 

4.5.5. Other Endpoint-specific Mechanistic Data .......................................................... 47 

4.5.6. Genotoxicity ......................................................................................................... 50 

4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 51 

4.6.1. Oral ....................................................................................................................... 51 

4.6.2. Inhalation .............................................................................................................. 54 

4.6.3. Mode-of-Action Information ................................................................................ 54 

iii 
4.7. EVALUATION OF CARCINOGENICITY ................................................................... 55 

4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................ 56 

4.8.1. Possible Childhood Susceptibility ........................................................................ 56 

4.8.2. Possible Gender Differences ................................................................................ 56 

5. DOSE-RESPONSE ASSESSMENTS ..................................................................................... 57 

5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 57 

5.1.1. Choice of Principal Study and Critical Effect—with Rationale and 

Justification .......................................................................................................... 57 

5.1.2. Methods of Analysis ............................................................................................. 60 

5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs)............... 63 

5.1.4. Candidate RfD Comparison Information ............................................................. 67 

5.1.5. Previous RfD Assessment .................................................................................... 75 

5.2. INHALATION REFERENCE CONCENTRATION (RfC) ........................................... 75 

5.3. CANCER ASSESSMENT .............................................................................................. 75 

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE 

RESPONSE ............................................................................................................................. 76 

6.1. HUMAN HAZARD POTENTIAL ................................................................................. 76 

6.2. DOSE RESPONSE .......................................................................................................... 78 

7. REFERENCES ........................................................................................................................ 79

APPENDIX A. Summary of External Peer Review and Public Comments and Disposition ..... A-1

APPENDIX B. Documentation of Benchmark Dose Modeling ................................................. B-1

iv 
LIST OF TABLES 

Table 2-1. Chemical and physical properties of thallium and selected thallium 

compounds ................................................................................................................... 4

Table 3-1. Urine concentrations of thallium for the U.S. population from NHANES, 

1999–2002 ................................................................................................................... 7

Table 4-1. Thallium toxicity in humans following oral exposure ............................................... 10 

Table 4-2. Selected clinical observations in Sprague-Dawley rats treated with thallium 

sulfate for 90 days ...................................................................................................... 20 

Table 4-3. Incidence of alopecia in rats ....................................................................................... 21 

Table 4-4. Selected blood chemistry values ................................................................................ 22

Table 4-5. Thallium toxicity in animals following oral exposure ............................................... 29 

Table 4-6. Thallium toxicity in animals via injection ................................................................ 366 

Table 5-1. Incidence data and BMD modeling results for selected clinical observations in 

Sprague-Dawley rats treated with thallium sulfate for 90 days ................................. 61 

Table B-1. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

rough coat in male Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................... B-1 

Table B-2. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

piloerection in male Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................... B-3 

Table B-3. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

shedding in male Sprague-Dawley rats exposed to thallium sulfate via gavage 

for 90 days ............................................................................................................... B-5 

Table B-4. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

alopecia in male Sprague-Dawley rats exposed to thallium sulfate via gavage 

for 90 days ............................................................................................................... B-6 

Table B-5. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

lacrimation in male Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 day ..................................................................................................... B-6 

Table B-6. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

exophthalmos in male Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................... B-8 

v 
Table B-7. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

miosis in male Sprague-Dawley rats exposed to thallium sulfate via gavage 

for 90 days ............................................................................................................. B-10 

Table B-8. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

behavioral findings in male Sprague-Dawley rats exposed to thallium sulfate 

via gavage for 90 days ........................................................................................... B-12 

Table B-9. A summary of BMDS (version 1.4.1) modeling results based on incidence of 

rough coat in female Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................. B-13 

Table B-10. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of piloerection in female Sprague-Dawley rats exposed to thallium sulfate 

via gavage for 90 days .......................................................................................... B-17 

Table B-11. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of shedding in female Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................ B-22 

Table B-12. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of alopecia in female Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................ B-24 

Table B-13. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of lacrimation in female Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................ B-28 

Table B-14. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of exophthalmos in female Sprague-Dawley rats exposed to thallium sulfate 

via gavage for 90 days .......................................................................................... B-29 

Table B-15. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of miosis in female Sprague-Dawley rats exposed to thallium sulfate via 

gavage for 90 days ................................................................................................ B-31 

Table B-16. A summary of BMDS (version 1.4.1) modeling results based on incidence 

of behavioral findings in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days ............................................................................... B-31 

vi 
LIST OF FIGURES 

Figure 5-1. POD (mg/kg-day) with corresponding derived candidate reference value that 

would result if histopathologic changes of the skin (hair follicle atrophy) 

were used as the critical effect. ................................................................................. 70 

Figure 5-2. PODs (mg/kg-day) with corresponding derived candidate reference values 

that would result if clinical observations from MRI (1988) were used as the 

critical effect ........................................................................................................... 71 

Figure 5-3. POD (mg/kg-day) with corresponding derived candidate reference value that 

would result if clinical chemistry changes (suggesting the liver or kidney as a 

target) were used as the critical effect ...................................................................... 72 

Figure 5-4. PODs (mg/kg-day) with corresponding derived candidate reference values 

that would result if reproductive toxicity endpoints were used as the critical 

effect ......................................................................................................................... 73 

Figure 5-5. PODs (mg/kg-day) with corresponding derived candidate reference values that 

would result if alternative endpoints were used as the critical effect .........................74 

vii 
LIST OF ABBREVIATIONS AND ACRONYMS

AchE acetyl cholinesterase 

AIC Akaike Information Criterion 

ALA aminolevulinic acid 

ALT alanine aminotransferase 

AST aspartate aminotransferase 

ATSDR Agency for Toxic Substance and Disease Registry 

BMD benchmark dose 

BMD10 benchmark dose corresponding to a 10% extra risk 

BMDL10 95% lower bound on the benchmark dose corresponding to a 10% extra risk 

BMDS benchmark dose software 

BMR benchmark response 

BUN blood urea nitrogen 

CASRN Chemical Abstracts Service Registry Number 

ChAT choline acetyltransferase 

CHO Chinese hamster ovary 

EC50 effective concentration necessary to produce a 50% response 

EPA Environmental Protection Agency 

GI gastrointestinal 

GLP good laboratory practice 

GSH reduced glutathione 

5-HT 5-hydroxytryptamine 

i.p. intraperitoneal 

IPCS International Programme on Chemical Safety 

i.v. intravenous 

IRIS Integrated Risk Information System 

LD50 median lethal dose 

LDH lactate dehydrogenase 

LOAEL lowest-observed-adverse-effect level 

MAO monoamine oxidase 

MDA malondialdehyde 

MEPP miniature endplate potential 

MRI Midwest Research Institute 

NA nucleus accumbens 

NHANES National Health and Nutrition Examination Survey 

NLM National Library of Medicine 

NOAEL no-observed-adverse-effect level 

NOEL no-observed-effect level 

OSHA Occupational Safety and Health Administration 

PAD peripheral arterial disease 

POD point of departure 

PBPK physiologically based pharmacokinetic 

RfC inhalation reference concentration 

RfD oral reference dose 

s.c. subcutaneous 

SCE sister chromatid exchange 

Tl thallium 

UF uncertainty factor 

viii 
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). 

ix 
AUTHORS, CONTRIBUTORS, AND REVIEWERS

 

 

CHEMICAL MANAGER/AUTHOR

Octavia Conerly, M.S.P.H. 

Office of Water 

U.S. Environmental Protection Agency 

Washington, DC 

AUTHORS

Susan Rieth, M.P.H. 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 

CONTRACTOR SUPPORT 

Robyn B. Blain, Ph.D. 

ICF Consulting 

Fairfax, VA 

OFFICE OF RESEARCH AND DEVELOPMENT CO-LEAD 

Susan Rieth, M.P.H. 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 

REVIEWERS 

 This document has been reviewed by EPA scientists, interagency reviewers from other 

federal agencies and White House offices, and the public, and peer reviewed by independent 

scientists external to EPA. A summary and EPA’s disposition of the comments received from 

independent external peer reviewers and from the public is included in Appendix A. 

INTERNAL EPA REVIEWERS

Joyce Donohue, Ph.D. 

Office of Water 

Elizabeth Doyle, Ph.D. 

Office of Water 

Steven Kueberuwa, Ph.D. 

Office of Water 

x 
xi 

Mike Hughes, Ph.D. 

Office of Research and Development 

Amal Mahfouz, Ph.D. 

Office of Water 

David Thomas, Ph.D. 

Office of Research and Development 

EXTERNAL PEER REVIEWERS

Ronald Baynes, DVM, Ph.D. 

North Carolina State University 

George Cherian, Ph.D. 

University of Western Ontario 

Lucio G. Costa, Ph.D. (chair) 

University of Washington 

George Daston, Ph.D. 

The Procter & Gamble Company 

Robert Hoffman, M.D. 

New York University 

Deborah Rice, Ph.D. 

Maine Center for Disease Control 
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 a plausible upper bound on 

the estimate of risk per mg/kg-day of oral exposure. Similarly, an inhalation unit risk is a 

plausible upper bound on the estimate of risk per μg/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), Recommendations for and 

Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988), Guidelines 

for Developmental Toxicity Risk Assessment (U.S. EPA, 1991a), Interim Policy for Particle Size 

1 
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), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996), Guidelines for 

Neurotoxicity Risk Assessment (U.S. EPA, 1998), Science Policy Council Handbook: Risk 

Characterization (U.S. EPA, 2000a), Benchmark Dose Technical Guidance Document (U.S. 

EPA, 2000b), Supplementary Guidance for Conducting Health Risk Assessment of Chemical 

Mixtures (U.S. EPA, 2000c), A Review of the Reference Dose and Reference Concentration 

Processes (U.S. EPA, 2002), Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 

Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens 

(U.S. EPA., 2005b), Science Policy Council Handbook: Peer Review (U.S. EPA, 2006a), and A 

Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 

2006b). 

 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 May 2009. 

2 
2. CHEMICAL AND PHYSICAL INFORMATION

 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– becomes 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 2-1. 

 Thallium occurs naturally in the earth’s crust, with a crustal abundance of approximately 

1 mg/kg. In soil, thallium concentrations are on the order of 0.1 to 1 mg/kg; higher 

concentrations occur in the vicinity of metallic ore deposits. Measureable concentrations of 

thallium are also found in marine water, freshwater, and air. Thallium is taken up by vegetation, 

with the extent of uptake determined by soil acidity and plant species (Kazantzis, 2007). 

 According to the International Programme on Chemical Safety (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 as well as a by-product of cadmium production. In 1981 the production of 

thallium in the U.S. was discontinued. Thallium is released to the environment through the 

combustion of fossil fuels (in particular from coal-fired power-generating plants), refinement of 

oil fractions, smelting of ferrous and non-ferrous ores (including lead, copper, and zinc), and by 

some other industrial processes such as cement production and brickworks (Kazantzis, 2007; 

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 U.S. since 

1972. Currently, thallium is used in the semiconductor industry and the manufacture of optic 

3 
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; National Library of Medicine [NLM], 

1998; IPCS, 1996; Agency for Toxic Substance and Disease Registry [ATSDR], 1992; 

U.S. EPA, 1991b). 

Table 2-1. Chemical and physical properties of thallium and selected 

thallium compounds 

Name CASRN

Chemical 

formula

Molecular 

weight

Melting point 

(°C)

Boiling point 

(°C)

Solubility in 

water (g/L)

Metallic thallium 7440-28-0 Tl 204.38 303.5 1,457 Insoluble 

Thallium (I) acetate 563-68-8 TlC2H3O2 263.43 131 No data Very soluble 

Thallium (I) carbonate 6533-73-9 Tl2CO3 468.78 273 No data 40.3 (15.5°C)

Thallium (I) chloride 7791-12-0 TlCl 239.84 430 720 

Very soluble 

(20°C) 

Thallium (I) nitrate 10102-45-1 TlNO3 266.39 206 430 95.5 (20°C) 

Thallium (I) oxide 1314-12-1 Tl2O 424.77 596 No data 

Soluble 

(as TlOH) 

Thallium (III) oxide 1314-32-5 Tl2O3 456.76 717 875 Insoluble 

Thallium (I) selenite 12039-52-0 Tl2SeO3 535.72 No data No data No data 

Thallium (I) sulfate 7446-18-6 Tl2SO4 504.82 632 Decomposes 48.7 (20°C) 

Sources: IPCS (1996); Downs (1993); ATSDR (1992). 

 

4 
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 Wellhöner, 1983), which implies absorption from environmental sources. 

 Shaw (1933) determined that 61.6% of an oral dose of thallium (I) sulfate (25 mg/kg Tl) 

was absorbed by a dog. Lie et al. (1960) determined that thallium was completely absorbed via 

the GI tract, following oral administration of 767 μg/kg 204Tl 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 μg/kg; intramuscular, 96 μg/kg; subcutaneous [s.c.], 96 μg/kg; intratracheal, 123 μg/kg; and 

intraperitoneal [i.p.], 146 μg/kg). Eighty percent of a single dose of 10 nmol of thallium, as 

thallium (I) sulfate, was absorbed within 1 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, treatment for ringworm of the 

scalp, and treatment for night sweats associated with tuberculosis suggests dermal absorption 

(Léonard 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; GalvánArzate and Rios, 1994; Aoyama, 1989; Rios et al., 1989; Talas and Wellhöner, 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; 

Barclay et al., 1953), regardless of the route of exposure, dose, and length of exposure (Sabbioni 

et al., 1980a, b; Lameijer and van Zwieten, 1977). The highest thallium concentrations have 

5 
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/kg Tl) had the 

highest levels of thallium in the testis, heart, and kidneys, in that order, 24 hours after 

administration (Galván-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). Galván-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 brains of 5- to 

20-day-old rats 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. Thallium deposition into hair and nails also is considered an 

important route of elimination (Kazantzis, 2007; IPCS, 1996). 

 A study of a human cancer patient orally administered thallium (I) sulfate and 

radiolabeled thallium (I) nitrate (204TlNO3) 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). 

 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), the geometric 

mean level of thallium in the urine was 0.16 μg/L, with a maximum of 0.86 μg/L (Navas-Acien 

et al., 2005). 

 The Third National Report on Human Exposure to Environmental Chemicals (Centers for 

Disease Control and Prevention [CDC], 2005) provides ongoing biomonitoring data for the U.S. 

population for environmental chemicals over the periods 1999–2000 and 2001–2002 collected 

from NHANES participants. Selected urinary thallium level data from this survey are provided 

in Table 3-1. For the U.S. population (ages 6 and older), the geometric mean urinary thallium 

6 
concentration for survey years 2001–2002 was 0.165 μg/L, and the 95th percentile concentration 

was 0.440 μg/L. 

Table 3-1. Urine concentrations of thallium for the U.S. population from 

NHANES, 1999–2002 

 

Survey 

years 

Sample 

size 

Urinary concentration of thallium in μg/L urine 

[μg/g creatinine]a

Selected percentiles of the U.S. population 

Geometric mean 50th 95th 

Total, ages 6 

and older 

99–00 2413 0.176 (0.162–0.192) 

[0.166 (0.159–0.173)] 

0.200 (0.180–0.210) 

[0.168 (0.162–0.176)] 

0.450 (0.420–0.470) 

[0.366 (0.338–0.387)] 

01–02 2653 0.165 (0.154–0.177) 

[0.156 (0.151–0.162)] 

0.180 (0.170–0.200) 

[0.156 (0.148–0.164)] 

0.440 (0.410–0.470) 

 [0.348 (0.337–0.365)] 

Age group 

6–11 years 99–00 336 0.201 (0.167–0.243) 

[0.221 (0.197–0.248)] 

0.200 (0.150–0.260) 

[0.221 (0.196–0.236)] 

0.440 (0.350–0.590) 

[0.424 (0.356–0.600)] 

01–02 362 0.172 (0.147–0.202) 

[0.211 (0.198–0.226)] 

0.200 (0.160–0.220) 

[0.207 (0.198–0.221)] 

0.380 (0.360–0.420) 

 [0.411 (0.389–0.456)] 

12–19 years 99–00 697 0.202 (0.181–0.225) 

[0.153 (0.146–0.160)] 

0.210 (0.200–0.240) 

[0.154 (0.146–0.162)] 

0.460 (0.430–0.510) 

[0.321 (0.265–0.364)] 

01–02 746 0.200 (0.182–0.220) 

[0.143 (0.137–0.150)] 

0.210 (0.190–0.240) 

[0.145 (0.135–0.152)] 

0.460 (0.400–0.500) 

 [0.307 (0.299–0.333)] 

20 years & 

older 

99–00 1380 0.170 (0.157–0.183) 

[0.162 (0.153–0.171)] 

0.180 (0.170–0.200) 

[0.167 (0.154–0.176)] 

0.450 (0.420–0.470) 

[0.364 (0.325–0.389)] 

01–02 1545 0.159 (0.147–0.173) 

[0.153 (0.147–0.159)] 

0.190 (0.170–0.200) 

[0.152 (0.144–0.161)] 

0.440 (0.400–0.490) 

 [(0.342 (0.313–0.362)] 

Gender 

Males 99–00 1200 0.197 (0.179–0.217) 

[0.154 (0.147–0.161)] 

0.220 (0.190–0.240) 

[0.156 (0.149–0.164)] 

0.440 (0.420–0.480) 

[0.338 (0.300–0.364)] 

01–02 1313 0.184 (0.173–0.196) 

[0.146 (0.140–0.153)] 

0.200 (0.190–0.220) 

[0.148 (0.141–0.156)] 

0.420 (0.390–0.460) 

 [0.307 (0.291–0.342)] 

Females 99–00 1213 0.159 (0.145–0.175) 

[0.178 (0.167–0.189)] 

0.180 (0.150–0.200) 

[(0.182 (0.169–0.196)] 

0.450 (0.410–0.490) 

[0.380 (0.333–0.462)] 

01–02 1340 0.149 (0.137–0.163) 

[0.167 (0.158–0.176)] 

0.150 (0.150–0.170) 

[0.167 (0.153–0.179)] 

0.430 (0.400–0.500) 

 [(0.375 (0.348–0.402)] 

a

95th percentile confidence interval in parentheses. 

Source: CDC (2005). 

 As noted above, thallium elimination is not limited to renal excretion. IPCS (1996) 

estimated that in humans renal excretion accounts for approximately 70% of total daily excretion 

of thallium. This estimate is based on limited human data. 

 In contrast to humans, thallium is excreted to a greater extent in the feces than in the 

urine of rats and rabbits. IPCS (1996) estimated that in rats about 2/3 of the intake of thallium 

7 
was excreted via the GI tract and about 1/3 via the kidney. Lund (1956) determined that, after 

26 days, 51.4% of an i.p. dose of 10 mg/kg thallium (I) sulfate in the rat was eliminated via the 

feces, while 26.4% was excreted in the urine. Talas and Wellhöner (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). Shaw (1933) demonstrated that 32 and 61.6% of a single oral dose of 

25 mg/kg Tl as thallium (I) sulfate administered to a dog was excreted in the urine at 3 and 

36 days after dosing, respectively. 

 Sabbioni et al. (1980b) determined that thallium (I) sulfate administered at doses of 

0.00004–2,000 μg/rat was persistent in the kidneys for 8 days (192 hours) after dosing with 2.5% 

of the dose still present at that time (suggesting a half-life of approximately 1.5 days). Lehmann 

and Favari (1985) and Lie et al. (1960) estimated the biological half-life of thallium in rats to 

range from 3–8 days. 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 thallium compounds. 

8 
9 

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. 

 In adults, the average lethal oral dose has been estimated to range from 10 to 15 mg/kg 

(Gosselin et al., 1984; Schoer, 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., 2006; 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/kg Tl, assuming a 

70 kg body weight) (Cavanagh et al., 1974). 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 4-1 summarizes the individual 

case reports.
Table 4-1. Thallium toxicity in humans following oral exposure 

Reference Sex Age Dose Symptomsa 

Males—adult

Gefel et al. (1970) Male 41 years Unknown but 

chronic; urine thallium  0.15 mg/100 mL 

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 

Dea

Cavanagh et al. (1974) Male 60 years 0.93 g thallium (I) 

acetate in 2 divided doses 

Diarrhea; vomiting; dizziness; back pain; paresthesia of the feet and lower legs; high blood pressure; facial weakness; dysphagia; difficulty breathing 

Deasym

Cavanagh et al. (1974) Male 56 years 0.93 g thallium (I) 

acetate in 3 divided doses 

Abdominal pain; diarrhea; vomiting; paresthesia; photophobia, nystagmus, visual impairment; facial weakness; bilateral ptosis 

Deasym

Cavanagh et al. (1974) Male 26 years 0.31 g thallium (I) 

acetate 

Paresthesia in both feet; chest pain; tenderness over the sternum; vomiting, weakness, pain in the knees and ankles that inhibited walking; alopecia 

Rec

Davis et al. (1981) Male 19 years 5–10 g thallium (I) 

nitrate 

Nausea; vomiting; slurred speech; paresthesia of hands and feet; respiratory weakness 

Dea

Limos et al. (1982) Male 56 years Unknown Visual disturbances; alopecia; elevated AST and 

ALT; high blood glucose and creatine kinase; decreased myelinated fibers; denervated Schwann cell clusters 

Bedspea

Limos et al. (1982) Male 26 years Unknown Visual disturbances; alopecia; elevated AST and 

ALT; high blood glucose and creatine kinase; decreased myelinated fibers; denervated Schwann cell clusters 

Resiextrwealimb

Roby et al. (1984) Male 45 years Unknown; 

urine thallium: 2,000 

μg/L 

Burning pain in feet; inability to walk; alopecia; acute fibrillation 

Condysf

10 
Table 4-1. Thallium toxicity in humans following oral exposure 

Reference Sex Age Dose Symptomsa 

4/5 rexpeneur

Heyl and Barlow (1989) Male “Five young 

men” 

Unknown 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 hair shafts, gross follicular plugging, and eosinophilic keratohyalin granules in the epidermis; necrotic sebaceous glands; pustular lesions on the face: folliculitis and necrosis of the follicles; (feet) marked hyperkeratosis and hypergranulosis. 

Yokoyama et al. (1990) Male 31 years Unknown; 

urine thallium: 3.5 mg/L 

Nausea, vomiting; leg pain; alopecia; abnormal behavior; decreased conduction velocity of fast nerve fibers 

Rec

Hantson et al. (1997) Male 48 years 200 mg thallium (I) 

sulfate 

No overt symptoms within 24 hours; increase in binucleated cells with micronuclei 15 days after exposure 

Rec

Hirata et al. (1998) Male 29 years Unknown; hair 

thallium: 20 ng/g (32 months after possible exposure) 

Alopecia; abdominal pain; diarrhea; tingling in extremities; neuropathy 

Rec

Atsmon et al. (2000) Male 40 years Unknown; 

urine thallium: 7 mg

Weakness of the limbs; vomiting; severe neurological symptoms; alopecia; high blood pressure; increased ALT and AST; Mees lines; decreased visual acuity; bilateral foot drop 

Rec

Sharma et al. (2004) Male 48 years Unknown; 

serum thallium: 870 

μg/100 mL 

urine thallium: 5,000 

μg/mL 

Painful peripheral neuropathy, decreased consciousness 

Dea

11 
Table 4-1. Thallium toxicity in humans following oral exposure 

Reference Sex Age Dose Symptomsa 

Females—adult

Roby et al. (1984) Female 51 years Unknown; 

serum thallium: 50 

μg/100 mL; 

urine thallium: 5,000 

μg/L 

Numbness and weakness of the legs and hands; alopecia; fluctuating pulse and blood pressure; bradycardia; hypotension 

Persectodysfneceat a 

Roby et al. (1984) Female 61 years Unknown; 

serum thallium: 740 

μg/100 mL 

Burning chest pain; paresthesia; difficulty speaking and swallowing; inability to walk; hypotension; acute respiratory distress syndrome (ARDS) 

Dea

Roby et al. (1984) Female 80 years Unknown; 

serum thallium: 422 

μg/100 mL; 

urine thallium: 21,600 

μg/L 

ARDS Dea

Hoffman (2000) Female Pregnant; ages 

not specified 

150–1,350 mg thallium (I) sulfate 

Paresthesia; abdominal pain; muscle weakness; lethargy; alopecia; Mees lines 

Non

Saha et al. (2004) Female 26 years Unknown; 

serum thallium: 12 

μg/100 mL 

Headache, lethargy, abdominal pain, muscle cramps, joint pain, backache, numbness of fingers, alopecia, erosion of nails 

Not 

Both sexes

—adult

Brockhaus et al. (1981) Both Not reported Unknown Sleep disorders; tiredness; weakness; nervousness; 

headache; other psychic alterations; neurological and muscular symptoms 

Not 

Schoer (1984); Gosselin et al. (1984) 

Both Adult 10–15 mg/kg 

thallium 

None specified Dea

dose

Rusyniak et al. (2002) Both Various Unknown; various 

levels were detected in urine 

Myalgia; arthralgia; paresthesia; dysesthesia; joint stiffness; insomnia; alopecia; abdominal pain 

Rechad prob

12 
Table 4-1. Thallium toxicity in humans following oral exposure 

Reference Sex Age Dose Symptomsa 

Tsai et al. (2006) Both 48-year old 

female; 52-year old male 

1.5–2 .4 g Confusion, disorientation, hallucination, anxiety, 

depression, memory impairment, peripheral neuropathy, erythematous skin rashes, diarrhea, tachycardia, alopecia 

Impand remneurimp9 m

At 1persdyseimpsensskin 

Lu et al. (2007); Kuo et al. (2005) 

Both 48 and 52 years 1.5 and 2.3 g/person 

(estimated); Serum thallium: 950–2,056 

μg/L 

Urine thallium: 11,325–14,520 

μg/L

Nausea, vomiting; general aching muscle pain; numbness of tongue and mouth within a few hours; severe paresthesia and dysesthesia in hands and feet (one day postexposure); 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). 

Children

Reed et al. (1963) Both 1–11 years Unknown Alopecia; lethargy; ataxia; abdominal pain; 

vomiting; abnormal reflexes; neuropathy; muscle weakness; coma; convulsion 

Neuabnoretardeat

Feldman and Levisohn (1993) 

Male 10 years Unknown; 

serum thallium: 296 

μg/L; 

urine thallium: 322 

μg/24 hours 

Alopecia; leg paresthesia; abdominal pain; seizures Rec

Hoffman (2000) Both Transplacental Unknown Premature birth; low birth weight; alopecia Non

13 
14 

Table 4-1. Thallium toxicity in humans following oral exposure 

Reference Sex Age Dose Symptomsa 

Ammendola et al. (2007) Male 16 years 1.3 g thallium 

sulfate; urine thallium: 3,400 μg/L 

Acute stage: GI disturbances, alopecia, and clinical and electrodiagnostic signs of severe polyneuropathy. 

3 yeneursymprogelecsignneurconf6 yeperssensdistaneurelecabnomain

aALT = alanine aminotransferase; AST = aspartate aminotransferase. 
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 serum glutamic oxaloacetic transferase) and 

serum alanine aminotransferase (ALT) (formerly referred to as serum glutamate pyruvate 

transaminase), 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 (1–11 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 μg/dL in blood at the time of 

hospital admission, and the concentration in urine was 3,804 μg/g Tl creatinine (reference value, 

<1 μg/g Tl). 

 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 2–24 ounces of the ointment. This was 

approximately equivalent to a dose of 53–636 mg/kg Tl 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 150–1,350 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 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 

15 
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 taken up by local crops and indigenous 

plants. People who lived near the plant and consumed 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 epidemiologic study of a group of 1,200 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 μg/L (range: <0.1–76.5 μg/L) in the study population 

compared to the reference population means of 0.4 ± 0.2 μg/L (rural) and 0.3 ± 0.2 μg/L (urban) 

(range: 0.1–1.2 μg/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 GI symptoms and thallium level was observed. There was a 

negative correlation between urinary thallium and hair loss (13.6% with urine levels <2 μg/L, 

6.6% with urine levels 2–20 μg/L, and 5.9% with urine levels >20 μg/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, headache, 

and psychological alterations as well as 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 

16 
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 (5/297) was 

compared to the expected rate of 0.8/297 births based on annual statistics from the North RhineWestphalia 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% of 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 1–42 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 μg/g Tl creatinine with a range of <0.3–6.3 μg/g Tl creatinine. The range in 

20 individuals without known occupational exposure was <0.3–1.1 μg/g Tl creatinine (median 

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 

17 
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. 

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

4.2.1.1.1. 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/kg-day Tl) by gavage 

for 90 days. The study was conducted in compliance with EPA good laboratory practice (GLP) 

mandates. The MRI (1988) study is an unpublished study; accordingly, an external peer review 

was initiated by EPA in November 2006. Body weight, food consumption, hematologic and 

clinical chemistry parameters, ophthalmologic examinations, gross pathological observations, 

and organ weights (liver, kidneys, brain, gonads, spleen, heart, and adrenals) were recorded for 

all animals. Neurotoxicological examinations (three times/week) were performed on six 

18 
rats/sex/group; these examinations were apparently observational (further details were not 

provided in the study report). Tissues from three rats/sex/group were prepared for 

neuropathologic examination. Complete histopathologic examinations (including 

neuropathologic examinations) were conducted for the vehicle control and 0.2 mg/kg-day Tl 

groups only; for the other three groups, only the livers, lungs, kidneys and gross lesions were 

examined histopathologically. Neuropathologic 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. The study authors concluded that the histopathologic examination did not reveal any 

treatment-related effects. 

 Lacrimation (secretion of tears), exophthalmos (abnormal protrusion of the eyeball), and 

miosis (contraction of the pupil) were observed at higher incidences in the treated male and 

female rats compared with both untreated and vehicle controls (Table 4-2). Ophthalmologic 

examination and gross and histopathologic examination of the eyes, however, revealed no 

treatment-related abnormalities. The incidence of clinical observations related to the coats 

(including rough coat, piloerection, shedding, and alopecia) and behavior (including aggression, 

tension/agitation, hyperactivity, vocalization, and self-mutilation) were also elevated in male and 

female rats at the higher doses (Table 4-2). 

 

19 
Table 4-2. Selected clinical observations in Sprague-Dawley rats treated 

with thallium sulfate for 90 days 

Observationa Untreated 

control

Vehicle 

control 0.008 mg/kg-day 0.04 mg/kg-day 0.2 mg/kg-day

Male 

Coat/skin 

Rough coat 1/20 3/20 11/20 16/20 19/20 

Piloerection 0/20 0/20 1/20 4/20 13/20 

Shedding 0/20 0/20 4/20 10/20 8/20 

Alopecia 2/20 1/20 4/20 9/20 4/20 

Eyes 

Lacrimation 1/20 6/20 19/20 20/20 20/20 

Exophthalmos 1/20 5/20 12/20 20/20 20/20 

Miosis 0/20 1/20 5/20 7/20 15/20 

Behaviorb 3/20 0/20 7/20 6/20 7/20 

Female 

Coat/skin 

Rough coat 1/20 0/20 1/20 5/20 11/20 

Piloerection 0/20 0/20 0/20 3/20 8/20 

Shedding 0/20 0/20 2/20 3/20 13/20 

Alopecia 4/20 1/20 4/20 9/20 12/20 

Eyes 

Lacrimation 7/20 6/20 20/20 20/20 20/20 

Exophthalmos 5/20 6/20 19/20 20/20 20/20 

Miosis 2/20 3/20 1/20 11/20 8/20 

Behaviorb 2/20 2/20 0/20 1/20 7/20 

a

Listed as number of animals with the sign observed at least once during the 90-day study. 

b

Animals exhibiting one or more behavioral observations at least once during the 90-day study, including the 

following: aggression, tension/agitation, hyperactivity, vocalization, self-mutilation. 

Source: MRI (1988). 

 As noted above, the incidence of alopecia was increased, particularly in female rats (see 

Table 4-3). Examination of individual animal clinical observation data for female rats from the 

MRI (1988) study showed that alopecia was first observed in control and treated groups 

anywhere from study day 44 to 60. 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 

 

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 EPA by using Fisher’s exact test. Incidence in the treated groups was compared with 

incidence in the untreated control, vehicle control, and pooled control. 

20 
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 12 high-dose females with alopecia, 5 instances were not 

totally attributed to barbering behavior. Histopathologic examination revealed atrophy of the 

hair follicles in two high-dose female rats. Because the skin was examined for histopathologic 

changes only in the vehicle control and high-dose groups, no information on dermal 

histopathology was available for the low- and mid-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 

study authors concluded that the alopecia was attributable to the cyclic pattern of hair growth in 

rodents. Consequently, the authors did not consider these findings to be toxicologically 

significant. 

Table 4-3. Incidence of alopecia in rats 

Dose 

(mg/kg-day Tl) 

Males Females 

Alopeciaa, b Hair follicle atrophyc Alopeciaa, b Hair follicle atrophyc

0 (untreated control) 2/20 --d 4/20 --d

0 (vehicle control) 1/20 0/20 1/20 0/20 

0.008 4/20 --d 4/20 --d

0.04 9/20e --d 9/20f --d

0.2 4/20 0/20 12/20e 2/20 

a

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-day, 2; 0.04 mg/kg-day, 4; 0.2 mg/kg-day, 1. 

 Females: untreated control, 0; vehicle control, 0; 0.008 mg/kg-day, 1; 0.04 mg/kg-day, 3; 0.2 mg/kg-day, 5. c

Based on histopathologic observation. 

d

Skin was not examined for histopathologic 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 EPA. f

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 

EPA. 

Source: MRI (1988). 

 Subtle but statistically significant changes were observed in several blood chemistry 

parameters that the investigators considered probably treatment related. Specifically, doserelated increases in 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 4-4. Other 

21 
changes in blood chemistry parameters were less consistent across species, dose groups, and 

exposure durations. 

 At 90 days, the differences in AST, LDH, sodium, and blood sugar levels in dosed male 

and female rats were no greater than +31, +38, +4, and –21%, 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 male or female rats during the study were of 

sufficient magnitude to significantly affect the health status of the animals. Further, 

histopathologic evaluation did not confirm any cellular damage suggested by the clinical 

chemistry findings. 

Table 4-4. Selected blood chemistry values 

Endpoint

Study 

day

Untreated 

control Vehicle control 0.008 mg/kg-day 0.04 mg/kg-day 0.2 mg/kg-day

Malesa

AST 

(I.U.) 

30 

90 

 91 ± 26.5 

 77 ± 19.7 

 108 ± 18.6 

 87 ± 17.8 

 128 ± 24.5b

 99 ± 20.4 

 134 ± 29.0b,c

 113 ± 27.0b,c

 152 ± 20.1b,c

 114 ± 31.1b,c

LDH 

(I.U.) 

30 

90 

 795 ± 322 

 587 ± 305 

 1206 ± 424b

 856 ± 385 

1333 ± 340b

1003 ± 363b

1396 ± 407b

1071 ± 507b

1802 ± 341b,c

1119 ± 477b

Na 

(meq/L) 

30 

90 

 148 ± 1.3 

 144 ± 1.6 

 149 ± 2.4 

 147 ± 2.0b

 152 ± 4.0b

 147 ± 1.9b

 154 ± 2.5b,c

 149 ± 2.0b,c

 153 ± 2.1b,c

 151 ± 2.2b,c

Blood sugar 

(mg/100 mL) 

30 

90 

 100 ± 22.1 

 158 ± 15.6 

 97 ± 18.1 

 138 ± 16.8b

 93 ± 10.0 

 131 ± 17.6b

 90 ± 18.3 

 121 ± 15.7b

 62 ± 14.8b,c

 113 ± 22.4b,c

Femalesa

AST 

(I.U.) 

30 

90 

 95 ± 22.8 

 77 ± 19.2 

 115 ± 30.3 

 90 ± 19.1 

 127 ± 27.8b

 93 ± 33.1 

 149 ± 26.8b,c

 111 ± 30.7b

 154 ± 18.2b,c

 112 ± 31.0b

LDH 

(I.U.) 

30 

90 

1047 ± 335 

 745 ± 320 

1277 ± 495 

 881 ± 273 

 1402 ± 501 

 823 ± 354 

1763 ± 370b,c

1044 ± 436 

 1764 ± 361b,c

 1219 ± 338b

Na 

(meq/L) 

30 

90 

 148 ± 1.7 

 146 ± 1.8 

 150 ± 1.9 

 146 ± 1.0 

 153 ± 4.1b,c

 148 ± 1.8b,c

 154 ± 2.8b,c

 150 ± 2.0b,c

 155 ± 2.5b,c

 152 ± 1.0b,c

Blood sugar 

(mg/100 mL) 

30 

90 

 103 ± 23.9 

 110 ± 28.7 

 80 ± 13.3b

 89 ± 15.9 

 80 ± 9.0b

 103 ± 19.9 

 67 ± 20.0b

 88 ± 20.4 

 50 ± 11.8b,c

 70 ± 18.0b

a

Mean ± standard deviation of 7–10 rats. 

b

Significantly different (p < 0.05) from the untreated control group. c

Significantly different (p < 0.05) from the vehicle control group. 

Source: MRI (1988). 

 The authors concluded that the minor dose-related changes in this study did not affect the 

health status of the treated animals and therefore were not toxicologically significant and 

22 
identified the highest dose, 0.25 mg/kg-day thallium (I) sulfate (0.20 mg/kg-day Tl), as a noobserved-effect level (NOEL). However, upon further analysis by EPA of the MRI (1988) 

findings as part of this health assessment, a different determination was reached regarding the 

no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) 

(see the discussion in Section 5.1.1). 

 Manzo et al. (1983) administered drinking water containing thallium (I) sulfate at a 

concentration of 10 mg/L Tl (approximately equivalent to a dose of 1.4 mg/kg-day Tl based on 

reported thallium intakes and an assumption that the rats weighed 200 g) to 80 female SpragueDawley 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 histopathologic changes were observed in the 

peripheral nerves, including changes in motor and sensory action potentials and histopathologic 

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 lysosomal activity. 

 Ten adult male albino rats were administered 0.8 mg/kg (1/20th of the LD50) 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 

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 

administration (gavage) 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 

(GSH) and caused a statistically significant (p < 0.05) increase in malondialdehyde (MDA) 

production and triglycerides in the liver 48 hours after treatment. (MDA production and GSH 

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. Furthermore, 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 

23 
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, or 3.9 mg/kg-day Tl 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/kg-day Tl) 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 treatment-related pathology, but they 

did not prepare skin sections. The study findings for alopecia suggest a NOAEL and LOAEL of 

0.4 mg/kg-day Tl and 1.2 mg/kg-day Tl, 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 Wistarderived albino rats (five rats/sex/treatment). Rats received 0, 20, 35, 50, 100, or 500 mg/kg (or 

ppm) thallium (III) oxide 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/kg-day Tl, 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 g in males treated 

with 20 and 35 ppm dietary doses, respectively, and 50 g 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. Histopathologic examination did not reveal any alterations 

in the kidney related to thallium treatment. Histopathologic evaluation of the skin revealed a 

24 
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/kg-day Tl (20 ppm 

thallium (III) oxide in the diet), is considered to be a LOAEL based on 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 (three 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 four 

doses began to lose their hair 96 hours after the first exposure. All treated animals had diarrhea. 

After the fourth gavage dose, 2/20 males and 2/20 females died. 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. 

4.2.1.1.2. Dogs. Reports of thallium toxicity in dogs are limited to a few cases in the literature 

of accidental exposure. A 9-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 1-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 2 weeks later by 

severe, rapidly progressing alopecia. No abnormalities were found in a complete blood count 

test, 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 

25 
pancreas. Histologic 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. 

4.2.2. Inhalation Exposure 

 No studies were identified that examined the effects of inhaled thallium in animal 

models. 

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES

4.3.1. 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/kg-day Tl based on reported daily thallium 

consumption [270 μg 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 β-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. 

β-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/kg-day Tl (10 mg/L) 

was identified. 

26 
 Gregotti et al. (1985) also reported β-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 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 μg/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 μg/kg-day) for 8 months and 

subsequently mated with untreated females. The authors concluded that thallium carbonate 

produced a treatment-related enhancement of embryonic mortality. The authors’ conclusion was 

not, however, supported by the data presented in the paper. The number of implantation sites 

(10.11 ± 0.48 to 11.05 ± 0.49), number of “yellow bodies” in pregnant rats (11.11 ± 0.35 to 

11.75 ± 0.33), and number of live embryos (9.77 ± 0.48 to 10.87 ± 0.37) were similar across the 

control and treated groups. (“Yellow bodies” were not further defined in the paper but may 

mean corpora lutea.) Because the paper lacked statistical analysis, it was unclear whether the 

differences were statistically significant. Only the number of resorptions in the control group 

(0.87 ± 0.13) was appreciably higher than that in the treated groups (0.22 ± 0.12 to 0.33 ± 0.13). 

In addition, the authors’ calculation of total embryonic deaths could not be reproduced from the 

data provided. Finally, overall confidence in the reported findings was low because of 

inadequate reporting (e.g., the number of male rats exposed and the rat strain were not reported), 

the use of nonstandard terminology, the relatively small number of pregnant females (16–18 per 

group), and lack of statistical analysis. 

 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 (20/group) weighing 15–20 g at 

study initiation. (Assuming an average body weight of 20 g over the exposure period and 

drinking water ingestion rate of 6 mL/day [Derelanko and Hollinger, 1995], these exposure 

levels are approximately equivalent to doses of 0.0003, 0.003, 0.03, 0.3, and 3 mg/kg-day Tl. 

These doses are approximate only because the age of animals at study initiation, terminal body 

weights, and water consumption were not reported.) At the end of the exposure period, half of 

the male mice (10/group) were sacrificed for epididymal sperm examination. The remaining 

males (10/group) were housed with untreated females (1:2 ratio) for 1 week to evaluate male 

reproductive function. At the end of the 1-week mating period, these male mice were also 

sacrificed for epididymal sperm examination. Untreated female mice were sacrificed on 

gestation day 20 and evaluated for the following measures of reproductive function: number of 

pregnant female mice, number of live and dead fetuses, number of implantations, and number of 

early resorptions. Water intake, body weights, behavior, and animal health were reportedly 

assessed; however, this information was not provided in the study report. The author reported 

that sperm motility (rapid speed, sperm immobility) was affected at the lowest drinking water 

27 
28 

concentration (0.001 mg/L) tested. Effects were shown to increase with increasing 

concentration, thus indicating a dose-response relationship. At 0.01 mg/L and higher, the 

number of dead sperm was statistically significantly increased. Sperm count was statistically 

significantly reduced and the percent of deformed sperm was increased at concentrations of 

0.1 mg/L and higher. The author observed that there was an adverse effect on sperm quality 

(motility) at low doses, and, as the dose increased, there was an accompanying decrease in sperm 

count in addition to the motility change. Examination of reproductive function in the group of 

mice housed for 1 week with untreated females revealed that the reproductive index (number of 

pregnant female mice/number of mated female mice) and the number of implantations were not 

statistically different between treated and control animals. The mean number of live fetuses was 

statistically significantly increased at concentrations of 0.01 mg/L and above. The percent of 

dead fetuses was significantly lower than in the control group at concentrations of 0.001, 0.01, 

and 0.1 mg/L but was increased at the two highest concentrations (1 and 10 mg/L). Review of 

the reported results reveals that a number of male mice were not accounted for at study 

termination. Of the initial 20 male mice/group, sperm results were provided for only 12 mice in 

the 0.1 mg/L group, 10 mice in the 10 mg/L group, and 16 mice in the remaining groups. No 

explanation is provided for the loss of animals over the 6-month study. The author concluded 

that the lowest dose tested (0.001 mg/L thallium (I) carbonate) was a LOAEL, causing 

reproductive effects in male mice. 

 Table 4-5 summarizes thallium toxicity in animals following oral exposure. 
Table 4-5. Thallium toxicity in animals following oral exposure 

Reference Species Age Sex Route Dose and duration NOAEL LOAEL 

Acute studies 

Leloux et al. (1987) 

Rat 3/sex 

Adult Both Oral 

(gavage) 

20 mg/kg thallium (I) nitrate; single dose 

NIa 15 mg/kg Tl Difficulty breathing

absolute kidney, ad

Leloux et al. (1987) 

Rat 10/sex/ group 

Adult Both Oral 

(gavage) 

0, 1 mg/kg thallium (I) nitrate; once daily for 4 days 

NI 0.77 mg/kg Tl Alopecia; diarrhea; 

kidney, eye weight

Mourelle et al. (1988) 

Rat 10/group 

NSb Male Oral 

(gavage) 

0, 10 mg/kg thallium (I) sulfate; single dose. Sacrificed at 24 hours to 2 days after dosing 

NI 8.1 mg/kg Tl Liver changes: incr

lipid peroxidation; glycogen; increased serum and liver cel

Subchronic studies 

Downs et al. (1960) 

Rat/ 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/kg-day Tl); 15 weeks 0 or 30 ppm (corresponding to 0 or 2.4 mg/kg-day Tl); 9 weeks 

0.4 mg/kgday Tl* 1.2 mg/kg- day Tl* Alopecia; increased 

in treated and contr*The NOAEL and Because of reporteand treated groups, LOAEL cannot be 

Downs et al. (1960) 

Rat 5/sex/ group 

Weanling Both Oral 

(feed) 

0, 20, 35, 50, 100, and 500 ppm thallium (III) oxide (corresponding to 0, 1.8, 3.1, 4.5, 9.0, and 44.8 mg/kg-day Tl); 15 weeks 

NI 1.8 mg/kgday Tl (20 

ppm) 

Reduced body weigmortality; increased kidney weights 

El-Garawany et al. (1990) 

Rat n = 10 

NS Male Oralc 0.8 mg/kg thallium 

(I) sulfate; 90 days 

 NI 0.65 mg/kgday Tl Increased blood ure

serum bilirubin; ser

Manzo et al. (1983) 

Rat n = 80 

NS Female Oral 

(DWd) 

10 mg/L Tl as thallium (I) sulfate; 36 weeks 

NI 1.4 mg/kgday Tl Nerve histopatholo

29 
30 

Table 4-5. Thallium toxicity in animals following oral exposure 

Reference Species Age Sex Route Dose and duration NOAEL LOAEL 

MRI (1988) Rat 

20/sex/ group 

45 days Both Oral 

(gavage) 

0, 0.01, 0.05, or 0.25 mg thallium (I) sulfate/kg (corresponding to 0, 

0.008, 0.04, or 0.20 mg/kg-day Tl); 90 days 

NI 0.008 mg/kgday Tle Increased incidence 

observations relatepiloerection, sheddexophthalmos, and behavioral observasignificant increasesodium levels; decrThe study authors iTl as the NOAEL. 

Reproductive and developmental toxicity

Formigli et al. (1986); Gregotti et al. (1985) 

Rat 10/group 

Adult Male Oral 

(DW) 

0, 10 ppm thallium (I) sulfate; 30 or 60 days 

NI 0.7 mg/kgday Tl Testicular effects: t

disarrangement; cyreduced sperm motendoplasmic reticureduced β-glucuron

Wei (1987) Mouse NS Male Oral 

(DW) 

0, 0.001, 0.01, 0.1, 1.0, and 10 mg/L thallium (I) carbonate (corresponding to 0, 0.0003, 0.003, 0.03, 0.3, and 3 mg/kgday Tl); 6 months 

NI 0.0003 mg/kg

-day Tl 

Decreased sperm mincrease in deformefetuses. Dose estimated frobody weight of 20 ingestion rate of 6 m

Rossi et al. (1988) 

Rat Perinatal Both Mother’s, 

then pup’s DW (DW) 

0, 1 mg/dL of thallium (I) sulfate Day 1 of gestation to weaning then thru 60 days 

NI NI Prenatal and postna

delay in the develoapparatus by 50 daβ-adrenergic and mreactivity noted. 

aNI = not identified. bNS = not specified.cPresumably via gavage. dDW = drinking water. eSee discussion of the NOAEL and LOAEL determination in Section 5.1.1. 
4.3.2. Developmental Toxicity 

 Developmental toxicity studies in the rat (Barroso-Moguel et al., 1992; Rossi et al., 1988; 

Gibson and Becker, 1970) and chicken embryo (Hall, 1985, 1972; 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 dams’ drinking water then 

through their own drinking water until 60 days of age (Rossi et al., 1988). These rats were 

considered prenatally exposed. Another group of NOS albino male and female rats was exposed 

to 1 mg/dL of thallium (I) sulfate via the dams’ 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 α- and β-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 αand β-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 nonossified 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. 

 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 

31 
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 postinjection. 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 pyknotic 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 and 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 8 2/3 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) was also 

induced in embryonic chicks via in vitro cultures with injection into the chorioallantoic 

membrane (Hall, 1985, 1972) or injection into the yolk sac (Karnofsky et al., 1950). Karnofsky 

et al. (1950) determined that thallium (I) sulfate was lethal to 2-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. 

4.4. OTHER ENDPOINT-SPECIFIC STUDIES 

 A number of investigators have specifically examined the effect of thallium compounds 

administered to experimental animals by injection (s.c., i.p., or i.v.) and reported effects on the 

liver, kidneys, heart, and nervous system. 

32 
4.4.1. Liver and Kidney Toxicity

 Liver and kidney were among the organs affected when male and female SpragueDawley rats were given s.c. 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 

(Herman and Bensch, 1967). Toxicity was observed in all treatment groups. 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 tubular cells 

and hepatocytes. In rats that received subacute injections of thallium acetate, eosinophilic 

granular casts occurred 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 tubules 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 

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, 

33 
but the levels did not increase from 60 to 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). 

Histologic 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 rats (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 

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., 

ß-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. 

34 
35 

 Woods and Fowler (1986) examined the effects of a single i.p. dose of thallium (III) 

chloride (TlCl3) 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 doserelated 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 (MAO) (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 μg/mL thallium (III) chloride 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 doserelated 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 4-6 summarizes toxicity data from animal studies involving i.p. or i.v. injection. 
 Table 4-6. Thallium toxicity in animals via injection 

Species

Age or 

weight Sex

Route/exposure 

Reference period Doses NOAEL/LOAEL 

Acute studies (single dose)

Ali et al. (1990) Rat Adult Male i.p./single injection 20 mg/kg Tl as 

thallium (I) acetate

LOAEL = 20 mg/kg Tl 

Neuroloneurochbrain thahrs 

Appenroth et al. (1995) 

Rat Adult Female i.p./single injection 5, 10, 15, and 

20 mg/kg thallium (I) sulfate 

LOAEL = 12 mg/kg Tl 

Kidney volume; thickeneloop of HNa+/K+-

Barroso-Moguel et al. (1990)

Rat Newborn Both i.p./single injection 32 mg/kg thallium 

(I) acetate 

LOAEL = 25 mg/kg Tl 

Neuroloand vasc

Barroso-Moguel et al. (1992) 

Rat Newborn Both i.p./single injection 32 mg/kg thallium 

(I) acetate 

LOAEL = 25 mg/kg Tl 

Developalopeciatissue alskeletal 

Barroso-Moguel et al. (1996) 

Rat Newborn Both i.p./single injection 16 mg/kg thallium 

(I) acetate 

LOAEL = 12 mg/kg Tl 

Developmuscle aalopeciabetween muscle f

Kuperberg et al. (1998) 

Rat 250–

300 g 

Male i.p./single injection 25 mg/kg thallium 

(I) acetate 

LOAEL = 19 mg/kg Tl 

Bladder distendecholinesand bladacetyltrabrain an

Lameijer and van Zwieten (1976) 

Rat Young 

adult 

Male i.v./single injection 3–100 mg/kg 

thallium (I) sulfate 

LOAEL = 24 mg/kg Tl (30 mg/kg thallium (I) sulfate) 

Cardioto

36 
 Table 4-6. Thallium toxicity in animals via injection 

Species

Age or 

weight Sex

Route/exposure 

Reference period Doses NOAEL/LOAEL 

Leung and Ooi (2000) 

Rat 210–

260 g 

Male i.p./single injection 30, 60, 120 mg/kg 

thallium (I) sulfate 

LOAEL = 24 mg/kg Tl 

General and ALTalopeciadiarrhealiver nec

Osorio-Rico et al. (1995) 

Rat 200–

250 g 

Male i.p./single injection 30 or 50 mg/kg 

thallium (I) acetate 

LOAEL = 23 mg/kg Tl 

NeuroloMAO anthe brain

Woods and Fowler (1986) 

Rat Young 

adult 

Male i.p./single injection 50, 100, and 200 

mg/kg thallium (III) chloride 

LOAEL = 42 mg/kg Tl 

Liver todensity olysosomreticulum cytoplasMAO anin severa

Acute studies (3–10 doses)

Brown et al. (1985) 

Rat 250 g Male i.p./6 days 4 or 8 mg/kg-day 

thallium (I) acetate 

LOAEL = 3.1 mg/kgday Tl Neurolo

lipid perincreasein the br

Gibson and Becker (1970) 

Rat Fetus; 8, 

9, and 10 or 12, 13, and 14 days of gestation 

Both Transplacental via 

i.p. injection to dam/3 days 

2.5 or 10 mg/kgday thallium (I) sulfate 

LOAEL = 1.9 mg/kgday Tl Develop

fetal bodhydronemissing bodies 

Gibson and Becker (1970) 

Rat Pregnant Female i.p./3 days 2.5 or 10 mg/kgday thallium (I) 

sulfate 

LOAEL = 1.9 mg/kgday Tl General 

lethargyluster; a

37 
 Table 4-6. Thallium toxicity in animals via injection 

Species

Age or 

weight Sex

Route/exposure 

Reference period Doses NOAEL/LOAEL 

Hasan et al. (1977) 

Rat ~150 g Male i.p./7 days 5 mg/kg thallium 

(I) acetate 

LOAEL = 3.9 mg/kgday Tl General 

hair lustwalkinglethargycomplexvesicles decreaseand guanin the br

Hasan et al. (1978)

Rat ~150 g Male i.p./7 days 5 mg/kg thallium 

(I) acetate 

LOAEL = 3.9 mg/kgday Tl Neurolo

dopamin5-hydrox

Hasan and Ali (1981) 

Rat ~150 g Male i.p./7 days 5 mg/kg thallium 

(I) acetate 

LOAEL = 3.9 mg/kgday Tl General 

hair lustwalkinglethargyperoxidalipofuscperikary

Hasan and Haider (1989) 

Rat ~150 g Male i.p./6 days 5 mg/kg thallium 

(I) acetate 

LOAEL = 3.9 mg/kgday Tl Neurolo

Kuperberg et al. (1998) 

Rat 250–

300 g 

Male i.p./5 days 0, 0.1, 1.0, or 

5.0 mg/kg thallium (I) acetate 

LOAEL = 0.08 mg/kg-day Tl 

Neurolowalking on the hcoordinalethargyconsumpdecreaseactivity 

Subchronic studies

Galván-Arzate et al. (2000) 

Rat 200– 

250 g 

Male i.p./30 days 0.8 or 1.6 mg/kgday thallium (I) 

acetate 

LOAEL = 0.6 mg/kgday Tl Neurolo

lipid per

38 
39 

Species

Age or 

weight Sex

Route/exposure 

period Doses NOAEL/LOAEL 

 Table 4-6. Thallium toxicity in animals via injection 

Reference

Kennedy and Cavanagh (1977) 

Cat Not 

specified 

Female s.c./4–26 weeks 2.3–4.5 mg/kg per 

week thallous acetate (unclear if dose was reported as thallous acetate or as thallium) 

0.32 mg/kg-day (unclear if dose was reported as thallous acetate or as thallium) 

Dying bperiphermotor ne
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 30–100 mg/kg causing a drop of 20–40% 

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 3–40 mg/kg had blood pressures resembling those prior to thallium injection. The higher 

doses had a more permanent effect on 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 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 inhalation or dermal 

routes of exposure were identified. Manzo et al. (1983) demonstrated functional and 

histopathologic changes in peripheral nerves in rats that received thallium sulfate in drinking 

water at a dose equivalent to approximately 1.4 mg/kg-day Tl (see Section 4.2.1.1). Study 

findings reported below involved administration of thallium compounds by injection (i.p., s.c., 

i.v.). 

 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). Glutamine and taurine levels were statistically 

significantly increased (p < 0.05) in the frontal cortex 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. 

40 
 Kennedy and Cavanagh (1977) examined the neurotoxic properties of thallous acetate in 

16 female cats. Cats were injected subcutaneously with thallous acetate in distilled water once 

per week (or in some cases every other week or every few weeks) at mean weekly doses of 2.3–

4.5 mg/kg per week for 4–26 weeks. (It was unclear if doses were reported as thallous acetate or 

thallium). Six cats died during the study without opportunity for neurological assessment. 

Remaining animals were observed daily for clinical signs. At intervals from 4–12 weeks after 

exposure was initiated, nine animals were sacrificed and nervous system tissues were subject to 

perfusion fixation; one cat was exposed weekly for 26 weeks. Ataxia and hypotonia were 

observed in nearly all the cats. Histopathologic examination revealed a distal degeneration 

confined to the central and peripheral axons of primary sensory neurons. No motor nerve fiber 

degeneration was found. The investigators proposed that muscle tissue, which has the largest 

reservoir of K+

 ions in the body, may serve as a sink for thallium ions such that thallium ions 

never reach a concentration in the extracellular space sufficient to damage nerve fibers. 

Experimental evidence for this hypothesis, however, was not available. 

 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) 

acetate was given to 15 newborn Wistar rats. Equal numbers were sacrificed at 24, 48, and 

72 hours and on days 7 and 51 (three 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 

41 
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 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 

increased (p < 0.05) 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 doses (10–20 mg/kg, followed by 

weekly injections of 5 mg/kg or occasionally 2.5 mg/kg for up to 26 weeks) 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 

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 histiocytelike 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, and the AchE in the NA region of the 

brain was back to control levels. AchE activity also was reduced in the duodenum and the 

sphincter-trigon region of the bladder following this single high dose, while 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 sphincter-trigon and detrusor regions of the 

bladder were still significantly (p ≤ 0.05) reduced. 

42 
 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 (6/8) treated at the high dose died by 

48 hours posttreatment. 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 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 

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. 

 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 included anorexia, failure to 

gain weight, irritability, tenderness during handling, poor hair luster, lethargy, diarrhea, dragging 

hind limbs, and fits of abnormal rotation of head and neck, curving the body. Eight of 55 treated 

rats died 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, MAO, adenosine triphosphate, and protease levels in the cerebrum were 

43 
unaffected. Mitochondrial succinic dehydrogenase also was decreased in the cerebrum of 

thallium-treated rats. 

 In a study by the same group of investigators (Hasan and Ali, 1981), male Charles Foster 

rats (approximately 150 g) injected with 5 mg/kg thallium (I) acetate daily for 7 days showed 

clinical symptoms similar to those reported by Hasan et al. (1977). 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 thalliumtreated 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. 

 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 days (Hasan and Haider, 1989) 

or 7 days (Hasan et al., 1978). 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%; p < 0.05) and corpus striatum (64%; 

p < 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%; p < 0.001), cerebellum (36%; p < 0.05), and brain stem (66%; p < 0.001) (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). 

 Galván-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 five 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 

44 
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 five 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 or mechanisms of toxicity are unknown. 

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 GómezPuyou (1975) reported that monovalent thallium also inhibits the influx and efflux of potassium 

in rat liver mitochondria at concentrations (10–15 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. 

45 
 Tao et al. (2008) reported that thallium (I) could functionally replace potassium ion when 

applied in an in vitro system and that glutamate transporters could interact with thallium (I). 

4.5.2. Disturbance of Mitochondrial Function and Energy Generation 

 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 ascites tumor cells in 

vitro (IPCS, 1996). 

 There is evidence that thallium reduces the available energy within peripheral nerves 

(resulting in a “dying back” type of neuronal degeneration) and other metabolically highly 

demanding cells (Kazantzis, 2007; Cavanagh, 1991). Cavanagh (1991) proposed that thallium in 

tissues produces a tissue deficiency of available riboflavin, leading to disturbances of metabolic 

reactions dependent on flavoproteins. Among these reactions would be steps in the passage of a 

number of important intermediate metabolites in the electron transport chain. This metabolic 

disruption could lead to substantial impairment of energy production in the cells. Cavanagh 

(1991) noted that support for this hypothesis includes the following: (1) riboflavin deficiency in 

the rat will lead to peripheral neuropathy and in the primate to loss of hair with circumoral skin 

lesions, and thallium toxicity in the primate produces a similar clinical picture to riboflavin 

deficiency; (2) the testis, which is peculiarly dependent on glucose as a substrate for energy 

metabolism, is sensitive to thallium toxicity; and (3) heart muscle, also known for high energy 

utilization, is also damaged as a result of chronic thiamine deficiency. 

4.5.3. Induction of Oxidative Stress 

 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 

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 GSH and inhibited 

glutathione peroxidase and glutathione reductase activity, suggesting that thallium impairs the 

glutathione-dependent antioxidant defense system. Using rat pheochromocytoma (P12) 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 cell viability, decreased 

mitochondrial 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 GSH content. These investigators postulated 

that both ionic species of thallium enhance reactive oxygen species production in the cell, 

decreasing mitochondrial functionality and cell viability. In a follow-up study with P12 cells in 

vitro, Hanzel and Verstraeten (2009) observed that thallium (I) and (III) do not cause cell 

46 
necrosis, but significantly increased the number of cells with apoptotic features. The oxidatation 

state (i.e., I vs III) appeared to influence the apoptotic pathways are involved. Thallium (I)-

mediated cell apoptosis was mainly associated with mitochondrial damage, whereas thallium 

(III) showed a mixed effect triggering both the intrinsic and extrinsic pathways of apoptosis. 

 Galván-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 from animals that received 16 mg/kg thallium acetate at 

day 7 postexposure (but not at days 1 and 3); antioxidants GSH and superoxide dismutase 

showed only a modest depletion in only one or two brain regions. 

4.5.4. 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 sulfur-containing 

amino acids (i.e., L-cysteine, DL-penicillamine, N-acetyl-L-cysteine, and N-acetyl-DLpenicillamine) 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. 

4.5.5. Other Endpoint-specific Mechanistic Data 

4.5.5.1. 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 2.4 to 9.4 mM) 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 (0.5 mM) (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 

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 

47 
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 μmol 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. Furthermore, potassium nitrate-treated hearts recovered completely when washed with 

nitrate-Krebs solution (Hughes et al., 1978). 

4.5.5.2. 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 concentrations of 1 × 10–3 and 5 × 10–4 M thallium (I) acetate, 

respectively, which was reversible. The amplitude was unchanged. Therefore, it was concluded 

that thallium interfered 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. 

 Windeback (1986) used an in vitro model system to compare the inhibitory effects of four 

metals on neurite outgrowth. Metals were added to cultures of E15 rat embryo dorsal root 

ganglion neurons; neurite outgrowth was measured during the linear phase of growth after 

24 and 40–80 hours. Compared to mercury and arsenic, which inhibited neurite outgrowth at 

very low concentrations (50% inhibition at 3.9 and 9.6 × 10–6 M, respectively), neurons were 

relatively resistant to thallium (50% inhibition at 1.3 × 10–4 M), suggesting that populations of 

neurons have different susceptibilities to various metals. The basis for these different 

sensitivities was not explored in this study. 

 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 

48 
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 morphologic changes in thalliumtreated 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 

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 bilayers using an in vitro system of liposomes 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. 

4.5.5.3. 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 

49 
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 result in cell 

death due to membrane damage and may partly account for thallium-induced alopecia. 

4.5.6. Genotoxicity 

Positive results were obtained for thallium (I) nitrate (1 mM) 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 typhimurium 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 μg/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 1,000 μg/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 EC50 (effective concentration necessary to 

produce a 50% response) values were 307 μg/mL for viability and 18 μg/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 

50 
(i.e., 10–5 and 10–4 M) 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 breaks in CBA mouse fibroblasts after treatment with 10–4–10–6 M 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 μg/kg-day) for 8 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. 

51 
 The nervous system as a target organ of thallium is supported by observations from 

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) (see Table 4-1). 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, psychological alterations, and 

neurological and muscular problems. 

 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 GI 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; Appenroth et al., 1996, 1995; Fleck and 

Appenroth, 1996; El-Garawany et al., 1990; Mourelle et al., 1988). 

 In experimental animal studies, thallium exposure has been associated with biochemical 

changes, lipid peroxidation, and histopathologic changes in the brain and functional and 

histopathologic changes in peripheral nerves (see Section 4.4.3). 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. 

 Despite the fact that the nervous system is a known target of thallium toxicity, studies 

using standard measures of neurobehavioral toxicity have not been performed. In a 90-day oral 

gavage study, MRI (1988) observed rats daily for clinical signs. Rats exposed to thallium sulfate 

showed consistently increased incidences of clinical observations related to the coat (rough coat, 

piloerection, shedding, and alopecia), eyes (lacrimation, exophthalmos, and miosis), and 

behavioral signs compared with untreated or vehicle controls. The underlying mode of action for 

these clinical observations is not known. Collectively, however, these observations suggest a 

52 
treatment-related effect of thallium on the rat and possibly an indirect measure of stress or other 

effects on the nervous system. For example, it has been suggested that barbering (or 

overgrooming) in rodents may represent a stress-evoked behavioral response or other nervous 

system dysfunction (Welch et al., 2007; Kalueff et al., 2006; Kalueff and Tuohimaa, 2005; Greer 

and Capecchi, 2002). 

 Thallium salts have been shown to affect reproductive function. A dose as low as 

0.7 mg/kg-day Tl (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. However, confidence in this study is low due to 

the non-reporting of several observations (water intake, body weights, behavior, and animal 

health). In addition, the numbers of animals examined for sperm and reproductive endpoints 

were ambiguously reported. Half of the animals were sacrificed at the end of the exposure 

period, while the other half were allowed to mate for 1 week and then sacrificed. The study 

results for male mice used for analysis of sperm and reproductive endpoints were reported 

together. That is, results for sperm count, sperm mobility, and all other epididymal sperm 

analysis for males sacrificed at the end of the exposure period were combined with the results for 

males that were allowed to mate and thus permitted a one-week recovery period prior to 

sacrifice. In addition, at the initiation of the study each group consisted of 20 animals. In the 

reporting of the results, however, sperm data were missing for 4 mice from each of the control, 

0.001, 0.01, and 1 mg/L groups, for 8 mice from the 0.1 mg/L group, and for 10 mice from the 

10 mg/L group. No explanation for the loss of male mice (ranging from 20 to 50%) is provided. 

 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 120–1,100 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 of 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 i.p. thallium exposure and low birth 

53 
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, GI 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 underlying mode of action for clinically observed effects of thallium has been 

studied. Verstraeten (2006) determined that Tl1+ can oxidize membrane fatty acids, causing an 

increased fluidity in the membrane and an increased concentration of cellular oxidants associated 

with thallium toxicity. Ensuing axonal degeneration characterized by a decrease in density of 

large myelinated fibers and loss of epidermal nerves, indicating small sensory nerve involvement 

in thallium toxicity, has been reported (Kuo et al., 2005). The skin experiences parakeratosis and 

vacuolar degeneration of the basal layer, resulting in a loss of epidermal nerves and persistent 

damage to sensory nerve endings (Lu et al., 2007). Collectively, these observations suggest a 

treatment-related effect of thallium on the rats and direct effects on the nervous system. 

 Both potassium and thallium are monovalent cations with similar atomic radii (Tl+: 

1.50 Å; K+: 1.38 Å) (Ibrahim et al., 2006). Thallium has been shown to replace potassium in the 

reaction of Na+

/K+-ATPase (Barrera and Gómez-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 Gómez-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 i.p. dose of thallium (10 mg/kg orally or 

25 mg/kg i.p.), the disruption of Na+

/K+-ATPase activity was found to be reversible. 

 In addition to effects related to interference with potassium transport and function, there 

is evidence that thallium uncouples oxidative phosphorylation, adversely affects protein 

synthesis, reduces the available energy within peripheral nerve axons, and inhibits a number of 

enzymes, including alkaline phosphatase and succinic dehydrogenase (Kazantzis, 2007). 

 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 

54 
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 cross-links during 

posttranslational modification of the nascent polypeptides. Thallium prevents keratinization of 

hair proteins by binding with cysteine and preventing the formation of the cross-linking 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 H17 and M45 (Kanematsu et al., 

1980). However, negative results were obtained in reverse mutation assays using several 

S. typhimurium and E. coli strains and mitogenic gene conversion and reverse mutation tests in 

yeast. Cytotoxic levels (1,000 μg/mL) of thallium (I) acetate caused depressed DNA synthesis in 

CHO cells (Garrett and Lewtas, 1983). Single-strand DNA breaks occurred in C57Bl/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 

day 15 postexposure and caused a 3.5-fold increase in binucleated cells with micronuclei 

(Hantson et al., 1997).

55 
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 compounds. 

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-day-old) rats, 

because 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 that used 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., 1960). 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. 

56 
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. Epidemiologic studies of either the 

general population or occupationally exposed groups are limited by inadequate study design 

and/or insufficient exposure characterization. Thus, available human studies do not provide data 

useful for dose-response analysis. 

 There are only four repeat-dose oral toxicity studies of thallium that used more than one 

dose level: MRI (1988), Wei (1987), Zasukhina et al. (1983), and Downs et al. (1960). Of these 

studies, the subchronic (90-day) toxicity study of thallium (I) sulfate in Sprague-Dawley rats by 

MRI (1988) is the most comprehensive study of thallium toxicity. 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 2/5 female rats at the lowest dose tested in this study was observed and may have been 

treatment related. The repeat-dose dominant lethal study of Zasukhina et al. (1983) suffered 

from critical reporting deficiencies and internal inconsistencies (see Section 4.3). Wei (1987) 

reported effects on sperm count, motility, and viability in Kunming mice exposed to drinking 

water concentrations of thallium (I) carbonate as low as 0.001 mg/L; however, when the treated 

males were mated with untreated females, the reproductive index and number of implantations 

were not affected at drinking water concentrations up to 10 mg/L (10,000-fold higher than the 

concentration identified by the study investigators as the LOAEL for sperm effects). The percent 

of dead fetuses was significantly lower than in the control group at concentrations of 0.001, 0.01, 

and 0.1 mg/L but was increased at the two highest concentrations (1 and 10 mg/L). Although the 

effects on sperm appeared to be dose related, some uncertainty is associated with the reporting of 

study findings (see Sections 4.3 and 4.6.1). Further, the unexplained absence of reported sperm 

results for 20–50% of the male mice in each of the treatment groups lowers confidence in these 

findings. Supporting literature on the reproductive toxicity of thallium is limited. Formigli et al. 

(1986) reported adverse effects on the testes and sperm of rats exposed to thallium sulfate in 

drinking water but at a drinking water concentration 10,000-fold higher than the LOAEL 

reported by Wei (1987). In the absence of confirmatory findings of sperm effects at the low 

drinking water concentrations used in the Wei (1987) study, the study findings were not 

considered sufficiently reliable to serve as the basis for RfD derivation. 

57 
 Other repeat-dose studies of thallium oral toxicity used study designs that included only a 

single-dose group and thus did not provide data useful for dose-response analysis (El-Garawany 

et al., 1990; Rossi et al., 1988; Formigli et al., 1986; Gregotti et al., 1985; Manzo et al., 1983). 

Manzo et al. (1983) reported mortality at the only dose tested, making this study unsuitable for 

RfD derivation. Finally, doses in mg/kg-day could not be estimated from the study information 

provided in Rossi et al. (1988). 

 Based on the above considerations, the 90-day MRI (1988) 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/kg-day Tl). 

No differences in body weight, body weight gains, food consumption, or absolute and relative 

organ weights were observed among control groups and groups receiving thallium sulfate. 

Lacrimation, exophthalmos, and miosis were observed at higher incidences in the treated male 

and female rats at all doses compared with both untreated and vehicle controls (see Table 4-2); 

however, ophthalmologic examination and gross and histopathologic examination of the eyes 

revealed no treatment-related abnormalities. The incidence of clinical observations related to the 

coat and skin (including rough coat, piloerection, shedding, and alopecia) and behavioral 

changes (including combined incidences of aggression, tense/agitated behaviors, hyperactivity, 

vocalization, and self-mutilation) were also elevated in treated male and female rats at all doses 

(see Table 4-2). The investigators attributed most, but not all, instances of alopecia to barbering 

behavior. For example, of the 12 high-dose females with alopecia, 5 instances were not totally 

attributed to barbering. Review of individual animal data revealed no discernable differences in 

either the severity or distribution pattern of alopecia across control and treated groups. 

Histopathologic examination did not reveal any statistically significant treatment-related effects, 

although it was noted that atrophy of the hair follicles occurred in two high-dose female rats. 

Tissue samples of the skin from low- and mid-dose groups, however, were not examined for 

histopathologic changes. Subtle, but statistically significant, changes were observed in several 

blood chemistry parameters (AST, LDH, sodium and blood sugar levels) (see Table 4-4). These 

changes were not confirmed by any histopathologic findings and were not considered by the 

investigators to be toxicologically significant. 

 Although the study authors identified the highest dose (0.20 mg/kg-day Tl) as a NOAEL 

based on lack of biological significance of the observed effects, EPA reached the determination 

that histopathologic findings in the skin of female rats and dose-related clinical findings, when 

considered collectively, may reflect an adverse effect on the health of the rats. 

 As noted above, 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; 

58 
Galván-Arzate and Santamaría, 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). Thus, 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 suggests that alopecia at the highdose (0.2 mg/kg-day Tl) may be related to thallium exposure. This endpoint was considered a 

candidate critical effect for derivation of the RfD. 

 The clinical observations from the MRI (1988) study were also considered as candidate 

critical effects for derivation of the RfD. As discussed in Section 4.6.1, dose-related increases in 

the incidence of lacrimation, exophthalomos, and miosis, coat-related findings, and behavioral 

observations suggest a possible effect on the health of the exposed rats from exposure to 

thallium, although the underlying basis for these observations is unknown. Increased incidences 

of barbering and behavioral changes are consistent with possible effects on the nervous system, a 

known target of thallium. 

 Clinical chemistry changes were not considered as the basis for determining the point of 

departure (POD) for the RfD. At 90 days, AST, LDH, sodium, and sugar levels in the blood of 

high-dose male and female rats differed by +31, +38, +4, and -21%, respectively, from vehicle 

control group values. Even with these changes, these clinical chemistry parameters are all well 

within two standard deviations of the mean for control Sprague-Dawley rats as reported by 

Petterino and Argentino-Storino (2006) and Matsuzawa et al. (1993). In the low-dose group, 

none of the blood chemistry parameters was statistically significantly different from the vehicle 

control group with the exception of the sodium level in female rats, which was increased over 

control values by only 1.4%. In light of these modest changes in blood chemistry parameters and 

the lack of other findings in exposed animals to confirm the biological significance of these 

changes, clinical chemistry parameter data were not selected for dose-response modeling. 

 In summary, two endpoints were considered as potential critical effects for determination 

of the POD for the RfD: (1) hair follicle atrophy in female rats that also had alopecia, and 

(2) clinical observations, including those related to animal coat (rough coat, piloerection, 

shedding, and alopecia), eyes (including lacrimation, exophthalmos, and miosis), and behavior. 

59 
5.1.2. Methods of Analysis 

Hair Follicle Atrophy

 The NOAEL-LOAEL approach was used for dose-response analysis of hair follicle 

atrophy in rats with alopecia. A benchmark dose (BMD) analysis was not conducted because the 

incidence of histopathologically-determined hair follicle atrophy was not considered amenable to 

BMD methods. Histopathological examination of the skin was performed for two groups only—

the high-dose group and vehicle control. Two of 20 female rats in the high-dose group (10%) 

had hair follicle atrophy and alopecia that is consistent with thallium toxicity in both animals and 

humans and was thus characterized by EPA as possibly treatment-related. The high dose 

(0.2 mg/kg-day Tl) was therefore characterized as a LOAEL. Because skin tissue from rats in 

the low- and mid-dose groups was not examined for histopathologic changes, the NOAEL for 

this endpoint cannot be determined with certainty. Given the low incidence of hair follicle 

atrophy in females in the high-dose group and absence of cases of hair follicle atrophy in male 

rats, the mid-dose can reasonably be assumed to approximate a NOAEL for skin histopathology. 

Thus, an estimated NOAEL of 0.04 mg/kg-day Tl was used as the POD for hair follicle atrophy 

from the MRI (1988) study. 

Clinical Observations 

 BMD modeling (U.S. EPA, 2000b) was used to analyze the clinical observation data 

from MRI (1988). Incidence data for the selected clinical observations in male and female rats 

are summarized in Table 5-1. All of the available dichotomous models in U.S. EPA’s BMDS 

(version 1.4.1) (U.S. EPA, 2007) were fit to these incidence data. 

60 
Table 5-1. Incidence data and BMD modeling results for selected clinical observations in 

Sprague-Dawley rats treated with thallium sulfate for 90 daysa 

Dose (mg/kg-day) 

BMD10b 

(mg/kg-day) 

BMDL10b 

(mg/kg-day) 

Untreated 

control

Vehicle 

Observation control 0.008 0.04 0.2 

Male 

Coat/skin 

Rough coat 1/20 3/20 11/20 16/20 19/20 BMD and BMDL well below experimental 

range.d

Piloerection 0/20 0/20 1/20 4/20 13/20 0.020 0.013 

Shedding 0/20 0/20 4/20 10/20 8/20 All dichotomous models in BMDS exhibited 

statistically significant lack of fit.e

Alopecia 2/20 1/20 4/20 9/20 4/20 All dichotomous models in BMDS exhibited 

statistically significant lack of fit.e

Eyes 

Lacrimation 1/20 6/20 19/20 20/20 20/20 BMD and BMDL well below experimental 

range.d

Exophthalmos 1/20 5/20 12/20 20/20 20/20 BMD and BMDL well below experimental 

range.d

Miosis 0/20 1/20 5/20 7/20 15/20 0.0069 0.0039 

Behaviorc 3/20 0/20 7/20 6/20 7/20 All dichotomous models in BMDS exhibited 

statistically significant lack of fit.e

Female 

Coat/skin 

Rough coat 1/20 0/20 1/20 5/20 11/20 0.021f 0.013f

Piloerection 0/20 0/20 0/20 3/20 8/20 0.043f 0.026f

Shedding 0/20 0/20 2/20 3/20 13/20 0.020 0.013 

Alopecia 4/20 1/20 4/20 9/20 12/20 0.018f 0.010f

Eyes 

Lacrimation 7/20 6/20 20/20 20/20 20/20 All dichotomous models in BMDS exhibited 

statistically significant lack of fit.e

Exophthalmos 5/20 6/20 19/20 20/20 20/20 BMD and BMDL well below experimental 

range.d

Miosis 2/20 3/20 1/20 11/20 8/20 All dichotomous models in BMDS exhibited 

statistically significant lack of fit.e

Behaviorc 2/20 2/20 0/20 1/20 7/20 0.14f 0.054f 

61 
Table 5-1. Incidence data and BMD modeling results for selected clinical observations in 

Sprague-Dawley rats treated with thallium sulfate for 90 daysa 

Dose (mg/kg-day) 

Observation 

BMD10b 

(mg/kg-day) 

BMDL10b 

(mg/kg-day) 

Untreated 

control

Vehicle 

control 0.008 0.04 0.2 

a

 Listed as number of animals with the sign observed at least once during the 90-day study. 

b

 BMD10 = Benchmark dose corresponding to a 10% extra risk; BMDL10 = 95% lower bound on the dose corresponding to 

a 10% extra risk. 

c Animals exhibiting one or more behavioral observations at least once during the 90-day study, including the following: 

aggressive, tense/agitated, hyperactive, vocalization, self-mutilation. 

d

 Data set not amenable to modeling because of steep slope of the dose-response curve in low-dose region; BMD and 

BMDL well below experimental range. 

e

 Some data sets shown in this table exhibited a statistically significant lack of fit with the models available in BMDS. 

Where lack of fit is due to characteristics of the dose-response data for high doses, one option sometime used is to adjust 

the data set by eliminating the high-dose group(s) (U.S. EPA, 2000b). In the absence of a mechanistic understanding of 

the biological response or other observed toxicity in the thallium-exposed animals that could explain the dose response at 

the higher doses, dose-response assessment with adjusted data sets (i.e., removing the high-dose group(s)) was not 

performed. 

f

 Reported BMD10 and BMDL10 represent averages of results from several similar model fits. See Appendix B for more 

details. 

Source: MRI (1988). 

 Consistent with EPA (2000b) BMD technical guidance, consideration was given to 

identifying biologically relevant response levels for developing the RfD. A BMR of 10% is 

generally used to facilitate a consistent basis of comparison across assessments and was used for 

these endpoints in the absence of information regarding the level of change considered to be 

biologically significant. Doses (i.e., BMD10 [BMD corresponding to a 10% extra risk] and 

BMDL10 [95% lower bound on the BMD corresponding to a 10% extra risk]) associated with a 

BMR of 10% extra risk are presented in Table 5-1. 

 Details of the BMD modeling conducted for each endpoint presented in Table 5-1 are 

provided in Appendix B. In general, model fit was assessed by a chi-square goodness-of-fit test 

(i.e., models with p < 0.1 failed to meet goodness-of-fit criterion) and visual inspection of the 

respective plots of observed versus predicted values from the various models. BMDL10

estimates from these models that were within a factor of three of each other suggested no 

appreciable model dependence. Fitted models exhibiting adequate fit (i.e., p ≥ 0.1) with Akaike 

Information Criterion (AIC) values within two units of the lowest AIC were considered 

indistinguishable from one another (Burnham and Anderson, 2002), and thus BMD10 and 

BMDL10 values from these models were averaged. Model fits that yielded the same 

mathematical model were counted as a single model for averaging purposes (see Appendix B for 

details). 

 As Table 5-1 shows, clinical observation data sets for female rats were generally more 

amenable to BMD modeling than the male rat data sets. The BMDL10 values for endpoints 

62 
related to the coat/skin in female rats ranged from 0.010 to 0.026 mg/kg-day, a range of only 

2.6-fold. The lowest BMDL10 value for female rats (0.010 mg/kg-day) comes from averaging 

the BMDL10 values from several similar model fits of incidence data for alopecia. As discussed 

in Section 5.1.1, alopecia is a hallmark of thallium poisoning. To the extent that instances of 

alopecia resulted from barbering, the occurrence of alopecia could also be consistent with 

possible effects of thallium on the nervous system, although no direct evidence for neurotoxicity 

was provided. 

 In male rats, the smallest BMDL10 (0.0039 mg/kg-day) is based on data for miosis. 

While elevated in thallium-treated animals, the biological significance of miosis is less clear than 

the collection of effects related to the rats coat and skin. Review of individual animal data from 

the MRI (1988) study revealed that at the high dose, miosis was observed between days 6 to 10 

only, and in the majority of animals (approximately 70%) miosis was observed on only one or 

two days. 

 

5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) 

5.1.3.1. Soluble Thallium Salts: Acetate, Carbonate, Chloride, Nitrate, and Sulfate 

 The principal study considered for RfD derivation – 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 to use 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. Only small differences in the 

toxicity of various water-soluble thallium (I) salts exist in mice, rats, rabbits, and dogs. In 

general, for most laboratory species at an observation period of approximately 1–2 weeks, the 

LD50 or minimum effective dose 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 considered appropriate. 

 Candidate RfD values for thallium were derived using PODs for two endpoints from the 

MRI (1988) study – a NOAEL of 0.04 mg/kg-day Tl for hair follicle atrophy and an average 

BMDL10 of 0.01 mg/kg-day Tl for alopecia (as representative of clinical observations more 

generally). 

 Some degree of uncertainty is associated with both PODs. Hair follicle atrophy was 

reported in the MRI (1988) study only in high-dose female rats. Because skin tissue from the 

low- and mid-dose groups was not examined histopathologically, the NOAEL for this endpoint 

could only be estimated. The biological significance of the dose-related clinical observations in 

rats in the MRI (1988) study is unclear. In general, the collection of clinical observations data is 

63 
relatively subjective and less rigorously measured than endpoints such as clinical chemistry or 

histopathology. While clinical observations reported in the MRI (1988) study could represent an 

indirect measure of stress or possible effects on the nervous system, no direct support for these 

etiologies is available. The increased incidence of alopecia in female rats was dose-related (less 

clearly so in male rats); however, the background incidence of alopecia in control animals and 

attribution of some cases of alopecia by the study authors to barbering behavior introduce 

uncertainty in dose-response analysis of this endpoint. Furthermore, examination of individual 

animal data from the MRI (1988) study revealed no discernable difference in the severity or 

distribution of alopecia across control and treated groups. Effects on the eyes based on clinical 

observations (in particular lacrimation and exophthalmos) were not supported by ophthalmic 

examination or by gross or histopathological examination of the eyes. 

 A total uncertainty factor (UF) of 3,000 (10 for interspecies extrapolation, 10 for 

intraspecies extrapolation, 3 for extrapolation from a subchronic to a chronic study, and 10 for 

database deficiencies) was applied to both PODs to estimate candidate oral RfD values for 

soluble thallium salts. 

• A default interspecies UF 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 UF 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 UF of 3 was applied 

to account for extrapolation from subchronic to chronic exposure duration. Oral 

toxicity data for thallium suggest that an UF of 10 would overestimate the difference 

in response following subchronic and chronic oral exposures. Effects on the coat/skin 

as well as other clinical observations occur within weeks of exposure to thallium (i.e., 

these sensitive effects do not require chronic exposure in order to manifest). 

 

• An UF for LOAEL to NOAEL extrapolation was not needed for hair follicle atrophy 

in rats with alopecia because a NOAEL was estimated from data provided in the 

principal study. 

Similarly, a UF to account for extrapolation from a LOAEL to NOAEL was not used 

for alopecia (as representative of clinical observations) because BMD methods were 

64 
used for dose-response analysis of these endpoints. The current approach is to 

address this extrapolation as one of the considerations in selecting a BMR for BMD 

modeling. In this case, a BMR of 10% increase in the incidence of alopecia was 

selected under the assumption that it represents a minimally biologically significant 

change. 

• 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 Sections 4.3 and 4.6.1). 

No studies of reproductive toxicity of thallium in females or multigeneration 

reproductive toxicity studies 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, these 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 neuropathologic 

examinations were included in the subchronic toxicity studies by MRI (1988) and 

Manzo et al. (1983), but no standard 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 

UF 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 candidate RfDs for thallium (I) are calculated as the POD (NOAEL or BMDL) 

divided by the composite UF, as follows: 

65 
Derivation of candidate RfD based on hair follicle atrophy in animals with alopecia:

 0.04 mg/kg-day Tl ÷ 3000 = 1 x 10-5 mg/kg-day Tl 

Derivation of candidate RfD based on clinical observations/alopecia: 

 0.01 mg/kg-day Tl ÷ 3000 = 3 x 10-6 mg/kg-day Tl 

 The available toxicity database for thallium contains studies that are generally of poor 

quality. The MRI (1988) study that was selected as a candidate principal study suffers from 

certain critical limitations (e.g., high background incidence of alopecia, lack of histopathological 

examination of skin tissue in low- and mid-dose groups, and inadequate examination of objective 

measures of neurotoxicity), and there are particular difficulties in the selection of appropriate 

endpoints. Therefore, even though an RfD would generally be derived with a combined 

uncertainty factor of 3000, an RfD for soluble thallium salts is not derived in this specific case. 

5.1.3.2. Insoluble Thallium Salts: Thallium (III) Oxide

 No oral studies of thallium (III) oxide were found 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 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 

thallium (III) oxide, toxicity information for thallium (I) sulfate cannot be used to inform the 

toxicity of thallium (III) oxide. 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 the distribution of 

thallium (I) and thallium (III) compounds and the 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, a similar distribution of thallium in the tissues was seen (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 LD50 values for thallium (I) acetate (32 mg/kg Tl) and thallium 

(III) oxide (39 mg/kg Tl) in female rats, indicating that lethality may be independent of valence 

66 
state. Whether other endpoints would respond similarly to different valence states of thallium is 

unknown. 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. 

 Overall, the available toxicity information for thallium (III) oxide specifically and 

thallium compounds more generally is insufficient to support derivation of an RfD for thallium 

(III) oxide. 

 

5.1.3.3. Thallium (I) Selenite 

 No toxicity studies of thallium (I) selenite are available. Thallium (I) selenite contains 

monovalent thallium as does thallium (I) sulfate. No information could be found in the 

literature, however, on the water solubility of thallium (I) selenite. In the absence of solubility 

information, toxicity information for thallium (I) sulfate cannot be used to inform the toxicity of 

thallium (I) selenite. Accordingly, the available data do not support derivation of an RfD for 

thallium (I) selenite. 

5.1.4. Candidate RfD Comparison Information 

 PODs and candidate RfD values based on selected studies included in Table 4-5 are 

arrayed in Figures 5-1 to 5-5 and provide perspective on the magnitude of PODs and candidate 

RfD values associated with different toxicity endpoints. These figures should be interpreted with 

caution because the PODs across studies are not necessarily comparable, nor is the confidence in 

the data sets from which the PODs were derived the same. PODs in these figures may be based 

on a LOAEL or a BMDL, and the nature, severity, and incidence of effects occurring at a 

LOAEL are likely to vary. To some extent, the confidence associated with the data sets is 

reflected in the magnitude of the total UF applied to the POD (i.e., the size of the bar); however, 

the text of Sections 5.1.1 and 5.1.2 should be consulted for a more complete understanding of the 

issues associated with each data set. 

 Thallium causes toxicity in a wide range of target organs, including the nervous system, 

kidney, cardiovascular system, liver, skin, reproductive system, and possibly the developing 

fetus. Figure 5-1 provides a graphical display of dose-response information for skin 

histopathology (hair follicle atrophy in female rats with alopecia) based on the 90-day MRI 

(1988) study. Uncertainties in this data set are discussed in Section 5.1.3.1. 

67 
 Figure 5-2 provides a graphical display of dose-response information for clinical 

observations from the 90-day study conducted by MRI (1988). Collectively, the dose-related 

increased incidences of effects on the coat, eyes, and behavior suggest a potential treatmentrelated effect of thallium, possibly including some measure of stress or other effect on the 

nervous system; however, the underlying basis for these clinical observations is unknown. It 

should be noted that Figure 5-2 includes PODs derived using BMDL10 values as the POD for 

those data sets for which a model fit could be obtained from the models in BMDS, as well as a 

reference value derived using the LOAEL as the POD (since some data sets were not fit by the 

models in BMDS). Uncertainties in these data sets are discussed in Section 5.1.3.1. 

 In some studies, doses of thallium that do not affect survival have been shown to affect 

clinical chemistry parameters (e.g., BUN, serum creatinine, bilirubin, and ALT) that may be 

indicative of effects on the kidney and liver. Changes in clinical chemistry parameters observed 

in El-Garawany et al. (1990) are plotted in Figure 5-3. It should be noted that application of a 

composite UF of 10,000, reflecting five areas of uncertainty, indicates that derivation of a 

reference value using such a data set is highly uncertain. In such cases, U.S. EPA (2002) 

recommends that an RfD not be derived. 

 Evidence from experimental animal studies suggests that thallium may produce effects on 

reproductive function. Figure 5-4 includes plots of LOAELs and associated UFs for data sets 

from Formigli et al. (1986) and Wei (1987). Formigli et al. (1986) reported testicular effects in 

rats exposed to thallium sulfate for 60 days but used only a single dose level of thallium. 

Therefore, this study has limited utility for dose-response analysis. Wei (1987) found effects on 

sperm in mice exposed to thallium carbonate at drinking water concentrations as low as 

0.001 mg/L. As discussed in Sections 4.6.1 and 5.1.1, confidence in this study is low because of 

uncertainties associated with estimates of exposure, reporting inconsistencies, and unexplained 

absence of sperm data for male mice in all dose groups (ranging from 20 to 50%). Composite 

UFs of 100,000 and 10,000 were applied to the LOAELs from the Formigli et al. (1986) and Wei 

(1987) data sets. As with the data from El-Garawany et al. (1990), the magnitude of the 

uncertainty associated with these data sets indicates that they are insufficient to support 

derivation of a reference value. 

 In humans, numerous case reports of neuropathy following thallium poisoning have been 

reported. In experimental animals, effects on the nervous system have been most clearly 

observed following oral exposure at levels also associated with increased mortality (e.g., Manzo 

et al. [1983]) or following injection exposure (see Section 4.4.3). Therefore, although the 

nervous system is known to be a target of thallium toxicity, the available studies do not provide 

adequate dose-response information on standard measures of nervous system toxicity at 

nonlethal doses that are appropriate for defining a POD. 

 Figure 5-5 displays PODs for the major targets of toxicity (from Figures 5-1 to 5-4) 

associated with oral exposure to thallium, including skin histopathology, alopecia and other 

68 
69 

general clinical observations, changes in clinical chemistry possibly indicative of the kidney and 

liver as targets of thallium toxicity, and the reproductive system, along with the UFs that would 

be applied for candidate RfD derivation. 
0.000001

0.00001

0.0001

0.001

0.01

0.1

MRI (1988); 90-d rat study (gavage); hair follicle atrophy; NOAEL

Dose (mg/kg-day Tl)

z POD

UF--animal to human 

 UF--human 

variation

 UF--LOAEL to 

NOAEL 

 UF--subchronic 

to chronic 

 UF--database 

deficiencies

 Derived 

candidate RfD

Figure 5-1. POD (mg/kg-day) with corresponding derived candidate reference value that would result changes of the skin (hair follicle atrophy) were used as the critical effect. 

70
1.0E-07

1.0E-061.0E-051.0E-041.0E-031.0E-021.0E-01

MRI (1988); 90-d rat study

(gavage); coat/skinpiloerection/male; BMDL

MRI (1988); 90-d rat study

(gavage); eyes-miosis/male;

BMDL

MRI (1988); 90-d rat study

(gavage); coat/skin-rough

coat/female; BMDL

MRI (1988); 90-d rat study

(gavage); coat/skinpiloerection/female; BMDL

MRI (1988); 90-d rat study

(gavage); coat/skinshedding/female; BMDL

MRI (1988); 90-d rat study

(gavage); coat/skinalopecia/female; BMDL

MRI (1988); 90-d rat study

(gavage); behavior/ female;

BMDL

MRI (1988); 90-day rat study

(gavage); other clinical

Dose (mg/kg-day Tl)

Figure 5-2. PODs (mg/kg-day) with corresponding derived candidate reference values that would resul

from MRI (1988) were used as the critical effect.

71
1.0E-05

1.0E-041.0E-031.0E-021.0E-01

1.0E+00

El-Garawany et al. (1990); 90-d rat study (gavage); clinical chem; LOAEL

Dose (mg/kg-day Tl)

UF--animal to human 

 UF--human 

variation

 UF--LOAEL to 

NOAEL 

 UF--subchronic 

to chronic 

 UF--database 

deficiencies

 Derived 

candidate RfD

z POD

Figure 5-3. POD (mg/kg-day) with corresponding derived candidate reference value that would result changes (suggesting the liver or kidney as a target) were used as the critical effect.

72
1.0E-08

1.0E-071.0E-061.0E-051.0E-041.0E-031.0E-021.0E-01

1.0E+00

Formigli et al. (1986); 60-d rat study (DW);

testicular effects; LOAEL

Wei (1987); 6-month mouse study (DW);

sperm effects; LOAEL

Dose (mg/kg-day Tl)

z POD

UF--animal to human 

 UF--human 

variation

 UF--LOAEL to 

NOAEL 

 UF--subchronic 

to chronic 

 UF--database 

deficiencies

 Derived 

candidate RfD

Figure 5-4. PODs (mg/kg-day) with corresponding derived candidate reference values that would resultoxicity endpoints were used as the critical effect.

73
74

1.0E-081.0E-071.0E-061.0E-051.0E-041.0E-031.0E-021.0E-01

1.0E+00

Skin histopathology Behavior/stress/general

health

Reproduction Clinical chemistry (liver,

kidney)

Dose (mg/kg-day Tl)

Figure 5-5. PODs (mg/kg-day) with corresponding derived candidate reference values that would resuendpoints were used as the critical effect.

UF--ato hum

 UF--h

variat

 UF--L

NOAE

 UF--s

to chr

 UF--d

deficie

 Derive

candi

z POD
5.1.5. 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 considered for the 

principal study in the current assessment (MRI, 1988). (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 candidate RfD values developed in the current assessment. There are no substantive 

differences in the findings and conclusions between the 1986 and 1988 versions of the MRI 

report.) Previous RfD values (adjusted for differences in molecular weight) ranged from 8 × 10–5

to 9 × 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 UF of 3,000 (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 both the previous and current assessments for soluble thallium salts (acetate, carbonate, 

chloride, nitrate, and sulfide) identified the same study as principal, the assessments differed in 

terms of the interpretation of the MRI (1988) findings and method for dose-response analysis. 

Most significantly, the current assessment does not recommend a value for the RfD. 

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. 

75
6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD 

AND DOSE RESPONSE 

6.1. HUMAN HAZARD POTENTIAL

 Thallium is well absorbed from the GI 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 

epidemiologic study reported a negative correlation between thallium exposure and hair loss 

(Brockhaus et al., 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. Neurotoxicity 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. Histopathologic 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 

increases in AST and LDH, which are general indicators of tissue damage (MRI, 1988). 

76
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 histopathologic 

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 90-day MRI (1988) toxicity study in rats; 

however, the increases remained within the range reported in control rats and were not 

accompanied by histopathologic changes of the liver or changes in related clinical chemistry 

parameters (i.e., ALT). 

 Low birth weight is a likely adverse effect of thallium exposure in females (humans and 

animals) exposed during pregnancy. Male mice exposed to thallium were reported to have 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 

reported an association with low birth weight. A survey of children born near a cement plant 

emitting thallium found an increase in congenital malformations over those reported to the 

government; however, the study authors did not consider these malformations to be related to 

thallium exposure because two of the cases were considered attributable to hereditary factors 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’ then offspring) affected bone development and vasomotor reactivity. Chick embryos 

77
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 oral toxicity study of thallium (I) sulfate in Sprague-Dawley rats (MRI, 1988) 

was selected as a potential principal study. PODs for two alternative endpoints from the MRI 

(1988) study were selected for dose-response analysis – (1) hair follicle atrophy in female rats 

with alopecia, and (2) clinical observations, including those related to animal coat (rough coat, 

piloerection, shedding, and alopecia), eyes (including lacrimation, exophthalmos, and miosis), 

and behavior. Using hair follicle atrophy, the high dose (0.2 mg/kg-day Tl) was identified as a 

LOAEL; the mid dose (0.04 mg/kg-day Tl) was considered a NOAEL and was used as a 

candidate POD. For clinical observations, an average BMDL10 of 0.01 mg/kg-day Tl was 

derived using BMD modeling methods. 

 A total uncertainty factor of 3,000 (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 PODs to yield candidate RfD values for thallium in the form of 

soluble thallium salts of 1 × 10-5 mg/kg-day Tl (for hair follicle atrophy) or 3 × 10-6 mg/kg-day 

Tl (for clinical observations). The available toxicity database for thallium contains studies that 

are generally of poor quality. The MRI (1988) study that was selected as a candidate principal 

study suffers from certain critical limitations (e.g., high background incidence of alopecia, lack 

of histopathological examination of skin tissue in low- and mid-dose groups, and inadequate 

examination of objective measures of neurotoxicity), and there are particular difficulties in the 

selection of appropriate endpoints. Therefore, even though an RfD would generally be derived 

with a combined uncertainty factor of 3000, an RfD for soluble thallium salts is not derived in 

this specific case. 

 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. 

78
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APPENDIX A 

Summary of External Peer Review and Public Comments and Disposition 

 The Toxicological Review of Thallium and Compounds (U.S. EPA, 2009) has undergone 

a formal external peer review performed by scientists in accordance with EPA guidance on peer 

review (U.S. EPA, 2006a, 2000a). The external peer reviewers were tasked with providing 

written answers to general questions on the overall assessment and on chemical-specific 

questions in areas of scientific controversy or uncertainty. A summary of significant comments 

made by the external reviewers and EPA’s responses to these comments arranged by charge 

question follow. In many cases the comments of the individual reviewers have been synthesized 

and paraphrased in development of Appendix A. EPA also received scientific comments from 

the public. These comments and EPA’s responses are included in a separate section of this 

appendix.

EXTERNAL PEER REVIEW PANEL COMMENTS 

EPA revised the Toxicological Review to present dose-response analyses for two data sets 

from MRI (1988), hair follicle atrophy and clinical observations, and derived candidate RfDs 

taking the peer reviewers recommendations into account. However, as pointed out by the peer 

reviewers, the MRI (1988) study that was selected as a principal study suffers from certain 

critical limitations (e.g., high background incidence of alopecia, lack of histopathological 

examination of skin tissue in low- and mid-dose groups, and inadequate examination of objective 

measures of neurotoxicity), and there are particular difficulties in the selection of appropriate 

endpoints. For these reasons, an RfD for soluble thallium salts was not derived in this specific 

case. Text explaining the basis for EPA’s decision was added to Section 5.1.3.1. This decision 

is considered consistent with the peer reviewers observations that the toxicity database for 

thallium is weak. EPA has provided responses to the reviewers’ comments in detail below, 

because the derivations of the candidate RfDs were retained in the assessment. 

 The reviewers made several editorial suggestions to clarify specific portions of the text. 

These changes were incorporated in the document as appropriate and are not discussed further. 

I. General Comments 

1. Is the Toxicological Review logical, clear, and concise? Has EPA accurately, clearly, and 

objectively represented and synthesized the scientific evidence for noncancer and cancer 

hazard? 

Comments: Four reviewers considered the Toxicological Review to be clearly written and/or to 

present a critical evaluation of the published literature. One of these reviewers stated that despite 

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considerable shortcomings in the overall database for thallium (which are acknowledged in the 

report), the authors of the review did a good job at synthesizing the available information and 

presenting it in a logical fashion. One reviewer observed that the synthesis was somewhat less 

than ideal in that it was interjected with editorial comments (some from original authors) and that 

it might have been more desirable to present the facts and leave the interpretation to the reader. 

This reviewer also believed that the Toxicological Review did not provide a sufficient review of 

the foreign language material or of environmental surveys. One reviewer stated that the reasons 

for EPA’s reevaluation of the data used as the basis for the RfD currently on IRIS and the 

different conclusion regarding the NOAEL and LOAEL from the MRI (1988) study were not 

fully explained. This reviewer did not consider the comparison of the LOAEL in the MRI study 

with LOAELs from other studies that were three- to ninefold higher to be a “logical argument.” 

 One reviewer noted that EPA’s case for thallium-induced alopecia could have been 

strengthened if the Toxicological Review had included a discussion of the hair growth cycle in 

rats and how a clinical condition such as alopecia can be distinguishable from hair loss 

associated with normal growth cycle in rats. One reviewer stated that the MRI (1988) study 

could have been better described and evaluated. Two reviewers criticized the Toxicological 

Review for rejection of studies (including Zasukhina et al. [1983] and Wei [1987]) that may have 

provided useful information for reasons that were inadequate. One reviewer noted that the title 

Toxicological Review of Thallium and Compounds was a bit unclear and confusing and 

suggested as potential alternatives: Toxicological Review of Thallium and Its Salts or 

Toxicological Review of Thallium and Thallium Compounds. 

 Other comments were provided in response to this general charge question that were 

repeated in response to other more specific charge questions. In these cases, the peer reviewer 

comments (and EPA’s responses) were summarized under the more specific charge question. 

Response: The general structure of a toxicological review is to present a factual summary of 

toxicity studies in Section 4 and critical interpretation/synthesis in Section 5. The study authors’ 

conclusions were presented in Sections 4 and 5 only where necessary (e.g., where it was 

necessary to document that EPA’s interpretation of the study findings differed from the 

authors’.) The comment regarding insufficient consideration of the foreign language literature is 

addressed under general charge question 2. 

 The health effects of thallium exposure were reevaluated in light of the availability of 

new data and the need for an up-to-date assessment for regulatory purposes. The comment 

related to determination of the NOAEL and LOAEL from MRI (1988) is considered further 

under charge question A3. Comparison to LOAELs from other studies was removed. 

 Alopecia was one of a number of potential critical effects considered for dose-response 

analysis. The POD derived from alopecia using BMD modeling was consistent with the PODs 

derived from other related clinical effects. EPA did not consider a discussion of the hair growth 

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cycle in rats and how alopecia can be distinguished from normal cyclical hair loss to be 

necessary. 

 The Toxicological Review was revised to include an expanded discussion of the findings 

from MRI (1988) (see Section 4.2.1.1). 

 The studies by Zasukhina et al. (1983) and Wei (1987) were critically reevaluated. EPA 

again reached the conclusion that the Zasukhina et al. (1983) study suffered from critical 

deficiencies and did not provide a scientifically defensible basis for the oral RfD. More thorough 

justification for this determination was added to Section 4.3. The discussion of the Wei (1987) 

study was revised (Section 4.3 and entry in Table 4-5). In light of the uncertainties associated 

with incomplete reporting and reporting inconsistencies and lack of confirmation of these lowexposure findings on sperm, the Wei (1987) study was not used as the principal study (see 

discussions in Sections 4.6.1 and 5.1.1). Nevertheless, the study was included in Section 5.1.5, 

Candidate RfD Comparison Information. See also the response to charge question A.1 for 

additional response to this comment related to consideration of other studies. 

 The title, Toxicological Review of Thallium and Compounds, was retained for 

consistency with other similar assessments on the IRIS database. 

2. Please identify any additional studies that should be considered in the assessment of the 

noncancer and cancer health effects of thallium and thallium compounds. 

Comments: Three reviewers did not identify any additional studies that should be included in 

the assessment. One of these reviewers noted that a rapid Medline search identified several 

articles dealing with thallium toxicity that were not cited in the Toxicological Review; however, 

this reviewer did not review the studies to determine whether they provided important new 

additional information. Other reviewers identified the following thallium studies that were not 

cited in the Toxicological Review: 

• Cavanagh, JB. (1988) Book chapter in Recent Advances in Nervous System Toxicology, Vol. 100, pp. 

177–202 Galli, GL; Manzo, L; Spencer, PS, eds. New York: Plenum Press. 

• Kazantzis, G. (2007) Thallium. In: Nordberg, GF; Fowler, BA; Nordberg, M; et al.; eds. Handbook on the 

toxicology of metals. New York, NY: Elsevier; pp. 827–837. 

• Granero, S; Domingo, JL. (2002) Levels of metals in soils of Alcalá de Henares, Spain: human health 

risks. Environ Int 28(3):159–164. 

• Kennedy, P; Cavanagh, JB. (1977) Sensory neuropathy produced in the cat with thallous acetate. Acta 

Neuropathol 39:81–88. 

• Windebank, AJ. (1986) Specific inhibition of myelination of lead in vitro; comparison with arsenic, 

thallium and mercury. Exp Neurol 94:203–212. 

 One of the reviewers noted that the foreign literature may be very significant. This 

reviewer identified the following papers and suggested these and other foreign language 

literature be translated and included in the review: 

• Kamil'dzhanov, AKh. (1993) [Experimental substantiation of maximum permissible concentration of 

thallium carbonate in environmental air]. Gig Sanit 5:8–10. 

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• Gerasimova, IL. (1991) [Establishment of MPEL for thallium iodide activated cesium iodide in the 

working zone air]. Gig Tr Prof Zabol 1:31. 

• Viereck, L; Kramer, M; Eikmann, T; et al. (1990) [Determining guidelines for metals in children’s 

playgrounds in North Rhine-Westphalia]. Öffentl Gesundheitswes 53(1):7–15. 

• Krasovskiĭ, GN; Kenesariev, UI. (1984) [Methodological outline for the experimental substantiation of a 

system of indices of the adverse effect of metals on the health status of the population (the example of 

thallium)]. Gig Sanit 2:22–25. 

• Zasukhina, GD; Vasil'eva, IM; Sdirkova, NI.(1980) [Approach to the determination of the mutagenic 

potential of environmental pollutants with the example of detecting the mutagenic action of thallium 

carbonate]. Dokl Akad Nauk SSSR 250(3):766–768. 

 One reviewer noted that “over-grooming” in any species may be a sign of stress, pain, or 

other changes in the central or peripheral nervous systems and provided the following references 

that address this issue: 

• Greer, JM; Capecchi, MR. (2002) Hoxb8 is required for normal grooming behavior in mice. Neuron 

33:23–34. 

• Kalueff, AV; Tuohimaa, P. (2005) Contrasting grooming phenotypes in three mouse strains markedly 

different in anxiety and activity (129S1, BALB/c and NMRI). Behav Brain Res 160:1–10. 

• Kalueff, AV; Minasyan, A; Keisala, T; et al. (2006) Hair barbering in mice: implications for 

neurobehavioral research. Behav Proc 71:8–15. 

• Welch, JM; Lu, J; Rodriguiz, RM; et al. (2007) Cortico-striatal synaptic defects and OCD-like behaviours 

in Sapap3-mutant mice. Nature 448:894–900.

 In addition, one reviewer noted that some of the cited references that include 

experimental studies using more than the LD50 values have little significance to the toxicity of 

thallium because of the high dose and suggested deleting most of them from the Toxicological 

Review. 

Response: Information from the papers on thallium toxicity by Cavanagh and colleagues, 

Windebank, and Kazantzis was added to relevant sections of the Toxicological Review. A 

discussion of the evidence that over-grooming may be indicative of effects on the nervous 

system was also added, including citations to the papers identified above. 

 The paper by Granero and Domingo (2002) presented a risk assessment for 12 metals in 

soil in a region of Spain. For thallium, the EPA RfD previously on IRIS was used in the risk 

assessment. No further discussion of health effects information for thallium was presented. 

 Three of the studies from the foreign literature identified by one reviewer appear to 

address the derivation of regulatory limits (Kamil'dzhanov, 1993; Gerasimova, 1991; Viereck et 

al., 1990); limits developed by other regulatory agencies are generally not included in IRIS 

toxicological reviews. Therefore, these papers from the foreign language literature were not 

considered useful additions to the thallium toxicological review. The paper (in Russian) by 

Zasukhina et al. (1980) appears to be the same as the Zasukhina et al. (1983) paper published in 

English. 

 In general, a toxicological review is not intended to be a comprehensive treatise (see 

Foreword to the thallium Toxicological Review). EPA acknowledges that additional literature on 

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thallium may be available; however, EPA considers all literature that has a bearing on the 

derivation of toxicity reference values to have been included in the Toxicological Review. 

3. Please discuss research that you think would be likely to increase confidence in the database 

for future assessments of thallium and compounds. 

Comments: Several reviewers noted that the toxicity database for thallium is very limited. 

Research suggested by the reviewers to increase the confidence in the thallium database included 

the following study types and suggestions for investigation of specific endpoints: 

• Acute dose-range finding studies and, if needed, a chronic inhalation study to identify the 

hazard of inhaled thallium. 

• A chronic bioassay that would provide information on chronic noncancer effects and 

cancer endpoints. (One reviewer noted that such studies are expensive and timeconsuming, and sources of funding may be difficult to find.) 

• Studies of general reproductive toxicity (in particular to improve the ability to interpret 

the results in Kunming mice observed by Wei). 

• Studies of developmental toxicity and developmental neurotoxicity. 

• A modern in vivo genotoxicity evaluation. Depending on the outcome of a genotoxicity 

assessment, the value of conducting a lifetime chronic bioassay could be weighed. 

• A much larger human investigation of an exposed population. (The reviewer noted that a 

human investigation would be very costly and that an animal model might be more 

practical.) 

• Endpoints that the various reviewers suggested would be better characterized in studies of 

subchronic or chronic duration included alopecia and its sequelae and neurological, 

reproductive, endocrine, and cardiovascular endpoints. 

• Additional clinical chemistry, functional, and histopathologic assessments to determine 

the source and intensity of the clinical chemistry changes observed in the MRI (1988) 

subchronic study. 

• Studies that more accurately define dose-response relationship for males and females 

with appropriate dose ranges that capture the alopecia endpoint, including supportive 

histopathologic examination of alopecia skin and apparently unaffected skin areas of all 

treated and untreated animals and supportive in vivo and in vitro experiments 

demonstrating thallium interaction with hair follicles at various stages of the hair cycle in 

both males and females. 

• More information on the interaction of thallium with trace elements such as selenium and 

potassium. 

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• More studies on the potential mechanisms of action of thallium, including alopecia and 

neurotoxicity (as perhaps the most economical way of addressing uncertainties about the 

target organs for thallium and the plausibility of some of the responses that have been 

observed). 

• Studies to establish whether absorption, distribution, and elimination of thallium are 

linear following oral and dermal absorption of thallium salts. 

• Studies on metabolism of thallium that address the question as to whether the body has 

the capability to convert thallium from one valence state to the other to determine the 

extent to which studies on monovalent thallium are relevant to the toxicity of trivalent 

thallium. (The reviewer noted that if there is little or no conversion, then it will be 

important to characterize the toxicity of trivalent thallium separately.) 

• Pharmacokinetic studies that would support the development of a physiologically based 

pharmacokinetic model for thallium (to better understand thallium dosimetry) as well as 

relative toxicity and pharmacokinetics of the various thallium salts. 

Response: No response required. 

4. Please comment on the identification and characterization of sources of uncertainty in 

Sections 5 and 6 of the assessment document. Please comment on whether the key sources 

of uncertainty have been adequately discussed. Have the choices and assumptions made in 

the discussion of uncertainty been transparently and objectively described? Has the impact 

of the uncertainty on the assessment been transparently and objectively described? 

Comments: Three reviewers observed that the sources of uncertainty were adequately addressed 

and that the discussion of uncertainty was comprehensive. One reviewer considered alopecia to 

be an acceptable marker of thallium toxicity until better markers become available, at least for 

female rats, but further noted that it may be difficult to use alopecia as a reliable marker in male 

rats in the absence of a statistically significant dose response effect for alopecia in males. 

 One reviewer observed that the very limited data set for thallium can be further 

appreciated by comparing the proposed RfD of 1 × 10–5 mg/kg-day (0.01 μg/kg-day) to 

background exposure to environmental levels of thallium. This RfD suggests that a 70 kg adult 

can consume 0.7 μg/day. The 90th percentile adult urinary thallium elimination from NHANES 

is 0.380–0.390 μg/L, which is about 0.760–0.780 μg/day in the urine alone. Because thallium 

has substantial fecal elimination, this suggests that, if the RfD is adopted, greater than 10% of 

Americans, and in reality probably close to 50% of Americans, would ingest more than the RfD. 

Because there is no evidence that thallium in the current U.S. diet poses any threat and because 

there is no possible remediation, this reviewer noted that adoption of this RfD would produce 

unnecessary concern if the above calculation were correct. This reviewer further noted that a 

A-6
more thorough use of the MRI (1988) study would probably further lower the RfD, suggesting 

possibly that the entire U.S. population is exposed above threshold. This reviewer considered 

such an analysis to be an example of how poor the existing data are and further questioned the 

validity of the analysis. 

 Five reviewers agreed that the Toxicological Review correctly characterized confidence in 

the RfD for thallium as low and/or that the thallium database is weak. In light of this low 

confidence, one of these reviews offered the opinion that it may be better to suggest a range of 

RfD values for thallium by using various UFs because of uncertain endpoint, inadequate 

scientific data, and high UFs. A second reviewer stated that, in light of the weakness of the data 

set, it is important to openly discuss in the document the pros and cons of calculating an IRIS 

RfD for thallium. A third reviewer noted that the available data are so poor that it was 

questionable whether such an analysis is even valid. A fourth reviewer considered the low 

confidence to be a reflection of the limited database, including the lack of studies addressing the 

known toxic effects of thallium, particularly neurotoxicity, developmental toxicity, and 

endocrine effects, failure of the MRI (1988) study to identify a NOAEL if all relevant endpoints 

are considered, and consideration of other studies rejected by EPA that suggest that effects may 

occur at lower doses than in the MRI study. 

 Other comments offered on specific UFs are summarized under charge question A5 along 

with EPA’s response. 

Response: In response to the reviewer who suggested that different UFs be used for males and 

females, EPA observes that the overall thallium database does not suggest appreciable gender 

differences in response to thallium (see Section 4.8.2) and that the development of genderspecific reference values is not supported. 

 EPA disagrees with the suggestion that a range of RfD values be developed by using 

various UFs because of uncertain endpoint, inadequate scientific data, and high UFs. Comments 

from the peer reviewers in response to charge questions A5 and A6 provide little agreement on 

alternative UFs. EPA considers the limitations in the database for thallium not to support an UF 

smaller than 3,000, and therefore a range of RfD values based on different composite UFs is not 

scientifically justified. 

 A summary of NHANES biomonitoring data was added to Section 3.4. Because an 

assessment of potential exposure is generally outside the scope of an IRIS assessment, a 

discussion of estimated intakes from background sources of thallium was not included in the 

Toxicological Review. 

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II. Chemical-Specific Charge Questions

A. Oral Reference Dose (RfD) for Thallium 

A1. The 90-day oral gavage study by MRI (1988) was selected as the basis for the RfD. Please 

comment on whether the selection of this study as the principal study has been 

scientifically justified. Has this study been transparently and objectively described in the 

document? Please identify and provide the rationale for any other studies that should be 

selected as the principal study. 

Comments: Four reviewers generally agreed with the selection of the MRI (1988) study as the 

most appropriate basis for the RfD. One reviewer noted that this study may be an acceptable 

basis for the RfD, although this was not clear without further analysis of other studies. One other 

reviewer raised significant concerns about the study, including the fact that the choice of animal 

model, the doses given, and the duration of investigation were not well substantiated; sample 

size, statistical analysis, and calculations were not presented; and there was lack of publication in 

a peer-reviewed journal. This reviewer did not identify an alternative study to use as the basis 

for the RfD. 

 Several reviewers recommended that the summary of the MRI (1988) study be expanded 

to include additional study details. One reviewer suggested that the Toxicological Review

provide a better time line for the appearance of alopecia as well as hair loss associated with the 

normal hair cycle in the rat and a better description of the distribution pattern of alopecia. Four 

reviewers indicated that other toxicological endpoints (including LDH activity, exophthalmos, 

lacrimation, and miosis) needed to be better presented/explained. 

 One reviewer noted that the Toxicological Review considered one or two other studies for 

use as the principal study and that a good rationale was provided as to why they were not as good 

a choice as the MRI study. A second reviewer stated that he was not aware of any other study 

that could have been used as a primary study to derive the POD and the RfD but, given the 

paucity of data available, suggested that other studies could be analyzed more in depth and 

information compared to that obtained from the MRI study. Three reviewers indicated that 

EPA’s justification for excluding other in vivo studies as the principal studies were not 

sufficient. One of these reviewers recommended that RfDs be derived from the other endpoints 

identified in the MRI study and from the Wei (1987) and Zasukhina et al. (1983) studies and the 

results compared to determine where the MRI study lies with respect to sensitivity. One 

reviewer observed that epidemiologic studies would be ideal, but all available epidemiologic 

studies provided limited evidence of cause and effect associated with exposure in food or 

inhalation. 

A-8
Response: Consistent with the feedback from the majority of reviewers, the MRI (1988) study 

was retained as a potential principal study. This study was subject to an independent peer review 

(as noted in Section 4.2.1.1). None of these independent reviewers considered the study to be 

inadequate as the basis for the RfD. 

 The summary of the MRI (1988) findings, including LDH activity, exophthalmos, 

lacrimation, and miosis, was expanded in the Toxicological Review, Section 4.2.1.1. Information 

on the time that alopecia was first observed was also added to this section based on examination 

of individual animal observational findings in the MRI (1988) study. Across control and treated 

groups, alopecia was first observed somewhere between study days 44 and 60. Severity scores 

across control and treated groups ranged from 1 to 5. There were no discernable differences in 

either the severity or distribution pattern of alopecia across control and treated groups. 

 Further consideration was given to the use of other in vivo studies as the basis for the 

RfD (see Sections 5.1.1 and 5.1.5). Where certain in vivo studies were not considered by EPA to 

be sufficiently reliable as the basis for the POD, more thorough justification was provided (see 

Section 5.1.1). Expanded discussion of the limitations of the Zasukhina et al. (1983) study was 

added to Section 4.3. As noted in response to general charge question 1, the discussion of the 

Wei (1987) study was revised (Section 4.3), and the study findings were further considered as 

the potential basis for the POD in Sections 5.1.1 and 5.1.5. For the reasons discussed in Sections 

4.6.1 and 5.1.1, the Wei (1987) study was not considered sufficiently reliable as the basis for the 

RfD. 

A2. Alopecia (hair loss) was selected as the most appropriate critical effect for the RfD. EPA 

characterizes alopecia as being an adverse effect. Please comment on whether the science 

and mode-of-action information supports alopecia as an adverse effect. EPA has stated: 

“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 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 an adverse effect.” Please comment on whether the selection of this critical 

effect has been scientifically justified. Is EPA’s choice transparently and objectively 

described in the document? Please provide a detailed explanation. Please identify and 

provide the rationale for any other endpoints that should be used instead of alopecia to 

develop the RfD. 

Comments: Three reviewers agreed that alopecia should be considered an adverse effect in and 

of itself. One reviewer considered alopecia to be undesirable. Another reviewer considered 

alopecia with histopathology of the hair follicle to be adverse. A final reviewer stated that use of 

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alopecia “as a biomarker” is justified until a better marker for adverse effect such as neurotoxic 

effects is identified. Several reviewers observed that the fact that alopecia may be reversible 

does not influence its adversity, whereas one review stated that a drawback to the use of alopecia 

as an endpoint for RfD is that it is a reversible effect. Reviewers pointed to other limitations in 

the use of alopecia as the critical effect. One reviewer considered limitations to the alopecia data 

set to be the facts that histopathology was only noted in the assigned LOAEL dose group and 

was not examined in the assigned NOAEL and lower dose groups and that there is no evidence 

that the skin sections examined were from the alopecia areas of the skin. A second reviewer 

considered a drawback to be that the MRI (1988) study did not show a statistically significant 

dose-response effect for alopecia in male rats. One reviewer suggested that the Toxicological 

Review could provide a more detailed discussion of mechanisms of alopecia, particularly with 

regard to thallium. 

 Two reviewers disagreed with the use of alopecia as the critical effect for RfD 

determination for thallium. One reviewer based this opinion on the fact that it was not clear to 

this reviewer from either the description of the study or the peer review of the study as to 

whether this effect was really treatment related. This reviewer noted that there was a high 

background incidence of alopecia in the study population and that the observation in the study of 

“barbering behavior” in the animals may have accounted for much of the alopecia. It was this 

reviewer’s experience with lab animals that there can be any number of reasons for hair loss, 

including changes in caging or husbandry, and the fact that there was such a high background 

incidence of alopecia suggested that the effect could have been unrelated to treatment. A second 

reviewer disagreed with the choice of alopecia in the MRI (1988) study because several findings 

(changes in biochemical parameters, exophthalmos, miosis, and changes in coat) appear to show 

better dose-response effects than alopecia. 

 In response to this and charge question A3, four reviewers suggested that other effects be 

considered as the basis for the RfD, including clinical chemistry, exophthalmos, miosis, changes 

in coat, lacrimation, and behavioral effects that appear to show dose-response effects and could 

be more defensible than alopecia as the critical effect. 

 One reviewer stated that data from several limited subchronic studies (Wei, 1987; 

Formigli et al., 1986) and in vitro studies (Gregotti et al., 1992) suggested that reproductive 

(especially male) endpoints are worthy of further investigation. This reviewer noted that these 

studies were poorly reported by the authors, and a dose-response relationship was difficult to 

ascertain, but that this was “however a poor excuse for not attempting to determine a doseresponse relationship and providing NOAELs and BMDLs.” This reviewer pointed to the study 

by Galván-Arzate et al. (2005) that describes a dose-related increase in thallium deposition in the 

brain and lipid peroxidation in male Wistar rats after 30 day exposure to 0.8 mg/kg or 1.6 mg/kg 

doses. This reviewer also suggested that EPA provide a more critical review of the 36-week oral 

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study by Manzo et al. (1983) that described in some detail functional and histopathologic 

changes in the peripheral nervous system. 

Response: Consistent with the position of three reviewers who agreed that alopecia is an adverse 

effect, alopecia was considered along with other clinical observations that showed an increased 

incidence with dose (see Table 5-1) as a candidate critical effect for establishing the POD for the 

RfD and as part of a spectrum of clinical observations in thallium-exposed rats. The limitations 

in the skin histopathology data were recognized (see Sections 4.2.1.1 and 5.1.1). EPA 

acknowledges that the incidence of alopecia in male rats does not increase monotonically with 

dose, although the incidence is higher in all groups of treated male rats compared with untreated 

and vehicle controls. Further, the incidences of other clinical observations were increased in 

treated male rats over the control groups, consistent with a treatment-related effect in male rats. 

Available information on the mechanism by which thallium induces alopecia is presented in 

Sections 4.5.5 and 4.6.3. 

 Consistent with the input from the reviewers, EPA expanded the analysis of the critical 

effect to include other clinical observations that showed a dose-response effect, including 

observations related to coat, lacrimation, exophthalmos, miosis, and behavior. For the reasons 

presented in Section 5.1.1, changes in clinical chemistry parameters were not considered as the 

basis for the POD. EPA acknowledges that other factors such as caging and husbandry can 

cause alopecia in laboratory rodents; however, the incidence was clearly elevated in both male 

and female rats over controls. Further, to the extent that alopecia was due to barbering, research 

has shown that barbering in rodents can reflect a stress-evoked behavioral response (see Section 

4.6.1). Accordingly, EPA retained alopecia as one of a set of clinical observations that were 

indicative of a potential treatment-related effect in rats. Limitations in clinical observation data 

were further discussed in Section 5.1.3.1. 

 EPA reconsidered the findings from other studies, including Galván-Arzate et al. (2000), 

Gregotti et al. (1992, 1985), Wei (1987), Formigli et al. (1986), and Manzo et al. (1983), as the 

basis for the critical effect. As discussed in Section 5.1.1, Formigli et al. (1986), Gregotti et al. 

(1985), and Manzo et al. (1983) were all single-dose studies and thus did not provide data useful 

for dose-response analysis. In addition, these studies administered doses higher than those used 

in the MRI (1988) study and therefore provided less information on low-dose toxicity. In vitro 

studies such as Gregotti et al. (1992) and single administration studies such as Galván-Arzate et 

al. (2005) do not provide information appropriate for characterization of long-term oral exposure 

to thallium. The Wei (1987) study was considered further as the basis for the POD for the oral 

RfD (see Section 5.1.5). In response to one reviewer comment, EPA reexamined the discussion 

of the Manzo et al. (1983) study in Section 4.2.1.1 and determined it to be adequate. Given the 

increased mortality in thallium-exposed rats at 40 and 240 days after treatment and the fact that 

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only a single dose level was used in this study, Manzo et al. (1983) was not considered 

appropriate as a principal study for RfD derivation. 

A3. At the high dose in the MRI (1988) study, two female rats exhibited moderate to severe 

alopecia that could not be attributed to self-barbering or normal cyclic hair growth. 

Histologic examination of skin samples from these high-dose females showed atrophy of 

hair follicles. EPA considered these findings to be adverse and thus the high dose in this 

study (0.25 mg/kg-day thallium sulfate) to be the lowest-observed-adverse-effect level 

(LOAEL). The mid-dose group (0.05 mg/kg-day thallium sulfate) was identified as the noobserved-adverse-effect level (NOAEL). Is EPA’s interpretation of the study findings 

scientifically justified? Has this interpretation of the findings been transparently and 

objectively described in the document? 

 As part of the evaluation of alopecia as a critical effect for the RfD, EPA performed a 

series of Fisher’s exact tests to determine if the incidence of alopecia in any of the three 

dose groups was statistically significantly elevated above controls by using all cases of 

alopecia reported by MRI (1988). Please comment on whether EPA chose the appropriate 

data set and the appropriate statistical test for this analysis. 

 The study investigators reached a different interpretation of the study findings than did 

EPA. The investigators considered alopecia to be attributable to the cyclic pattern of hair 

growth in rodents and, consequently, did not consider these findings to be biologically 

significant. The high dose (0.25 mg/kg-day thallium sulfate) was identified in the MRI 

(1988) study as the NOAEL. Is the study authors’ conclusion that the high dose (0.25 

mg/kg-day thallium sulfate) represents a NOAEL justified and supported by the study data? 

Comments: One reviewer offered the opinion that EPA correctly identified an adverse effect that 

cannot be “attributable to the cyclic pattern of hair growth in rodents.” This reviewer stated that 

EPA needs to clearly define what a NOAEL is versus a LOAEL as it pertains to alopecia; the 

Toxicological Review needs to make clear whether a dose of 0.04 mg/kg that caused significant 

incidence of alopecia with no evidence of histopathologic change in skin/hair follicle is a 

NOAEL. A second reviewer could not fully agree with lowering the NOAEL value to 

0.05 mg/kg because it was based on a change in interpretation of the data rather than any new 

scientific evidence and because male rats did not show a statistically significant dose response 

for alopecia. 

 One reviewer considered the high dose of thallium (0.2 mg/kg-day), and possibly the 

middle dose (0.04 mg/kg), to be a LOAEL rather than a NOAEL. This reviewer also considered 

data on the incidence of alopecia not attributable to barbering to be amenable to BMD modeling. 

A-12
 One reviewer found it difficult to conclude definitively that the alopecia in two animals 

with hair follicle atrophy was in fact treatment related. This reviewer noted that hair follicles go 

through a natural cycle of activity and inactivity; it was not clear from the descriptions of atrophy 

that what was being observed was anything more than an observation of a normal condition in 

these animals; there was no systematic evaluation of dermal tissue from other areas in the same 

animals; and there was no evaluation of hair follicle status in all dose groups. Because this is not 

a standard assessment in subchronic studies, it was not possible to know whether what was 

observed is within the range of normal. 

 One reviewer found the use of alopecia findings to be questionable, noting that the middose group also had alopecia and, although it may have been a result of barbering, barbering is 

not a normal behavior and suggests that the animals were under stress, possibly in pain; thus, this 

dose level could not be a NOAEL. This reviewer also stated that it was not valid to discount a 

sex difference because sex may affect sensitivity to a given toxin. Finally, this reviewer noted 

that other parameters that show a dose-response relationship might be amenable to BMD 

analysis. 

 One reviewer observed that the incidences of alopecia in middle- and high-dose groups 

were both significantly different from controls, whereas EPA considered the middle dose to 

represent a NOAEL with no explanation. It appeared to this reviewer that EPA considers hair 

follicle atrophy to be the adverse effect. Because histopathologically observed atrophy was 

examined only at the high dose, this reviewer believed that the high dose should be considered a 

LOAEL for hair follicle atrophy and a UF of 10 applied. More importantly, this reviewer 

believed that barbering represents a change in behavior (e.g., caused by pain, an increased 

arousal level, or stress) and should be considered an adverse effect. This reviewer noted that 

barbering increased in a dose-dependent manner. This reviewer considered many of the 

endpoints in the rat study to be consistent with neurological effects in humans and that they 

should not have been dismissed. This reviewer considered the lowest dose to be a LOAEL. 

 One reviewer suggested that EPA recognize in their review that there are possible 

estrogen receptor pathways within the dermal papilla that regulate the telogen-anagen follicle 

transition and that diffusible factors associated with the anagen follicle influence cell 

proliferation in the epidermis (Oh and Smart, 1996). This may explain male versus female 

differences observed in the MRI study. 

Response: In response to peer reviewer comments, EPA broadened the evaluation of the MRI 

(1988) study findings beyond alopecia in the presence of hair follicle atrophy to include all 

clinical observations in male and female rats and presented the possibility that the dose-related 

increase in the incidence of clinical effects indicated a possible treatment-related effect. EPA 

identified two possible critical effects from the MRI (1988) study – hair follicle atrophy and 

clinical observations – reflecting different interpretations of MRI study findings. With respect to 

A-13
hair follicle atrophy, EPA in Section 5.1.2 clarified that skin tissue was not examined for 

histopathological changes in the low- and mid-dose groups. The mid-dose group was assumed to 

approximate a NOAEL for this endpoint in light of the low incidence of hair follicle atrophy in 

high-dose female rats and absence in male rats at all dose levels. EPA acknowledges this to be a 

change in the interpretation of the data that was made in light of all relevant literature on 

thallium toxicity and considered this to be an appropriate basis for reaching a different 

determination of the NOAEL and LOAEL from the authors of the MRI (1988) study. 

 In the revised discussion of alopecia and other clinical observations, EPA considered the 

possibility that barbering may indicate that animals were under stress or that barbering (and other 

clinical observations) may reflect some other change in behavior (e.g., see Section 4.6.1). 

 As suggested by several reviewers, BMD methodology was applied to the various clinical 

observation data sets and was used to derive the potential PODs, including the POD for alopecia. 

 EPA appreciated one reviewer’s suggestion of a possible estrogen receptor pathway as an 

underlying basis for alopecia; however, there is no evidence in the thallium toxicity literature for 

such a mode of action. Because of the lack of data to support this hypothesis, it was not added to 

the Toxicological Review. 

 In Section 4.8.1, EPA concluded that the available thallium toxicity literature as a whole 

showed no consistent pattern of gender-related difference in toxicity. 

Comments: Two reviewers considered the nonparametric statistical analysis using Fisher’s exact 

test to be appropriate. One of the reviewers, however, noted that the choice to include all 

animals that had alopecia is problematic, especially given that the study investigators did not 

attribute all instances of alopecia to thallium treatment. A third reviewer stated that a Fisher’s 

exact test is a standard procedure for pair-wise comparisons but fails to take advantage of the fact 

that there are three dose groups. This reviewer suggested that a more appropriate analysis would 

be a trend analysis. A fourth reviewer stated that, whereas a Fisher’s exact test is specifically 

designed for a simple comparison, a more complex analysis is generally performed in a doseresponse relationship and it is quite likely that there would be no significance had that approach 

been taken. 

Response: As noted previously, EPA revised the dose-response analysis to include consideration 

of a range of clinical observations and used a BMD approach in place of a NOAEL/LOAEL 

approach for identifying a POD. Therefore, less importance was placed on pair-wise comparison 

as the basis for identifying a NOAEL and LOAEL from the MRI (1988) study. 

Comments: Two reviewers specifically commented on the study authors’ identification of the 

NOAEL. One reviewer stated that the conclusion as to whether the observation of alopecia is an 

adverse one is a matter of judgment and that the investigators who wrote the original study report 

A-14
had a different interpretation of the alopecia; however, it was less clear to this reviewer why they 

concluded that the clinical chemistry observations or exophthalmos were not adverse. A second 

reviewer noted that the presence of follicle changes suggests that this was truly a toxic effect and 

that barbering represented stress and possibly pain. This reviewer further noted that the study 

investigators’ interpretation of these data added considerable doubt on their ability to interpret 

the other findings in their study and further calls into question the choice of this study as the 

critical data for determining the RfD. 

Response: EPA disagrees with the reviewer who called into question the choice of the MRI 

(1988) study as a potential principal study because of doubt about the ability of the study authors 

to interpret study findings. EPA notes that this study was subject to an independent peer review. 

The peer reviewers of the MRI (1988) study generally found the study to have been conducted 

according to guideline protocols in place at the time. Further, EPA reached its own conclusions 

based on an independent review of study findings and did not rely only on the authors’ 

interpretation of the data. Accordingly, EPA considers the selection of the MRI (1988) study as 

a principal study to be supported, although it suffers from some limitations. Limitations in study 

design and uncertainties in data sets from MRI (1988) were addressed in Section 5.1.3.1. 

 Additional comments in response to this charge question, related to the consideration of 

other endpoints as critical effects, are summarized under charge question A2. 

A4. The traditional NOAEL-LOAEL approach was used to define the point of departure (POD) 

for the RfD. A benchmark dose (BMD) analysis was considered but was not conducted 

because of the nature of the data set for alopecia. Please provide comments with regards to 

whether a NOAEL-LOAEL approach is the best approach for determining the POD. Has 

the approach been scientifically justified? Is it transparently and objectively described? 

Please identify and provide a rationale for any alternative approaches for the determination 

of the POD and if such approaches are preferred to EPA’s approach. 

Comments: Five reviewers agreed that the NOAEL-LOAEL approach is the most appropriate 

method to define the POD if it is derived using data for alopecia. One reviewer stated that, if the 

LOAEL-NOAEL approach from the MRI (1988) study is used, the lowest dose should be the 

POD as a LOAEL. 

 Five reviewers noted that there are data sets for other endpoints from the MRI (1988) 

study (e.g., exophthalmos, lacrimation, blood chemistry) for which BMD modeling should be 

considered. One of these reviewers also noted that the BMD approach should be tried for each 

of the endpoints that exhibits a dose-response relationship in the Wei (1987) and Zasukhina et al. 

(1983) studies. In this case, the POD used to derive the RfD may be the lowest BMDL, the one 

that EPA thinks is the most reliable or most orderly under analysis, or some kind of average. 

A-15
 One reviewer suggested deriving a range of RfD values rather than a single RfD value. 

Response: BMD modeling of all appropriate data sets from the MRI (1988) study was 

conducted and presented in Appendix B of the Toxicological Review. BMD modeling was not 

performed for the Zasukhina et al. (1983) study because, as discussed in the response to charge 

question A1 comments, the study results were not considered scientifically reliable. The Wei 

(1987) study was included in Section 5.1.5, Candidate RfD Comparison Information, and the 

LOAEL was considered as a potential POD. Given the uncertainties associated with incomplete 

reporting and the lack of confirmatory findings at dose levels close to those used in the Wei 

(1987) study, data sets from this study were not analyzed using BMD methods. 

 As noted in response to general charge question 4 comments, it is EPA’s general practice 

in developing IRIS reference values to derive a single value and not a range. 

A5. Please comment on the selection of the uncertainty factors applied to the POD for the 

derivation of the RfD. For instance, are they scientifically justified and transparently and 

objectively described in the document? If changes to the selected uncertainty factors are 

proposed, please identify and provide a rationale(s). 

Comments: None of the reviewers disagreed with the UF applied for interspecies or LOAEL to 

NOAEL extrapolation. Two reviewers questioned the need for application of an intraspecies UF. 

(One of these comments was offered in response to general charge question 4 but is summarized 

here.) In one case, this opinion was based on the fact that metals such as thallium are not 

metabolized and that differences in the sensitivity to thallium in humans will therefore be 

insignificant. In the second case, the reviewer identified limited dose-response data for human 

dermal exposure (resulting from the routine practice of dermal administration of thallium salts to 

children with ringworm) and, in particular, 1930s papers from Munch (1934) that demonstrated 

the distinction between epilation and toxicity and suggested a possible range for which animal 

effects can be correlated with human effects. This reviewer noted that it was unclear whether the 

addition of these data would improve uncertainty. 

 Only one reviewer questioned the subchronic to chronic UF of 3. It was this reviewer’s 

opinion that there is little or no uncertainty when alopecia occurs following oral exposure to 

thallium. The effect occurs in less than a subchronic time frame, and therefore the UF for 

subchronic to chronic extrapolation may not be necessary. This reviewer also stated that EPA 

needs to counter this argument if they are concerned about toxic effects other than alopecia 

following chronic exposure. 

 Input on the database UF is discussed under charge question A6 below. 

A-16
Response: Consistent with the input from the peer reviewers, the UFs for interspecies and 

LOAEL to NOAEL extrapolation were retained. 

 The paper by Munch (1934) was reviewed for information that would support reducing 

the uncertainty associated with intraspecies variability. This paper, which generally reported 

symptoms of overt toxicity, including death, was determined not to be useful for characterizing 

variation in intraspecies sensitivity to environmental exposures to thallium. Accordingly, the 

intraspecies UF of 10 was retained. 

 Consistent with the majority of reviewers, a subchronic to chronic UF of 3 was retained. 

One reviewer suggested that a subchronic to chronic UF might not be necessary; however, the 

UF of 3 was retained because, in the absence of any chronic toxicity information, it is unknown 

whether effects other than alopecia and other clinical observations could manifest at low doses. 

A6. Please comment specifically on the database uncertainty factor of 10 applied in the RfD 

derivation. Please comment on the use of the database uncertainty factor specifically for 

the 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. Please comment on whether the selection of the database uncertainty 

factor for the RfD has been scientifically justified. Has this selection been transparently 

and objectively described in the document? 

Comments: Three reviewers considered EPA’s database UF to be appropriate. One of these 

reviewers stated that the absence of specific dose-response studies addressing the issues of 

neurotoxicity, reproductive toxicity, and developmental toxicity of thallium suggests that a UF to 

account for an incomplete database is appropriate. Use of a database UF was supported by 

evidence that neurotoxicity is seen in humans upon (high) exposure to thallium and in animal 

studies (e.g., Manzo et al., 1983) and that reproductive toxicity is also seen in animal studies 

(Wei, 1987) at doses below those used in the MRI (1988) study. A second reviewer similarly 

noted that neurotoxic effects and reproductive effects were not adequately evaluated in the 

available animal studies and that available developmental toxicity studies, although not state-ofthe-art, appear adequate to conclude that developmental toxicity would not drive the risk 

assessment for thallium. A third reviewer considered the database to be so weak that a UF of 10 

must be utilized and that this choice was clearly described and appropriate. 

 One reviewer stated that a UF of 10 for deficiencies in the thallium toxicity database may 

be deemed to be too conservative. Another reviewer noted that a database UF of 10 may not be 

necessary if all the endpoints in the MRI (1988) study are considered, some of which may be 

indicative of neurotoxicity. This reviewer noted that the lack of a robust database on 

developmental toxicity is problematic, that developmental neurotoxicity and endocrine studies 

A-17
have apparently not been performed, and that there are some data providing evidence for 

reproductive toxicity, but only for one sex. This reviewer suggested that the three studies should 

be used to generate sample RfDs from the endpoints that exhibit a dose-effect function; in this 

case, a database UF of 3 may be more appropriate. 

 One reviewer did not take issue with the database UF but proposed changing the single 

RfD to a range of RfDs. 

Response: Consistent with the opinion of three of the external peer reviewers that the database 

UF of 10 is appropriate, the opinion of essentially all of the reviewers that the limited database 

for thallium toxicity results in an RfD of low confidence, the lack of adequate developmental 

toxicity studies and a two-generation reproductive toxicity study, and the uncertainty associated 

with the limited neurotoxicity data in light of the potential for neurotoxicity to represent a 

sensitive endpoint for thallium exposure, the full default database UF of 10 was retained. One 

reviewer observed that, based on the available studies, developmental toxicity would not likely 

drive the risk assessment for thallium. EPA does not believe that this observation should change 

the size of the database UF since the database deficiencies associated with reproductive toxicity 

and neurotoxicity also support a database UF of 10. 

B. Inhalation Reference Concentration (RfC) for Thallium 

B1. Has the rationale and justification for not deriving an RfC for thallium been transparently 

described in the document? 

Comments: Three reviewers agreed that the available data on inhalation exposure to thallium 

were insufficient to support derivation of an RfC. One reviewer noted that an Occupational 

Safety and Health Administration (OSHA) threshold limit value of 0.10 mg/m3

 Tl is available 

and should be reported in the Toxicological Review. 

Response: IRIS toxicological reviews generally do not include a summary of other Agency 

regulatory guidelines and standards. Regulatory values included in an IRIS assessment could 

become irrelevant with time as they are updated. Further, OSHA occupational limits take into 

consideration technological achievability and economic costs in addition to toxicity and therefore 

are not comparable to IRIS reference values. Therefore, the OSHA occupational limit was not 

included in the thallium Toxicological Review. 

A-18
C. Carcinogenicity of Thallium and Compounds 

C1. Under the EPA’s (2005a) Guidelines for Carcinogen Risk Assessment

(www.epa.gov/iris/backgr-d.htm), the Agency concluded that there is “inadequate 

information to assess the carcinogenic potential” of thallium and compounds. Please 

comment on the scientific justification for the cancer weight-of-evidence characterization. 

A quantitative cancer assessment was not derived for thallium. Has the scientific 

justification for not deriving a quantitative cancer assessment been transparently and 

objectively described? 

Comments: All six reviewers agreed that the available literature does not support a 

characterization of the carcinogenicity of thallium and that the rationale for not performing a 

quantitative risk assessment for cancer was appropriate. 

Response: No response needed.

PUBLIC COMMENTS 

 Two submissions from the public were received. The submissions received during the 

official public comment period were distributed to the external peer review panel prior to the 

public meeting and discussion of the assessment. Submissions offered some editorial comments 

and suggestions for clarification of specific portions of the text. Changes were incorporated in 

the Toxicological Review as appropriate and are not discussed further in this appendix. 

A. General Comments 

Comment: One public commenter considered thallium to be a very dangerous substance and 

urged EPA to retain the IRIS assessment for thallium on the IRIS database. 

Response: EPA intends to retain an assessment of the health effects of thallium and compounds 

on the IRIS database. The draft Toxicological Review provided for public comment and external 

peer review represented an effort to update the health assessment for thallium and thallium 

compounds to reflect the current available science on this compound. However, EPA has not 

recommended an RfD for thallium compounds in this specific case. Justification for this 

decision is provided in Section 5.1.3.1. 

A-19
B. Oral Reference Dose (RfD) for Thallium 

Comment: One public commenter did not consider the 0.25 mg/kg-day dose to be a biologically 

significant LOAEL because there is inadequate evidence to link the high dose alopecia with 

biologically significant effects. Specific reasons for failing to establish this link included the 

following: (1) complete histopathologic examinations were conducted only in vehicle control 

and high‐dose groups; therefore, the dose‐response relationship of this effect was not established; 

(2) background occurrence of alopecia in study animals and the potential for misclassification 

adds uncertainty regarding the incidence of treatment‐related alopecia in study animals; 

(3) patterns of alopecia and hair follicle atrophy were inconsistent between male and female rats; 

increases in the incidence of alopecia in male rats were not dose related; and atrophy of the hair 

follicles in male rats was absent; and (4) there is incomplete information on, and inconsistencies 

in, anatomical patterns of effects. 

Response: As discussed in response to peer reviewer comments on charge question A2, EPA 

expanded the analysis of potential critical effects to include other clinical observations that 

showed a dose-response effect, including observations related to coat, lacrimation, 

exophthalmos, miosis, and behavior. Collectively, these effects were considered evidence of a 

possible treatment-related effect and to be biologically significant. Uncertainties associated with 

these endpoints were also discussed (Section 5.1.3.1). 

Comment: One public commenter stated that EPA failed to adequately support its determination 

that the study dose selected as the POD constitutes a biologically significant endpoint. This 

commenter observed that alopecia should not be considered adverse because it is reversible after 

exposure ceases and noted that one reviewer of the MRI (1988) study described alopecia as an 

“early (low grade) lesion” and added that “it is not a lesion that could be considered as an 

adverse health effect at that stage, and it certainly is not life threatening.” 

Response: External peer reviewers generally considered alopecia to be an adverse effect. Several 

reviewers strongly recommended, however, that EPA consider other effects from the MRI (1988) 

study in addition to (or in place of) alopecia because these other effects were either more 

sensitive than alopecia, displayed a better dose response, and/or were more clearly treatment 

related. A more rigorous dose-response analysis of data sets for these other effects was added to 

the Toxicological Review. 

Comment: One public commenter observed that available human data do not provide support for 

the choice of the LOAEL or NOAEL established by EPA, noting that, although limited in 

number and methodology, population-based surveys do not provide evidence for alopecia in 

A-20
thallium-exposed populations. This commenter also noted that the draft RfD is inconsistent with 

the World Health Organization evaluation of thallium toxicity (presented in IPCS [1996]) that 

considers urinary concentrations <5 μg/L (assumed to be associated with a daily intake of 10 μg 

thallium) unlikely to cause adverse health effects based on the Brockhaus et al. (1981) study of 

residents living near a thallium‐emitting cement plant in Germany. The commenter further 

observed that thallium exposures up to 100 times greater than the draft RfD did not include 

effects consistent with the draft RfD. 

Response: EPA considered the use of the Brockhaus et al. (1981) and other population-based 

surveys as a basis for the RfD; however, the available studies were not considered sufficiently 

rigorous for reference value derivation. 

Comment: One commenter considered the draft RfD (0.7 μg/day Tl for a 70 kg adult) to be of 

questionable relevance for protection of public health because intake of thallium from background 

sources (according to ATSDR [1992] as high as 5 μg/day from food and 2 μg/day from drinking 

water) exceeds levels of thallium oral exposure corresponding with the draft RfD. The commenter 

noted that, although some of this intake may be in less soluble and less well absorbed forms of 

thallium than the soluble salts upon which the draft RfD is based, these forms may better represent 

the forms of thallium present in soil and produce at many contaminated sites. 

Response: Because the scope of an IRIS assessment does not generally include an analysis of 

potential exposure, a discussion of intake of thallium compounds from background sources was 

not included in the Toxicological Review. As noted in response to general charge question 4, 

EPA is not recommending an RfD value for thallium compounds. 

Comment: One public commenter observed that the draft RfD applies only to soluble forms of 

thallium and strongly urged EPA to restrict application of the draft RfD for soluble salts to only 

those cases where these forms of thallium are known to be present. 

Response: EPA is not recommending an RfD for soluble thallium salts. Therefore, restrictions 

on the application of an RfD is not an issue at this time. 

Comment: One public commenter observed that, although human biomonitoring studies provide 

direct evidence of widespread, low-level thallium exposures in the general population, 

biomonitoring estimates from these studies describe uptake rather than intake, do not account for 

the unabsorbed fraction of the ingested dose, and need to be coupled with a better understanding 

of the absorption fraction for dietary thallium and fraction excreted in urine in order to estimate 

daily intakes more reliably. 

A-21
A-22

Response: A summary of NHANES biomonitoring data was added to Section 3.4. Because an 

assessment of potential exposure is generally outside the scope of an IRIS assessment, an 

analysis of thallium intake based on available biomonitoring data was not included in the 

Toxicological Review. 
APPENDIX B 

Documentation of Benchmark Dose Modeling 

B.1. Summary of BMDS Modeling Results for Clinical Observations in the Male Rat 

(MRI, 1988) 

Table B-1. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of rough coat in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.0000 95.1404 0.003737 0.002460 

Logistic 0.0000 104.547 0.009731 0.006365 

Log-logistic 0.8762 85.7472 0.001063 0.0005675 

Multistage (1°) 0.0000 95.1404 0.003737 0.002460 

Probit 0.0000 106.954 0.01361 0.009597 

Log-probit 0.0008 92.4736 0.004137 0.002679 

Weibull 0.0000 95.1404 0.003737 0.002460 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

 

Data source: MRI (1988). 

 Only the log-logistic model had a p ≥ 0.1; however, the data set was not considered 

amenable to modeling because of the steep slope of the dose-response curve in the low-dose 

region and because the BMD10 and BMDL10 were well outside experimental range of the data. 

BMDS output from the log-logistic model is provided below. 

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\ROUGH_COAT-MALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\ROUGH_COAT-MALE.plt 

 Fri Jun 13 08:32:57 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #RoughCoat 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

B-1 
 Default Initial Parameter Values 

 background = 0.1 

 intercept = 4.47108 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 *** The model parameter(s) -slope 

have been estimated at a boundary point, or have been specified by the user, and do not appear in 

the correlation matrix ) 

 background intercept 

background 1 -0.26 

 intercept -0.26 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.101788 * * * 

 intercept 4.64934 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -40.7444 4 

 Fitted model -40.8736 2 0.258303 2 0.8788 

 Reduced model -69.3147 1 57.1405 3 <.0001 

 AIC: 85.7472 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1018 4.072 4 40 -0.037 

 0.0080 0.5108 10.216 11 20 0.351 

 0.0400 0.8266 16.532 16 20 -0.314 

 0.2000 0.9590 19.180 19 20 -0.203 

 Chi^2 = 0.26 d.f. = 2 P-value = 0.8762 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.00106311 

 BMDL = 0.000567469 

B-2 
0

0.2

0.4

0.6

0.8

1

0 0.05 0.1 0.15 0.2

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

08:32 06/13 2008

BMDLBMD

 

Log-Logistic

Table B-2. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of piloerection in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p-valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.9976 55.896 0.01958 0.01339 

Logistic 0.0868 63.7889 0.06642 0.04852 

Log-logistic 0.9609 57.9327 0.01813 0.008735 

Multistage (1°) 0.9976 55.896 0.01958 0.01339 

Probit 0.1124 63.1776 0.0596 0.04436 

Log-probit 0.3004 60.4202 0.03242 0.02167 

Weibull 0.9976 55.896 0.01958 0.01339 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 All models with the exception of the logistic model provided adequate fits of the data as 

assessed by a chi-square goodness-of-fit test (p ≥ 0.1) and visual inspection of the respective 

plots of observed versus predicted values from the various models. The gamma, multistage, and 

Weibull models provided the same fit of the data and were judged to provide the best model fit 

based on the lowest AIC value. The BMDS output for the gamma model is provided below. 

B-3 
==================================================================== 

Gamma Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\PILOERECTION-MALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\PILOERECTION-MALE.plt 

 Fri Jun 13 09:33:49 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #Piloerection 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.0121951 

 Slope = 6.76558 

 Power = 1.26625 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Background -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Slope 

 Slope 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0 NA 

 Slope 5.38237 1.31322 2.8085 7.95624 

 Power 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -26.9273 4 

 Fitted model -26.948 1 0.0414636 3 0.9978 

 Reduced model -47.1393 1 40.4241 3 <.0001 

 AIC: 55.896 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0 40 0.000 

 0.0080 0.0421 0.843 1 20 0.175 

 0.0400 0.1937 3.874 4 20 0.071 

 0.2000 0.6592 13.184 13 20 -0.087 

 Chi^2 = 0.04 d.f. = 3 P-value = 0.9976 

B-4 
 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0195751 

 BMDL = 0.0133909 

0

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Fraction Affected

dose

Gamma Multi-Hit Model with 0.95 Confidence Level

09:33 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

Table B-3. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of shedding in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.0001 97.3226 0.02650 0.01557 

Logistic 0.0000 101.522 0.06984 0.04768 

Log-logistic 0.0018 89.706 0.009591 0.005740 

Multistage (1°) 0.0001 97.3226 0.02650 0.01557 

Probit 0.0001 101.233 0.06524 0.04472 

Log-probit 0.0000 103.483 0.06468 0.02975 

Weibull 0.0001 97.3226 0.02650 0.01557 

a

Chi-square p-value = p value from the Chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 

This data set was not fit by any of the models in BMDS. 

B-5 
Table B-4. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of alopecia in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.0006 106.08 201851 0.04072 

Logistic 0.0029 103.671 0.2356 0.07835 

Log-logistic 0.0032 103.436 0.1419 0.02992 

Multistage (1°) 0.0031 103.514 0.1701 0.04426 

Probit 0.0030 103.655 0.2283 0.07445 

Log-probit 0.0006 106.08 0.8226 0.1092 

Weibull 0.0031 103.514 0.1701 0.04426 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 This data set was not fit by any of the models in BMDS. 

Table B-5. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of lacrimation in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 day 

Model

Chi-square 

p-valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.9986 51.0387 0.0004624 0.0001676 

Logistic 1.0000 49.0387 0.0008749 0.0005251 

Log-logistic 0.9996 51.0387 0.004725 6.03 × 10–6

Multistage (2°) 1.0000 51.0387 0.000374 0.0001676 

Probit 1.0000 49.0387 0.000879 0.0005970 

Log-probit 0.9990 51.0387 0.002302 0.0001857 

Weibull 1.0000 49.0388 0.0003007 0.0001676 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 This data set was not considered amenable to modeling because of the steep slope of the 

dose-response curve in the low-dose region and because the BMD10 and BMDL10 values were 

well outside the experimental range of the data. The BMDS output for the logistic model is 

presented below. 

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\LACRIMATION-MALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\LACRIMATION-MALE.plt 

 Fri Jun 13 09:43:31 2008 

 ==================================================================== 

 BMDS MODEL RUN 

B-6 
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = 1/[1+EXP(-intercept-slope*dose)] 

 Dependent variable = #Lacrimation 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is not restricted 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 background = 0 Specified 

 intercept = 1.2157 

 slope = 14.6477 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 -0.38 

 slope -0.38 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -1.5506 0.416124 -2.36618 -0.735007 

 slope 561.879 138.394 290.632 833.127 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -22.5194 4 

 Fitted model -22.5194 2 3.27387e-008 2 1 

 Reduced model -64.1035 1 83.1684 3 <.0001 

 AIC: 49.0387 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1750 7.000 7 40 -0.000 

 0.0080 0.9500 19.000 19 20 -0.000 

 0.0400 1.0000 20.000 20 20 0.000 

 0.2000 1.0000 20.000 20 20 0.000 

 Chi^2 = 0.00 d.f. = 2 P-value = 1.0000 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.000874909 

 BMDL = 0.000525133 

B-7 
0

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Fraction Affected

dose

Logistic Model with 0.95 Confidence Level

09:43 06/13 2008

BMDLBMD

 

Logistic

Table B-6. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of exophthalmos in male Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.9995 66.7372 0.004381 0.0006528 

Logistic 0.9987 64.7422 0.002070 0.001434 

Log-logistic 0.9996 66.7372 0.006493 0.001206 

Multistage (2°) 1.0000 64.7372 0.002991 0.0006528 

Probit 1.0000 64.7372 0.001947 0.001373 

Log-probit 0.9995 66.7372 0.005341 0.001283 

Weibull 0.9980 66.7372 0.002766 0.0006528 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 This data set was not considered amenable to modeling because of the steep slope of the 

dose-response curve in the low-dose region and because the BMD10 and BMDL10 values were 

well outside the experimental range of the data. Of the models with the lowest AIC values, the 

model with the lowest BMDL10 (i.e., the two-stage multistage model) is presented below. 

 ==================================================================== 

Multistage Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\EXOPHTHALMOS-MALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\EXOPHTHALMOS-MALE.plt 

 Fri Jun 13 09:56:05 2008 

 ==================================================================== 

 BMDS MODEL RUN 

B-8 
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP( 

 -beta1*dose^1-beta2*dose^2)] 

 The parameter betas are restricted to be positive 

 Dependent variable = #Exophthalmos 

 Independent variable = Dose(mg/kg-d) 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Total number of parameters in model = 3 

 Total number of specified parameters = 0 

 Degree of polynomial = 2 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 Background = 1 

 Beta(1) = 4.41266e+020 

 Beta(2) = 0 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Beta(1) 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Beta(2) 

Background 1 -0.44 

 Beta(2) -0.44 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.15 * * * 

 Beta(1) 0 * * * 

 Beta(2) 11777.7 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -30.3686 4 

 Fitted model -30.3686 2 2.2259e-007 2 1 

 Reduced model -68.0292 1 75.3212 3 <.0001 

 AIC: 64.7372 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1500 6.000 6 40 0.000 

 0.0080 0.6000 12.000 12 20 -0.000 

 0.0400 1.0000 20.000 20 20 0.000 

 0.2000 1.0000 20.000 20 20 0.000 

 Chi^2 = 0.00 d.f. = 2 P-value = 1.0000 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

B-9 
 BMD = 0.00299095 

 BMDL = 0.000652821 

 BMDU = 0.00435446 

Taken together, (0.000652821, 0.00435446) is a 90 % two-sided confidence 

interval for the BMD 

0

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Fraction Affected

dose

Multistage Model with 0.95 Confidence Level

09:56 06/13 2008

BMDL BMD

 

Multistage

Table B-7. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of miosis in male Sprague-Dawley rats exposed to thallium sulfate 

via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.0924 88.4982 0.01341 0.009005 

Logistic 0.0201 93.2144 0.03912 0.02853 

Log-logistic 0.3209 86.2645 0.006854 0.003910 

Multistage (1°) 0.0924 88.4982 0.01341 0.009005 

Probit 0.0218 92.9002 0.03674 0.02777 

Log-probit 0.0214 91.7394 0.02461 0.01547 

Weibull 0.0924 88.4982 0.01341 0.009005 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 The log-logistic model was the only model that did not exhibit statistically significant 

lack of fit. The BMDS output from this model is provided below. 

B-10 
 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\MIOSIS-MALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\MALE\MIOSIS-MALE.plt 

 Fri Jun 13 10:00:04 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #Miosis 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.025 

 intercept = 2.67092 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.38 

 intercept -0.38 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0342297 * * * 

 intercept 2.78563 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -40.1186 4 

 Fitted model -41.1323 2 2.02732 2 0.3629 

 Reduced model -59.2953 1 38.3534 3 <.0001 

 AIC: 86.2645 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0342 1.369 1 40 -0.321 

 0.0080 0.1451 2.902 5 20 1.332 

 0.0400 0.4141 8.282 7 20 -0.582 

 0.2000 0.7723 15.447 15 20 -0.238 

 Chi^2 = 2.27 d.f. = 2 P-value = 0.3209 

 Benchmark Dose Computation 

B-11 
Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0068545 

 BMDL = 0.00391034 

0

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Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

10:00 06/13 2008

BMDL BMD

 

Log-Logistic

\

Table B-8. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of behavioral findings in male Sprague-Dawley rats exposed to 

thallium sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.0271 108.74 0.06920 0.03038 

Logistic 0.0251 109.105 0.09757 0.05538 

Log-logistic 0.0283 108.549 0.05662 0.02007 

Multistage (1°) 0.0271 108.74 0.06920 0.03038 

Probit 0.0253 109.067 0.09430 0.05269 

Log-probit 0.0191 109.827 0.1271 0.06223 

Weibull 0.0271 108.74 0.06920 0.03038 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 This data set was not fit by any of the models in BMDS. 

B-12 
B.2. Summary of BMDS Modeling Results for Clinical Observations in the Female Rat 

(MRI, 1988) 

Table B-9. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of rough coat in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.6681 72.0684 0.02434 0.01597 

Logistic 0.0831 75.8559 0.06646 0.04900 

Log-logistic 0.8772 71.5823 0.01778 0.01008 

Multistage (1°) 0.6681 72.0684 0.02434 0.01597 

Probit 0.1033 75.4298 0.06033 0.04503 

Log-probit 0.2042 74.1826 0.03935 0.02596 

Weibull 0.6681 72.0684 0.02434 0.01597 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 All models with the exception of the logistic model provided adequate fits to the data as 

assessed by a chi-square goodness-of-fit test (p ≥ 0.1) and visual inspection of the respective 

plots of observed versus predicted values from the various models. BMDL10 estimates from 

these models were within a factor of three of each other, suggesting no appreciable model 

dependence. Fitted models exhibiting adequate fit with AIC values within two units of the 

lowest AIC were considered indistinguishable from one another; thus, BMD10 and BMDL10

values from these models were averaged to derive the POD. Model fits that yielded the same 

mathematical model were counted as a single model for averaging purposes (these models 

included gamma, multistage, and Weibull). Therefore, the BMD10 and BMDL10 values for these 

models were averaged as follows: 

 Average BMD10 = (0.02434 + 0.01778) ÷ 2 = 0.02106 mg/kg-day 

 Average BMDL10 = (0.01597 + 0.01008) ÷ 2 = 0.01303 mg/kg-day 

 BMDS outputs from the gamma and log-logistic models are presented below. 

B-13 
 ==================================================================== 

Gamma Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ROUGH_COAT-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ROUGH_COATFEMALE.plt 

 Fri Jun 13 08:50:07 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #RoughCoat 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.0365854 

 Slope = 8.19903 

 Power = 1.3 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Slope 

Background 1 -0.27 

 Slope -0.27 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.0268981 0.0242052 -0.0205432 0.0743394 

 Slope 4.32831 1.21395 1.94901 6.70761 

 Power 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -33.6561 4 

 Fitted model -34.0342 2 0.756278 2 0.6851 

 Reduced model -47.1393 1 26.9666 3 <.0001 

 AIC: 72.0684 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0269 1.076 1 40 -0.074 

 0.0080 0.0600 1.200 1 20 -0.189 

 0.0400 0.1816 3.632 5 20 0.794 

 0.2000 0.5905 11.811 11 20 -0.369 

B-14 
 Chi^2 = 0.81 d.f. = 2 P-value = 0.6681 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0243422 

 BMDL = 0.0159664 

0

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Fraction Affected

dose

Gamma Multi-Hit Model with 0.95 Confidence Level

08:50 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ROUGH_COAT-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ROUGH_COATFEMALE.plt 

 Fri Jun 13 08:52:08 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #RoughCoat 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.025 

 intercept = 2.22927 

 slope = 1.17797 

 Asymptotic Correlation Matrix of Parameter Estimates 

B-15 
 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.26 

 intercept -0.26 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0230944 * * * 

 intercept 1.83236 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -33.6561 4 

 Fitted model -33.7911 2 0.270147 2 0.8737 

 Reduced model -47.1393 1 26.9666 3 <.0001 

 AIC: 71.5823 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0231 0.924 1 40 0.080 

 0.0080 0.0696 1.392 1 20 -0.345 

 0.0400 0.2184 4.369 5 20 0.342 

 0.2000 0.5658 11.315 11 20 -0.142 

 Chi^2 = 0.26 d.f. = 2 P-value = 0.8772 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0177817 

 BMDL = 0.0100819 

0

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Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

08:52 06/13 2008

BMDL BMD

 

Log-Logistic

B-16 
Table B-10. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of piloerection in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.8149 47.1544 0.03857 0.02426 

Logistic 0.0484 54.0549 0.1008 0.07462 

Log-logistic 0.6738 48.9941 0.03656 0.01845 

Multistage (1°) 0.8149 47.1544 0.03857 0.02426 

Probit 0.0600 53.5635 0.09134 0.06737 

Log-probit 0.2492 49.1272 0.05296 0.03658 

Weibull 0.8149 47.1544 0.03857 0.02426 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 All models with the exception of the logistic and probit models provided adequate fits to 

the data as assessed by a chi-square goodness-of-fit test (p ≥ 0.1) and visual inspection of the 

respective plots of observed versus predicted values from the various models. BMDL10

estimates from these models were within a factor of three of each other, suggesting no 

appreciable model dependence. Fitted models exhibiting adequate fit with AIC values within 

two units of the lowest AIC were considered indistinguishable from one another; thus BMD10

and BMDL10 values from these models (gamma, log-logistic, multistage, log-probit, and 

Weibull) were averaged to derive the POD. Model fits that yielded the same mathematical 

model were counted as a single model for averaging purposes (these models included gamma, 

multistage, and Weibull). Therefore, the BMD10 and BMDL10 values for these models were 

averaged as follows: 

 Average BMD10 = (0.03857 + 0.03656 + 0.05296) ÷ 3 = 0.04270 mg/kg-day 

 Average BMDL10 = (0.02426 + 0.0184 + 0.03658) ÷ 3 = 0.02641 mg/kg-day 

 BMDS outputs from the gamma, log-logistic, and log-probit models are presented below. 

 ==================================================================== 

Gamma Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTION-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTIONFEMALE.plt 

 Fri Jun 13 08:56:08 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

B-17 
 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #Piloerection 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.0121951 

 Slope = 5.0954 

 Power = 1.3 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Background -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Slope 

 Slope 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0 NA 

 Slope 2.73196 0.831275 1.10269 4.36123 

 Power 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -21.9144 4 

 Fitted model -22.5772 1 1.32556 3 0.7231 

 Reduced model -34.6515 1 25.4742 3 <.0001 

 AIC: 47.1544 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0 40 0.000 

 0.0080 0.0216 0.432 0 20 -0.665 

 0.0400 0.1035 2.070 3 20 0.682 

 0.2000 0.4210 8.419 8 20 -0.190 

 Chi^2 = 0.94 d.f. = 3 P-value = 0.8149 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0385659 

 BMDL = 0.024262 

B-18 
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Fraction Affected

dose

Gamma Multi-Hit Model with 0.95 Confidence Level

08:56 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTION-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTIONFEMALE.plt 

 Fri Jun 13 08:56:57 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #Piloerection 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0 

 intercept = 1.35689 

 slope = 1.02772 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 0.92 

 slope 0.92 1 

B-19 
 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0 * * * 

 intercept 1.45513 * * * 

 slope 1.10379 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -21.9144 4 

 Fitted model -22.497 2 1.16526 2 0.5584 

 Reduced model -34.6515 1 25.4742 3 <.0001 

 AIC: 48.9941 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0 40 0.000 

 0.0080 0.0203 0.407 0 20 -0.644 

 0.0400 0.1093 2.186 3 20 0.583 

 0.2000 0.4203 8.407 8 20 -0.184 

 Chi^2 = 0.79 d.f. = 2 P-value = 0.6738 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0365553 

 BMDL = 0.018448 

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dose

Log-Logistic Model with 0.95 Confidence Level

08:56 06/13 2008

BMDL BMD

 

Log-Logistic

B-20 
==================================================================== 

Probit Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTION-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\PILOERECTIONFEMALE.plt 

 Fri Jun 13 08:59:17 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = Background 

 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

 where CumNorm(.) is the cumulative normal distribution function 

 Dependent variable = #Piloerection 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial (and Specified) Parameter Values 

 background = 0 

 intercept = 1.70413 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0 NA 

 intercept 1.65675 0.228852 1.20821 2.10529 

 slope 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -21.9144 4 

 Fitted model -23.5636 1 3.29839 3 0.3479 

 Reduced model -34.6515 1 25.4742 3 <.0001 

 AIC: 49.1272 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

B-21 
 0.0000 0.0000 0.000 0 40 0.000 

 0.0080 0.0008 0.015 0 20 -0.123 

 0.0400 0.0591 1.183 3 20 1.723 

 0.2000 0.5189 10.377 8 20 -1.064 

 Chi^2 = 4.12 d.f. = 3 P-value = 0.2492 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0529554 

 BMDL = 0.0365797 

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dose

Probit Model with 0.95 Confidence Level

08:59 06/13 2008

BMDL BMD

 

Probit

Table B-11. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of shedding in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.5894 59.2904 0.01968 0.01347 

Logistic 0.1620 64.9908 0.06624 0.04847 

Log-logistic 0.4442 61.4053 0.01453 0.008519 

Multistage (1°) 0.5894 59.2904 0.01968 0.01347 

Probit 0.1783 64.6269 0.05923 0.04416 

Log-probit 0.1332 64.1872 0.03710 0.02449 

Weibull 0.5894 59.2904 0.01968 0.01347 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

B-22 
 All models provided adequate fits of the data as assessed by a chi-square goodness-of-fit 

test (p ≥ 0.1) and visual inspection of the respective plots of observed versus predicted values 

from the various models. The gamma, multistage, and Weibull models provided the same fit of 

the data and were judged to provide the best model fit based on the lowest AIC value. The 

BMDS output for the gamma model is provided below. 

==================================================================== 

Gamma Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\SHEDDING-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\SHEDDING-FEMALE.plt 

 Fri Jun 13 09:02:02 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #Shedding 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.0121951 

 Slope = 8.9948 

 Power = 1.64923 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Background -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Slope 

 Slope 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0 NA 

 Slope 5.35376 1.30563 2.79477 7.91275 

 Power 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -27.9048 4 

 Fitted model -28.6452 1 1.48083 3 0.6867 

 Reduced model -47.1393 1 38.4691 3 <.0001 

 AIC: 59.2904 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

B-23 
 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0 40 0.000 

 0.0080 0.0419 0.839 2 20 1.296 

 0.0400 0.1928 3.855 3 20 -0.485 

 0.2000 0.6572 13.145 13 20 -0.068 

 Chi^2 = 1.92 d.f. = 3 P-value = 0.5894 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0196797 

 BMDL = 0.0134653 

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Gamma Multi-Hit Model with 0.95 Confidence Level

09:02 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

Table B-12. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of alopecia in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.2392 111.335 0.02280 0.01389 

Logistic 0.0863 113.282 0.04556 0.03215 

Log-logistic 0.4922 109.978 0.01338 0.00665 

Multistage (1°) 0.2392 111.335 0.02280 0.01389 

Probit 0.0924 113.141 0.04351 0.03125 

Log-probit 0.0695 113.624 0.04057 0.02328 

Weibull 0.2392 111.335 0.02280 0.01389 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

B-24 
 The gamma, log-logistic, multistage, and Weibull models provided adequate fits to the 

data as assessed by a chi-square goodness-of-fit test (p ≥ 0.1) and visual inspection of the 

respective plots of observed versus predicted values from the various models. BMDL10

estimates from these models were within a factor of three of each other, suggesting no 

appreciable model dependence. Fitted models exhibiting adequate fit with AIC values within 

two units of the lowest AIC were considered indistinguishable from one another; thus, BMD10

and BMDL10 values from these models (gamma, log-logistic, multistage, and Weibull) were 

averaged to derive the POD. Model fits that yielded the same mathematical model were counted 

as a single model for averaging purposes (these models included gamma, multistage, and 

Weibull). Therefore, the BMD10 and BMDL10 values for these models were averaged as follows: 

 Average BMD10 = (0.02280 + 0.01338) ÷ 2 = 0.01809 mg/kg-day 

 Average BMDL10 = (0.01389 + 0.00665) ÷ 2 = 0.01027 mg/kg-day 

 BMDS outputs from the gamma and log-logistic models are provided below. 

==================================================================== 

 Gamma Model. (Version: 2.8; Date: 02/20/2007) 

 Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ALOPECIAFEMALE.(d) 

 Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ALOPECIAFEMALE.plt 

 Fri Jun 13 09:06:01 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #Alopecia 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.134146 

 Slope = 17.289 

 Power = 1.3 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Slope 

Background 1 -0.42 

B-25 
 Slope -0.42 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.160192 0.0508961 0.0604373 0.259946 

 Slope 4.62078 1.59736 1.49 7.75156 

 Power 1 NA 

NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -52.3019 4 

 Fitted model -53.6677 2 2.73165 2 0.2552 

 Reduced model -61.0864 1 17.5691 3 0.0005397 

 AIC: 111.335 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1602 6.408 5 40 -0.607 

 0.0080 0.1907 3.813 4 20 0.106 

 0.0400 0.3019 6.038 9 20 1.443 

 0.2000 0.6667 13.334 12 20 -0.633 

 Chi^2 = 2.86 d.f. = 2 P-value = 0.2392 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0228015 

 BMDL = 0.0138895 

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Gamma Multi-Hit Model with 0.95 Confidence Level

09:06 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

B-26 
 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ALOPECIA-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\ALOPECIA-FEMALE.plt 

 Fri Jun 13 09:07:14 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #Alopecia 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.125 

 intercept = 2.11821 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.48 

 intercept -0.48 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.138817 * * * 

 intercept 2.11678 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -52.3019 4 

 Fitted model -52.9891 2 1.3744 2 0.503 

 Reduced model -61.0864 1 17.5691 3 0.0005397 

 AIC: 109.978 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1388 5.553 5 40 -0.253 

 0.0080 0.1925 3.849 4 20 0.085 

 0.0400 0.3536 7.071 9 20 0.902 

 0.2000 0.6764 13.527 12 20 -0.730 

 Chi^2 = 1.42 d.f. = 2 P-value = 0.4922 

 Benchmark Dose Computation 

B-27 
Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0133799 

 BMDL = 0.0066454 

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Log-Logistic Model with 0.95 Confidence Level

09:07 06/13 2008

BMDL BMD

 

Log-Logistic

Table B-13. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of lacrimation in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 1.0000 54.4465 4.808 × 10–5 BMD computation failed. Lower 

Logistic 1.0000 54.4465 0.0001258 limit includes zero. 

Log-logistic 1.0000 54.4465 1.517 × 10–11

Multistage (2°) 0.9996 56.4465 4.882 × 10–5 8.1310 × 10–9

Probit 1.0000 54.4465 0.00024051 BMD computation failed. Lower 

Log-probit 1.0000 54.4465 9.098 × 10 limit includes zero. –6

Weibull 1.0000 54.4465 4.72 × 10–5

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 All models in BMDS failed to estimate useful BMD and BMDL values without excessive 

extrapolation. 

B-28 
Table B-14. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of exophthalmos in female Sprague-Dawley rats exposed to 

thallium sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.9983 60.9941 0.0005049 0.0001719 

Logistic 1.0000 58.9941 0.0006936 0.0004144 

Log-logistic 0.9996 60.9941 0.004856 6.86 × 10–6

Multistage (2°) 1.0000 60.9941 0.001588 0.0001719 

Probit 1.0000 58.9941 0.0007337 0.0004976 

Log-probit 0.9969 60.9941 0.002044 0.0001944 

Weibull 0.9962 60.9942 0.0003155 0.0001719 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 The data set was not considered amenable to modeling because of the steep slope of the 

dose-response curve in the low-dose region and because the BMD10 and BMDL10 values were 

well outside the experimental range of the data. Of the models with the lowest AIC values, the 

one with the lowest BMDL10 (i.e., the logistic model) is presented below.

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\EXOPHTHALMOS-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\EXOPHTHALMOSFEMALE.plt 

 Fri Jun 13 09:15:35 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = 1/[1+EXP(-intercept-slope*dose)] 

 Dependent variable = #Exophthalmos 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is not restricted 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 background = 0 Specified 

 intercept = 1.43545 

 slope = 13.3397 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

B-29 
 intercept slope 

 intercept 1 -0.33 

 slope -0.33 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -0.96942 0.354104 -1.66345 -0.275389 

 slope 489.249 135.678 223.326 755.172 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -27.4971 4 

 Fitted model -27.4971 2 3.53613e-007 2 1 

 Reduced model -61.0864 1 67.1787 3 <.0001 

 AIC: 58.9941 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.2750 11.000 11 40 0.000 

 0.0080 0.9500 19.000 19 20 -0.000 

 0.0400 1.0000 20.000 20 20 0.000 

 0.2000 1.0000 20.000 20 20 0.000 

 Chi^2 = 0.00 d.f. = 2 P-value = 1.0000 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.000693631 

 BMDL = 0.000414359 

0.2

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Fraction Affected

dose

Logistic Model with 0.95 Confidence Level

09:15 06/13 2008

BMDLBMD

 

Logistic

B-30 
Table B-15. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of miosis in female Sprague-Dawley rats exposed to thallium 

sulfate via gavage for 90 days 

Model 

Chi-square 

p valuea AIC 

BMD10

(mg/kg-day) 

BMDL10 

(mg/kg-day) 

Gamma 0.0010 109.237 0.03729 0.02024 

Logistic 0.0004 111.015 0.07143 0.04590 

Log-logistic 0.0028 107.854 0.02252 0.01048 

Multistage (1°) 0.0010 109.237 0.03729 0.02024 

Probit 0.0004 110.867 0.06780 0.04360 

Log-probit 0.0001 112.733 0.08222 0.03640 

Weibull 0.0010 109.237 0.03729 0.02024 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 This data set was not fit by any of the models in BMDS. 

Table B-16. A summary of BMDS (version 1.4.1) modeling results based on 

incidence of behavioral findings in female Sprague-Dawley rats exposed to 

thallium sulfate via gavage for 90 days 

Model

Chi-square 

p valuea AIC

BMD10

(mg/kg-day)

BMDL10 

(mg/kg-day)

Gamma 0.1256 69.3045 0.1594 0.04585 

Logistic 0.2197 67.905 0.1009 0.07207 

Log-logistic 0.1256 69.3045 0.1736 0.04377 

Multistage (2°) 0.2766 67.482 0.1081 0.04445 

Probit 0.2100 68.0129 0.09473 0.06621 

Log-probit 0.1256 69.3045 0.1541 0.05892 

Weibull 0.1256 69.3045 0.1760 0.04585 

a

Chi-square p value = p value from the chi-square test for lack of fit. Values <0.1 fail to meet conventional 

goodness-of-fit criteria. 

Data source: MRI (1988). 

 All of the models provided adequate fits of the data as assessed by a chi-square goodnessof-fit test (p ≥ 0.1) and visual inspection of the respective plots of observed versus predicted 

values from the various models. BMDL10 estimates from these models were within a factor of 

three of each other, suggesting no appreciable model dependence. Fitted models exhibiting 

adequate fit with AIC values within two units of the lowest AIC were considered 

indistinguishable from one another; thus BMD10 and BMDL10 values from all seven models were 

averaged to derive the POD. Therefore, the BMD10 and BMDL10 values for these models were 

averaged as follows: 

B-31 
Average BMD10 = (0.1594 + 0.1009 + 0.1736 + 0.1081 + 0.09473 + 0.1541 + 0.1760) ÷ 7 

= 0.1381 mg/kg-day 

Average BMDL10 = (0.04585 + 0.07207 + 0.04377 + 0.04445 + 0.06621 + 0.05892 + 

0.04585) ÷ 7 = 0.05387 mg/kg-day 

BMDS outputs from each model are provided below. 

 ==================================================================== 

Gamma Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:23:45 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.109756 

 Slope = 7.56372 

 Power = 2.63978 

 Asymptotic Correlation Matrix of Parameter Estimates 

 Background Slope Power 

Background 1 -0.0024 -0.0022 

 Slope -0.0024 1 1 

 Power -0.0022 1 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.0625 0.0270635 0.00945649 0.115543 

 Slope 59.7049 4193.5 -8159.41 8278.82 

 Power 14.0574 900.278 -1750.45 1778.57 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.6523 3 3.45942 1 0.06289 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 69.3045 

B-32 
 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0625 2.500 4 40 0.980 

 0.0080 0.0625 1.250 0 20 -1.155 

 0.0400 0.0625 1.250 1 20 -0.231 

 0.2000 0.3500 7.000 7 20 0.000 

 Chi^2 = 2.35 d.f. = 1 P-value = 0.1256 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.159402 

 BMDL = 0.0458492 

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Fraction Affected

dose

Gamma Multi-Hit Model with 0.95 Confidence Level

09:23 06/13 2008

BMDL BMD

 

Gamma Multi-Hit

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:24:08 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = 1/[1+EXP(-intercept-slope*dose)] 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is not restricted 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

B-33 
 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 background = 0 Specified 

 intercept = -2.96071 

 slope = 11.6261 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 -0.74 

 slope -0.74 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -2.81211 0.489479 -3.77147 -1.85275 

 slope 10.758 3.50284 3.89255 17.6234 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.9525 2 4.05988 2 0.1313 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 67.905 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0567 2.267 4 40 1.185 

 0.0080 0.0615 1.229 0 20 -1.144 

 0.0400 0.0846 1.691 1 20 -0.556 

 0.2000 0.3406 6.813 7 20 0.088 

 Chi^2 = 3.03 d.f. = 2 P-value = 0.2197 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.10089 

 BMDL = 0.0720676 

B-34 
0

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Fraction Affected

dose

Logistic Model with 0.95 Confidence Level

09:24 06/13 2008

BMDL BMD

 

Logistic

 ==================================================================== 

Logistic Model. (Version: 2.9; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:24:29 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.1 

 intercept = 0.293481 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 background intercept slope 

background 1 0.0045 0.0046 

 intercept 0.0045 1 1 

 slope 0.0046 1 1 

 Parameter Estimates 

B-35 
 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0625 * * * 

 intercept 14.8768 * * * 

 slope 9.75033 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.6523 3 3.45942 1 0.06289 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 69.3045 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0625 2.500 4 40 0.980 

 0.0080 0.0625 1.250 0 20 -1.155 

 0.0400 0.0625 1.250 1 20 -0.231 

 0.2000 0.3500 7.000 7 20 -0.000 

 Chi^2 = 2.35 d.f. = 1 P-value = 0.1256 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.173579 

 BMDL = 0.0437732 

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Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

09:24 06/13 2008

BMDL BMD

 

Log-Logistic

B-36 
 ==================================================================== 

Multistage Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:25:07 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP( 

 -beta1*dose^1-beta2*dose^2)] 

 The parameter betas are restricted to be positive 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Total number of parameters in model = 3 

 Total number of specified parameters = 0 

 Degree of polynomial = 2 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 Background = 0.0459871 

 Beta(1) = 0 

 Beta(2) = 9.5796 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Beta(1) 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Beta(2) 

Background 1 -0.4 

 Beta(2) -0.4 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.060443 * * * 

 Beta(1) 0 * * * 

 Beta(2) 9.01875 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.741 2 3.63685 2 0.1623 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 67.482 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

B-37 
 ------------------------------------------------------------------------ 

 0.0000 0.0604 2.418 4 40 1.050 

 0.0080 0.0610 1.220 0 20 -1.140 

 0.0400 0.0739 1.478 1 20 -0.409 

 0.2000 0.3450 6.900 7 20 0.047 

 Chi^2 = 2.57 d.f. = 2 P-value = 0.2766 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.108085 

 BMDL = 0.0444457 

 BMDU = 0.173737 

Taken together, (0.0444457, 0.173737) is a 90 % two-sided confidence 

interval for the BMD 

0

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Fraction Affected

dose

Multistage Model with 0.95 Confidence Level

09:25 06/13 2008

BMDL BMD

 

Multistage

 ==================================================================== 

Probit Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:25:44 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = CumNorm(Intercept+Slope*Dose), 

 where CumNorm(.) is the cumulative normal distribution function 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is not restricted 

B-38 
 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 background = 0 Specified 

 intercept = -1.68929 

 slope = 6.25307 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 -0.66 

 slope -0.66 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -1.58535 0.232401 -2.04084 -1.12985 

 slope 5.83053 1.91096 2.08512 9.57595 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -32.0065 2 4.16782 2 0.1244 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 68.0129 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0564 2.258 4 40 1.194 

 0.0080 0.0619 1.239 0 20 -1.149 

 0.0400 0.0882 1.763 1 20 -0.602 

 0.2000 0.3375 6.750 7 20 0.118 

 Chi^2 = 3.12 d.f. = 2 P-value = 0.2100 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0947316 

 BMDL = 0.0662085 

B-39 
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0 0.05 0.1 0.15 0.2

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

09:25 06/13 2008

BMDL BMD

 

Probit

 ==================================================================== 

Probit Model. (Version: 2.8; Date: 02/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:26:03 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = Background 

 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

 where CumNorm(.) is the cumulative normal distribution function 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial (and Specified) Parameter Values 

 background = 0.1 

 intercept = 1.18165 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 background intercept slope 

background 1 -0.001 -0.00087 

 intercept -0.001 1 1 

 slope -0.00087 1 1 

B-40 
 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0625 0.0270635 0.00945646 0.115544 

 intercept 4.28948 360.951 -703.162 711.741 

 slope 2.97918 224.271 -436.585 442.543 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.6523 3 3.45942 1 0.06289 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 69.3045 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0625 2.500 4 40 0.980 

 0.0080 0.0625 1.250 0 20 -1.155 

 0.0400 0.0625 1.250 1 20 -0.231 

 0.2000 0.3500 7.000 7 20 0.000 

 Chi^2 = 2.35 d.f. = 1 P-value = 0.1256 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.154125 

 BMDL = 0.0589218 

0

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Fraction Affected

dose

Probit Model with 0.95 Confidence Level

09:26 06/13 2008

BMDL BMD

 

Probit

B-41 
 ==================================================================== 

Weibull Model using Weibull Model (Version: 2.7; Date: 2/20/2007) 

Input Data File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.(d) 

Gnuplot Plotting File: M:\IRIS CHEMICALS\THALLIUM\BMD\POST EPR 6-2008\FEMALE\BEHAVIOR-FEMALE.plt 

 Fri Jun 13 09:26:52 2008 

 ==================================================================== 

 BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP(-slope*dose^power)] 

 Dependent variable = #Behavior 

 Independent variable = Dose(mg/kg-d) 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.109756 

 Slope = 9.64766 

 Power = 2.10563 

 Asymptotic Correlation Matrix of Parameter Estimates 

 Background Slope Power 

Background 1 0.017 0.017 

 Slope 0.017 1 1 

 Power 0.017 1 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.0625 0.0270671 0.00944955 0.11555 

 Slope 2.30426e+006 1.04698e+011 -2.05203e+011 2.05207e+011 

 Power 9.72683 28231.5 -55323 55342.4 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -29.9226 4 

 Fitted model -31.6523 3 3.45942 1 0.06289 

 Reduced model -36.6925 1 13.5399 3 0.003603 

 AIC: 69.3045 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0625 2.500 4 40 0.980 

 0.0080 0.0625 1.250 0 20 -1.155 

 0.0400 0.0625 1.250 1 20 -0.231 

 0.2000 0.3500 7.000 7 20 0.000 

 Chi^2 = 2.35 d.f. = 1 P-value = 0.1256 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

B-42 
B-43 

Confidence level = 0.95 

 BMD = 0.175955 

 BMDL = 0.0458492 

0

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0 0.05 0.1 0.15 0.2

Fraction Affected

dose

Weibull Model with 0.95 Confidence Level

09:26 06/13 2008

BMDL BMD

 

Weibull