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# Provisional Peer

- Reviewed Toxicity Values for

Thallium and Compounds

Metallic Thallium (7440

- 28

- 0), Thallium (I) acetate (563

- 68

- 8),
Thallium (I) carbonate (6533

- 73

- 9), Thallium (I) chloride (7791

- 12

- 0),
Thallium (I) nitrate (10102

- 45

- 1), and Thallium (I) sulfate (7446

- 18

- 6)

Superfund Health Risk Technical Support Center

National Center for Environmental Assessment Office of Research and Development
U.S. Environmental Protection Agency Cincinnati, OH 45268

### Thallium and Compounds i AUTHORS, CONTRIBUTORS, AND REVIEWERS

CHEMICAL MANAGER

Nina Ching Y. Wang, PhD National Center for Environmental Assessment, Cincinnati, OH

DRAFT DOCUMENT PREPARED BY

ICF International 9300 Lee Highway Fairfax, VA 22031

PRIMARY INTERNAL REVIEWERS

Ambuja Bale, PhD, DABT
National Center for Environmental Assessment, Washington, DC

Ghazi Dannan, PhD National Center for Environmental Assessment, Washington, DC

Paul G. Reinhart, PhD, DABT National Center for Environmental Assessment, Research Triangle Park, NC

Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development’s National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300)

### Thallium and Compounds ii TABLE OF CONTENTS

COMMONLY USED ABBREVIATIONS

................................................................................... iii

BACKGROUND .............................................................................................................................1

HISTORY ....................................................................................................................................1
DISCLAIMERS ...........................................................................................................................2 QUESTIONS REGARDING PPRTVS .......................................................................................2

INTRODUCTION ...........................................................................................................................2

REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) ..............3

HUMAN AND ANIMA L STUDIES ........................................................................................10 Carcinogenicity Studies ........................................................................................................ 10
Inhalati on Exposures ............................................................................................................. 10

DERIVATION OF PROVISIONAL VALUES ............................................................................10

DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES ........................................10
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS ..............................11
CANCER WEIGHT

- OF

- EVIDENCE DESCRIPTOR .............................................................11
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES ....................................11

APPENDIX A. PROVISIONAL SCREENING VALUES ..........................................................12

APPENDIX B. DATA TABLES ..................................................................................................17

APPENDIX C. REFERENCES ....................................................................................................20

### Thallium and Compounds iii COMMONLY USED ABBREVIATIONS

BMC Benchmark Concentration

BMD Benchmark Dose
BMCL Benchmark Concentration Lower bound 95% confidence interval

BMDL Benchmark Dose Lower bound 95% confidence interval
HEC Human Equivalent Concentration

HED Human Equivalent Dose
IRIS Integrated Risk Information System

IUR inhalation unit risk
LOAEL lowest -observed- adverse

- effect level
LOAEL ADJ 

### LOAEL adjusted to continuous exposure duration
LOAEL HEC 

### LOAEL adjusted for dosimetric differences across species to a human
NOAEL no-observed-adverse- effect level
NOAEL ADJ 

### NOAEL adjusted to continuous exposure duration
NOAEL HEC 

### NOAEL adjusted for dosimetric diff erences across species to a human
NOEL no-observed- effect level
OSF oral slope factor

p- IUR provisional inhalation unit risk

p- OSF provisional oral slope factor

p- RfC provisional reference concentration (inhalation)

p- RfD provisional reference dose (oral)
POD point of departure (oral)
RfC reference concentration (inhalation)
RfD reference dose

UF uncertainty factor

UF A 

### animal to human uncertainty factor

UF C 

### composite uncertainty factor

UF D 

### incomplete to complete database uncertainty factor

UF H 

### interhuman u ncertainty factor

UF L 

### LOAEL to NOAEL uncertainty factor

UF S 

### subchronic to chronic uncertainty factor
WOE weight of evidence

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Thallium and Compounds 1 PROVISIONAL PEER

- REVIEWED TOXICITY VALUES FOR THALLIUM AND
COMPOUNDS: METALLIC THALLIUM (7440-28-0), THALLIUM (I) ACETATE (563-68- 8), THALLIUM (I) CAR BONATE (6533-73-9), THALLIUM (I) CHLORID E (7791-12- 0), THALLIUM (I) NIT RATE (10102-45-1), THALLIUM (I) OX IDE (1314-12- 1), THALLIUM (III) O XIDE (1314-32-5), THALLIUM (I) SELENIT E (12039-52- 0), AND THALLIUM (I) SULFATE (7446-18-6)

BACKGROUND

HISTORY On December 5, 2003, the U.S. Environmental Protection Agency’s (EPA) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy:

1) EPA ’s Integrated Risk Information System (IRIS). 2) Provisional Peer- Reviewed Toxicity V alues (PPRTVs) used in EPA’s Superfund Program. 3) Other (peer -reviewed) toxicity values, including

 Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR),

 California Environmental Protection Agency (CalEPA) values, and

 EPA Health Effects Assessment Summary Table (HEAST) values.

A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA’s IRIS. PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scienti fic literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program.

This PPRTV assessment was developed using only information provided in the Toxicological Review of Thallium and Compounds (CAS No. 7440-28- 0) ( U.S. EPA, 2009 ) . All of the information provided in this document was available to peer reviewers according to the standard IRIS peer review process.

No toxicity values were posted on the IRIS database ( U.S. EPA, 2009 ) for thallium because of limitations in the database of toxicological information. However, the Toxicological Review presents information which could be used for development of an RfD. In this document, an appendix with a “screening subchronic and chronic p-RfD” is provided, recognizing the quality decrements, which may be of value under certain circumstances, described later in this
document.

Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5

- year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that a PPRTV cannot be derived based on inadequate data.

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Thallium and Compounds 2 DISCLAIMERS Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Su perfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.

It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV document and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development’s National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program.

QUESTIONS REGARDING PPRTVS Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development’s National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.

INTRODUCTION

An IRIS Toxicological Review of Thallium and Compounds was previously developed and posted ( http://www.epa.gov/iris/toxreviews/1012tr.pdf ). However, due to study an d data quality limitations as stated in the IRIS Toxicological Review , an RfD was not derived. Although these limitations preclude d the derivation of an RfD, there are dose- response data that

may be used in the derivation of screening subchronic and chron ic p- RfD s (see Appendix A)

. This PPRTV for Thallium and Compounds is based mostly on the IRIS Toxicological Review;
all relevant text and tables were either reproduced or adapted from the IRIS Toxicological

R eview.

Metallic thallium (Tl) is insoluble in water; however, the majority of the thallium salts are soluble in water with the exception of thallium (III) oxide. Thallium compounds and their chemical and physical properties are listed in Table 1. Thallium occurs naturally in the earth’s crust. It is used in industry, but is also released due to combustion of fossil fuels, refinement of oil fractions, smelting of ores, and by some other industrial processes such as cement production and brickworks ( Kazantzis, 2007 ; IPCS, 1996 ). A summary of past uses and possible health
effects of thallium (I) sulfate as cited in the IRIS Toxicological Review is provided as follows:

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Thallium and Compounds 3 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 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, 1991).

Table 1. Chemical and Physical Properties of Thallium and Selected Thallium Compounds a

Name CASRN Chemical
Formula Molecular Weight Melting Point (°C) Boiling Point (°C) Solubility in Water (g/L)

Metallic thallium 7440

- 28

- 0 T l 204.38 303.5 1457 Insoluble

Thallium (I) acetate 563

- 68

- 8 T l C 2 H 3 O 2 263.43 131 No data Very soluble

Thallium (I) carbonate 6533

- 73

- 9 T l 2 C O 3 468.78 273 No data 40.3 (15.5°C)

Thallium (I) chloride 7791

- 12

- 0 T l C l 239.84 430 720 Very soluble (20°C)

Thallium (I) nitrate 10102

- 45

- 1 T l NO 3 266.39 206 430 95.5 (20°C)

Thallium (I) oxide 1314

- 12

- 1 T l 2 O 424.77 596 No data Soluble (as T l OH)

Thallium (III) oxide 1314

- 32

- 5 T l 2 O 3 456.76 717 875 Insoluble

Thallium (I) selenite 12039

- 52

- 0 T l 2 Se O 3 535.72 No data No data No data

Thallium (I) sulfate 7446

- 18

- 6 T l 2 S O 4 504.82 632 Decomposes 48.7 (20°C)

a Sources: IPCS ( 1996 ) ; Downs ( 1993 ) ; ATSDR ( 1992 ) . Table was obtained directly from Table 2

- 1 in U.S. EPA ( 2009 ).



### REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)

Table 2 provides a summary of studies of thallium toxicity in humans. Table 3 provides a summary of oral toxicity studies of thallium (and compounds) in animals. No inhalation studies in animals or human were identified. A literature search through May 2009 was conducted in support of the IRIS Toxicological Review of Thallium and Compounds ( U.S. EPA,
2009 ) ; a n updated literature search was not conducted in developing the PPRTV for T hallium and Compounds. All p ertinent data on t hallium and related c ompounds have been reviewed by
IRIS

, and a Toxicological Review is available ( U.S. EPA, 2009 ) . Tables 2 and 3 are adapted from the Toxicological Review with minor clarifications (U.S. EPA ( 2009 ) , Tables 4-1 and 4-5, respectively ).

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Thallium and Compounds 4 Table 2. Thallium Toxicity In Humans Following Oral Exposure

Reference Sex Age Dose Symptoms a Final Outcome

Males

- Adult

Gefel et al. ( 1970 ) M ale 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 Death

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 Death within a week of
symptoms

Cavanagh
et al. ( 1974 ) Male 56 ye ars 0.93 g thallium (I)
acetate in 3 divided
doses Abdominal pain; diarrhea; vomiting; paresthesia; photophobia, nystagmus, visual impairment; facial weakness; bilateral ptosis Death within 3 weeks of
symptoms

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

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

Davis et al. ( 1981 ) Male 19 years 5

– 10 g thallium (I)
nitrate Nausea; vomiting; slurred speech; paresthesia of hands and feet; respiratory
weakness Death

Limos et al. ( 1982 ) Male 56 years Unknown Visual disturbances; alopecia; elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT); high blood glucose and creatine kinase; decreased myelinated fibers; denervated Schwann cell clusters Bedridden; could not speak

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 cel l clusters Residual tremors of the
extremities and muscle
weakness of the lower
limbs
Roby et al. ( 1984 ) Male 45 years Unknown; urine
thallium: 2000 μg/L Burning pain in feet; inability to walk; alopecia; acute fibrillation Continued neurological dysfunction

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 k eratohyalin granules in the epidermis; necrotic sebaceous glands; pustular lesions on the face: folliculitis and necrosis of the follicles; (feet) marked hyperkeratosis and hypergranulosis 4/5 recovered; 1/5 experienced permanent neurological damage

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Thallium and Compounds 5 Table 2. Thallium Toxicity In Humans Following Oral Exposure

Reference Sex Age Dose Symptoms a Final Outcome
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 Recovery

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 Recov ery

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 Recovery

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 Recovery

Sharma et al. ( 2004 ) Male 48 years Unknown; serum
thallium: 870 μg/100 mL urine
thallium: 5000 μg/mL Painful peripheral neuropathy; decreased consciousness Death

Females

- Adult
Roby et al. ( 1984 ) Female 51 years Unknown; serum
thallium: 50 μg/100 mL; urine thallium: 5000 μg/L Numbness and weakness of the legs and hands; alopecia; fluctuating pulse a nd blood pressure; bradycardia; hypotension Persistent ventricular ectopy and neurological dysfunction, necessitating placement at a nursing
home
Roby et al. ( 1984 ) Female 61 years Unknown; serum
thallium: 740 μg/100 mL Burning c hest pain; paresthesia; difficulty speaking and swallowing; inability to walk; hypotension; acute respiratory distress syndrome b (ARDS) Death

Roby et al. ( 1984 ) Female 80 years Unknown; serum
thallium: 422 μg/100 mL; urine thallium: 21,600 μg/L ARDS Death

Hoffman ( 2000 ) Female Pregnant; ages not specified 150

– 1350 mg thallium (I) sulfate Paresthesia; abdominal pain; muscle weakness; lethargy; alopecia; Mees lines [lines of discoloration across the nails of the fingers and toes] None specified

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Thallium and Compounds 6 Table 2. Thallium Toxicity In Humans Following Oral Exposure

Reference Sex Age Dose Symptoms a Final Outcome

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 specified

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 reported

Schoer ( 1984 ) ; Gosselin et
al. ( 1984 ) Both Adult 10

– 15 mg/kg thallium None specified Death (average lethal dose)

Rusyniak et
al. ( 2002 ) Both Various Unknown; various
l evels were detected in
urine Myalgia; arthralgia; paresthesia; dysesthesia; joint stiffness; insomnia; alopecia; abdominal pain Recovery in seven adults; five had ongoing psychiatric problems

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 Impairment of memory and verbal fluency remained at six months; neuropsychological impairment persisted at
nine months

Lu et al. ( 2007 ) ; Kuo
et al. ( 2005 ) Both 48 and 52

years 1.5 and 2.3 g/person (estimated); serum
thallium:
950−2056 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 post exposure); erythematous rash; diarrhea; urine retention; hyporeflexia; muscle weakness; hypoes thesia; 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.
Cutaneou s nerve biopsy: axonal degeneration; loss of epidermal nerves indicating involvement of the small sensory nerves (2 months). At 1

- year follow

- up, persistent paresthesia, dysesthesia, and impairment of small sensory nerve fibers in skin

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Thallium and Compounds 7 Table 2. Thallium Toxicity In Humans Following Oral Exposure

Reference Sex Age Dose Symptoms a Final Outcome

Children

Reed et al. ( 1963 ) Both 1

– 11

years Unknown Alopecia; lethargy; ataxia; abdominal pain; vomiting; abnormal reflexes; neuropathy; muscle weakness; coma; convulsion N e u rological abnormalities; retardation; psychosis;
death

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 Recovery

Hoffman ( 2000 ) Both Trans

placental Unknown Premature birth; low birth weight; alopecia None specified

Ammendola
et al. ( 2007 ) Male 16 years 1.3 g thallium sulfate;
urine thallium:
3400 μg/L Acute stage: gastrointestinal disturbances; alopecia; clinical and electrodiagnostic signs of severe polyneuropathy 3 years postpoisoning: neurological symptoms making progress; electrophysiological signs of peripheral neuropathy mainly confined to lower limbs. 6 years postpoisoning: persistent weakness and sensory
disturbances of distal lower
extremities ; neurological and electrodiagnostic abnormalities affecting mainly the feet.

a ALT = alanine aminotransferase; AST = aspartate aminotransferase

b ARDS = acute respiratory distress syndrome

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Thallium and Compounds 8 Table 3. Thallium Toxicity in Animals Following Oral Exposure a

Reference Species Age Sex Route Dose and Duration NOAEL LOAEL Effect

Acute studies

Leloux et al. ( 1987 ) Rat
3/sex Adult Both Oral (gavage) 20 mg/kg thallium (I)
nitr ate; single dose NI b 15 mg/kg Tl Difficulty breathing; rough coat; increased absolute kidney, adrenal weights; death

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; increased absolute kidney, eye weights; death

Mourelle et
al. ( 1988 ) Rat 10/group NS c 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: increased triglycerides and lipid peroxidation; decreased glutathione and glycogen; increased alkaline phosphatase in serum and liver cell
membranes

Subchronic studies

Downs et al. ( 1960 ) Rat/
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/kg

- day
Tl* 1.2 mg/kg

- day Tl* Alopecia; increased kidney weight; mortality in treated and control groups. *The NOAEL and LOAEL are for alopecia. Because of reported mortali ty in the control and treated groups, a study NOAEL and LOAEL cannot be reliably determined.

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/kg

- day Tl (20 ppm) Reduced body weight; alopecia; increased mortality; increased absolute and relative kidney weights

El

- Garawany
et al. ( 1990 ) Rat

n = 10 NS Male Oral d 0.8 mg/kg thallium (I) sulfate; 90 days NI 0.65 mg/kg

- day Tl Increased blood urea; serum creatinine; serum bilirubin; serum ALT

Manzo et al. ( 1983 ) Rat

n = 80 NS Female Oral (DW e ) 10 mg/L Tl as thallium (I) sulfate;
36 weeks NI 1.4 mg/kg

- day Tl Nerve histopathology; alopecia; mortality

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Thallium and Compounds 9 Table 3. Thallium Toxicity in Animals Following Oral Exposure a

Reference Species Age Sex Route Dose and Duration NOAEL LOAEL Effect

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/kg

- day
Tl f Increased incidence of alopecia and other observations related to coat (rough coat, piloerection, shedding); lacrimation, exophthalmos, and mi osis; and various behavioral observations; statistically significant increases in AST, LDH, and sodium levels; decreased blood sugar levels. The study authors identified 0.2 mg/kg

- day
Tl 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/kg

- day Tl Testicular effects: tubular epithelium disarrangement; cytoplasmic vacuolation;
reduced sperm motility; distention of smooth endoplasmic reticulum of Sertoli cells; reduced β

- glucuronidase activity

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/kg

- day Tl); 6 months NI 0.0003 mg/kg

- day
Tl Decreased sperm motility and counts; increase in deformed sperm; decrease in live
fetuses. Dose estimated from an assumed average body weight of 20 g and drinking water ingestion rate of 6 mL/day.

Rossi et al. ( 1988 ) Rat Perinatal Both [Oral (Mother’s, then pup’s DW)] 0, 1 mg/dL of thallium (I) sulfate Day 1 of gestation to weaning then thru
60 days NI NI Prenatal and postnatal exposure caused a delay in the development of the pilus apparatus [the formation of hair] by 50 days;
reduction of the α

- and β

- adrenergic and muscarinic vasomotor reactivity noted.

a U.S. EPA ( 2009 ) Table 4

- 5.

b NI = not identified.

c NS = not specified.

d Presumably via gavage.

e DW = drinking water.

f See discussion of the NOAEL and LOAEL determination in Section 5.1.1 of U.S. EPA ( 2009 ).

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Thallium and Compounds 10 HUMA N AND ANIMAL STUDIES Refer to the IRIS Toxicological Review ( U.S. EPA, 2009 ) for summaries of human and animal studies. The principal st udy selected for derivation of screening subchr onic and chronic

p- RfD s ( Midwest Research Institute, 1988 ) is summarized in Appendix A.

Carcinogenicity Studies No studies of the carcinogenicity of thallium or thallium compounds were identified in
the IRIS Toxic ological Review ( U.S. EPA, 2009 ).

Inhalation Exposures No studies were identified in the IRIS Toxicological Review ( U.S. EPA, 2009 ) regarding the effects of subchronic or chronic inhalation exposure of animals to thallium or thallium compounds.

DERIVATION OF PROVISIONAL VALUES

DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES Although there are substantial data available on human exposure to thallium, the majority are case reports of poisonings, suicide attempts, or accidental ingestion of rodenticides. There are two population surveys with oral thallium exposure through contaminated homegrown foods ( Dolgner et al., 1983 ; Brockhaus et al., 1981 ) . However, these studies are limited by the lack of objective tests for toxi city, 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 singl e point in time ( U.S. EPA, 2009 ). In addition, three occupational exposu re studies ( Ludolph et al., 1986 ; Marcus, 1985 ; Schaller et al., 1980 ) provide no conclusive associations between thallium exposure and any specific health effects, possibly due to the small study populations and study design limitations. Therefore, the available human studies are not suitable for
derivation of a p

- RfD

.

There are numerous animal studies on the effects of thallium; however only four
repeat -dose oral toxicity studies with more than one dose level were identifi ed ( Midwest

Res earch Institute, 1988 ; Wei, 1987 ; Zasukhina et al., 1983 ; Downs et al., 1960 ) . Wei ( 1987 ),
Zasukhina et al. ( 1983 ), and Downs et al. ( 1960 ) were not considered adequate for RfD derivation (see U.S. EPA ( 2009 ) for details). The MRI ( 1988 ) 90-day study in rats was evaluated in the IRIS Toxicological Review as a candidate principal study as the most comprehensive of the available thallium studies. Histopathological changes in the skin (hair follicle atrophy in high

- do se female rats with alopecia) and clinical observations, including those related to animal coat (rough coat, piloerection, shedding, and alopecia), eyes (including lacrimation, exophthalmos, and miosis), and behavior were considered as possible endpoints f or POD derivation.

The conclusion reached in the IRIS Toxicological Review of Thallium and Compounds ( U.S. EPA, 2009 ) was that 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 for RfD derivation 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

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Thallium and Compounds 11 inadequate examination of objective measures of neurotoxicity), and there are particular difficulties in the selection of appropriate endpoints. Therefore, a RfD for soluble thallium salts
was not derived.

However, Appendix A of this document contains Screening Values (screening subchronic and chronic p- RfD) that may be useful in certain instances. See the attached Appendix A.

DERIVATION OF INHALATION REFERENCE CONCENTRATIONS As reviewed in the Toxicological Review of Thallium and Compounds ( U.S. EPA, 2009 ) no subchronic or chronic p- RfC values can be derived because there are no suitable studies of inhalation exposures.

CANCER WEIGHT

- OF

- EVIDENCE DESCRIPTOR The Cancer WOE descriptor for thallium is provided in the Toxicological Review of
Thalliu m and Compounds ( U.S. EPA, 2009 ) as “ Inadequate Information to Assess Carcinogenic Potential (both oral and inhalation) .”

DERIVATION OF PROVISIONAL CANCER POTENCY VALUES The lack of data on the carcinogenicity o f any thallium compound as indicated in the
IRIS Toxic ological Review ( U.S. EPA, 2009 ) precludes the derivation of quantitative estimates for either oral (p -OSF) or inhalation (p-IUR) exposure.

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Thallium and Compounds 12 APPENDIX A. PROVISIONAL SCREENING VALUES

For the reasons noted in the main document, it is inappropriate to derive a subchronic or chronic p-RfD for thallium. However, information is available which, although insufficient to support derivation of a provisional toxicity value, under current guidelines, m ay be of limited use to risk assessors. In such cases, the Superfund Health Risk Technical Support Center summarizes available information in an appendix and develops a screening value. Users of screening toxicity values in an appendix to a PPRTV assessm ent should understand that there is considerably more uncertainty associated with the derivation of a supplemental screening toxicity value than for a value presented in the body of the assessment. Questions or concerns about the appropriate use of screening values should be directed to the Superfund Heath Risk Technical Support Center.

DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCES DOSES
The 90- day study by MRI ( 1988 ) is selected as the principal study for derivation of the screening subchronic and chronic p-RfD. This study was summarized in the Toxic ological
Review ( U.S. EPA, 2009 ) as follows:

In a study performed by Midwe st Research Institute ( Midwest Research Institute, 1988 ) for EPA’s Office of Solid Waste, male and female SpragueDawley 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 rats/sex/group; these examinations were appa rently 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 ( Midwest Research Institute, 1988 ) . The study authors concluded that the histopathologic examination did not reveal any

treatment

- related effects.

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Thallium and Compounds 13 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 ( see Table B.1;Midwest Research Institute, 1988 )

. 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) w ere also elevated in male and female rats at the higher doses ( see Table B.1; Midwest Research Institute, 1988 )

. As noted above, the incidence of alopecia was increased, particularly in female rats ( see Table B.2; Midwest Research Institute, 1988 ). 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. EPA, the incidence of alopecia (total number of cases in each dose group) was statistically significantly elevated relative to controls in mid -dose males and mid- and high-dose females. Most instances of alopecia in females

were a ttributed 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 atro phy 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.

Subtle but statistically significant changes were observed in several blood chemistry parameters that the investigators considered probably treatment
related ( Midwest Research Institute, 1988 ) . Specifically, dose- related 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 B.3. Other changes in blood chemistry parameters were less consistent across species, do se 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 ( Midwest Research Institute,
1988 ) . 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

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Thallium and Compounds 14 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.

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 identified the highest do se, 0.25 mg/kg- day thallium (I) sulfate (0.20 mg/kg

- day T l [2 moles of soluble thallium (I) in one mole of the soluble thallium salt, Tl 2 

### SO 4 

### ] ), as a no -observed- effect level (NOEL). However, after review, EPA ( 2009 ) came to different conclusions as indicated
below:

Several candidates for critical effects were con sidered, but ultimately EPA ( 2009 ) considered that only two endpoints were appropriate for RfD development: (1) hair follicle atrophy in female rats that also had alopecia and (2) clinical observations; those related to animal coat (rough coat, piloerection, shedding, and alopecia), eyes (including lacrimation, exophthalmos, and miosis) and behavior. Endpoint (2) was not selected as the critical effect in
this PPRTV because there is a high background occurrence of alopecia in control animals and the potential for misclassification. As a result, there is some uncertainty about the incidence of

treatment

- related alopecia in the treated animals. In addition, the underlying basis for oth er clinical observations is unknown. Endpoint (1) was selected as the critical effect because atrophy of hair follicles is consistent with the atrophic changes observed in the cases of human thallium poisoning (e.g., follicular plugging of the skin includ ing alopecia) and may be the best indicator for human response to thallium exposure. For this PPRTV, hair follicle atrophy is
selected as the critical effect because it may serve as a better indicator of alopecia resulting from thallium exposure.

The high dose (0.25 mg/kg- day thallium [I] sulfate or 0.2 mg/kg- day soluble Tl) was
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
0.05 mg/kg

- day thallium (I) sulf ate (Tl 2 

### SO 4 

### ) or 0.04 mg/kg- day Tl (soluble form) was used as the POD for hair follicle atrophy from the MRI (1988) study.

The screening subchronic p-RfD was derived using a composite UF of 1000 as follows:

Screening Subchronic p

- RfD = NOAEL ÷ UF C 

### (Thallium [I] Sulfate) = 0.05 mg/kg- day Tl 2 

### SO 4 

### ÷ 1000

= 5 × 10 -5 

### mg/kg

- day Thallium (I) Sulfate

Screening Subchronic p

- RfD = NOAEL ÷ UF C 

### (Soluble Thallium; 2 moles) = 0.04 mg/kg- day Tl ÷ 1000

= 4 × 10 -5 

### mg/kg -day Tl

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Thallium and Compounds 15 An interspecies UF A 

### of 10 is applied for extrapolation from laboratory animals to humans since no information is available to characterize the toxicokinetic or toxicodynamic differences between experimental animals and humans.

An intraspecies UF H 

### of 10 is applied to account for variation in human susceptibility in the absence of information on the variability of response to thallium in the human population.

A database UF D 

### of 10 is applied to account for a lack of adequate developmental toxicity
studies and a two- generation r eproductive study, and additional uncertainty associated with the limited data available on neurotoxicity.

An UF S 

### of 1 applied for extrapolation from subchronic studies since the principal study is considered a subchronic study.

An UF L 

### of 1 is applied to account for extrapolation from LOAEL to NOAEL, because a
NOAEL was utilized.

The screening chronic RfD was derived using a composite UF of 3000 as follows:

Screening Chronic p

- RfD = NOAEL ÷ UF C 

### (Thallium [I] Sulfate) = 0.05 mg/kg- day Tl 2 

### SO 4 

### ÷ 3000

= 2 × 10 -5 

### mg/kg

- day Thallium (I) Sulfate

Screening Chronic p

- RfD = NOAEL ÷ UF C 

### (Soluble Thallium; 2 moles) = 0.04 mg/kg- day Tl ÷ 3000

= 1 × 10 -5 

### mg/kg -day Tl

An interspecies UF A 

### of 10 is applied for extrapolation from laboratory animals to humans since no information is available to characterize the toxicokinetic or toxicodynamic differences between experimental animals and humans.

An intraspecies UF H 

### of 10 is applied to account for variation in human susceptibility in the absence of information on the variability of response to thallium in the human population.

A database UF D 

### of 10 is applied to account for a lack of adequate developmental toxicity
studies and a two- generation re productive study, and additional uncertainty associated with the limited data available on neurotoxicity.

An UF S 

### of 3 is applied to account for extrapolation from subchronic to chronic exposure
duration. As explained in the IRIS Toxicological Review

, “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 L 

### of 1 is applied to account for extrapolation from LOAEL to NOAEL, because a NOAEL was utilized

.

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Thallium and Compounds 16 Based on molecular weight (MW) adjustments and stoichiometri c calculations, a summary of screening subchronic and chronic p- RfDs for other soluble thallium salts is presented in Table A.1.

Table A.1. Screening Subchronic and Chronic p

- RfD s for Other Thallium Salts

Thallium S alt ( Formula ; MW) Screening Subchronic p

- RfD (mg/kg

- day) Screening Chronic p

- RfD (mg/kg

- day)

Thallium (I) acetate a 

### (TlC 2 

### H 3 

### O 2 

### ; 263.43) 3 × 10 - 5 

### 6 × 10 - 6



### Thallium (I) carbonate b



### (Tl 2 

### CO 3 

### ; 468.78) 5 × 10 - 5 

### 2 × 10 - 5



### Thallium (I) chloride a 

### (TlCl; 239.84) 2 × 10 - 5 

### 6 × 10 - 6



### Thallium (I) nitrate a 

### (Tl NO 3 

### ; 266.39) 3 × 10 - 5 

### 7 × 10 - 6

a Based on the screening p

- RfD for soluble thallium and the molecular weight conversion as follows: screening p

RfD of (1:1) thallium salt = screening p

- RfD of soluble thallium (2 moles) ÷ 2 × (Molecular weight of (1:1) thallium salt ÷ Molecular weight of one mole of thallium in the salt), rounded to one significant figure. For example, for the screening chronic p

- RfD of thalli um (I) acetate, 1 × 10 -5 mg/kg

- day Tl ÷ 2 × MW( TlC 2 H 3 O 2 )/MW(Tl) = 1 × 10 -5 mg/kg

- day ÷ 2 × (263.43/204.38) = 6 × 10 -6 mg/kg

- day

. b Based on the screening p

- RfD for thallium (I) sulfate and the molecular weight conversion as follows:

screening p- RfD of (2:1) thallium salt = screening p

- RfD of thallium (I) sulfate × (Molecular weight of (2:1) thallium salt ÷ Molecular weight of thallium [I] sulfate), rounded to one significant figure. For example, for the screening chronic p

- RfD of thallium (I) carbonate, 2 × 10 -5 mg/kg

- day Tl 2 SO 4 × MW(Tl 2 CO 3 )/MW(Tl 2 SO 4 ) = 2 ×
10 -5 mg/kg

- day × (468.78/504.82) = 2 × 10 -5 mg/kg

- day.

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Thallium and Compounds 17 APPENDIX B. DATA TABLES

Table B.1. Selected Clinical Observations in Sprague

- Dawley Rats Treated with Thallium Sulfate for 90 Days a

Observation b 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

Behavior c 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

Behavior c 2/20 2/20 0/20 1/20 7/20

a MRI ( 1988 ) . T able was obtained directly from Table 4

- 2 in U.S. EPA ( 2009 )

. b Listed as number of anima ls with the sign observed at least once during the 90

- day study.

c 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.

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Thallium and Compounds 18 Table B.2. Incidence of Alopecia in Rats a

Dose (mg/kg

- day T l ) Males Females
Alopecia b,c Hair follicle atrophy c Alopecia b,c Hair follicle atrophy d

0 (untreated control) 2/20

-- e 4/20

-- e

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

0.008 4/20

-- e 4/20

-- e

0.04 9/20 f

-- e 9/20 g

-- e

0.2 4/20 0/20 12/20 f 2/20

a MRI ( 1988 ) . Ta ble was obtained directly from Table 4

- 3 in U.S. EPA ( 2009 )

. b Number of animals with alopecia at least once during the 90

- day study based on clinical observations.

c Of the animals with alopecia, the following are the numbers of cases in each dose group that the study authors stated

are 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.

d Based on histopathologic observation.

e Skin was not examined for histopathologic lesions.

f 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 vehicl e and untreated control, based on Fisher’s exact test performed by EPA.

g 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.

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Thallium and Compounds 19 Table B.3. Selected Blood Chemistry Values a

Endpoint Study Day Untreated
Control Vehicle
Control 0.008 mg/kg

- day 0.04 mg/kg

- day 0.2 mg/kg

- day

Males b

AST (I.U.) 30
90 91 ± 26.5
77 ± 19.7 108 ± 18.6
87 ± 17.8 128 ± 24.5 c

99 ± 20.4 134 ± 29.0 c,d

113 ± 27.0 c,d 152 ± 20.1 c,d

114 ± 31.1 c,d

LDH (I.U.) 30
90 795 ± 322
587 ± 305 1206 ± 424 c

856 ± 385 1333 

### ± 340 c

1003 

### ± 363 c 1396 ± 407 c

1071 ± 507 c 1802 ± 341 c,d

1119 

### ± 477 c

Na (meq/L) 30
90 148 ± 1.3
144 ± 1.6 149 ± 2.4
147 ± 2.0 c 152 ± 4.0 c

147 ± 1.9 c 154 ± 2.5 c,d

149 ± 2.0 c,d 153 ± 2.1 c,d

151 ± 2.2 c,d

Blood sugar (mg/l00 mL) 30
90 100 ± 22.1
158 ± 15.6 97 ± 18.1
138 ± 16.8 c 93 ± 10.0
131 ± 17.6 c 90 ± 18.3
121 ± 15.7 c 62 ± 14.8 c,d

113 ± 22.4 c,d

Females b

AST (I.U.) 30
90 95 ± 22.8
77 ± 19.2 115 ± 30.3
90 ± 19.1 127 ± 27.8 c

93 ± 33.1 149 ± 26.8 c,d

111 ± 30.7 c 154 ± 18.2 c,d

112 ± 31.0 c

LDH (I.U.) 30
90 1047 ± 335
745 ± 320 1277 ± 495
881 ± 273 1402 ± 501
823 ± 354 1763 ± 370 c,d

1044 ± 436 1764 ± 361 c,d

1219 ± 338 b

Na (meq/L) 30
90 148 ± 1.7
146 ± 1.8 150 ± 1.9
146 ± 1.0 153 ± 4.1 c,d

148 ± 1.8 c,d 154 

### ± 2.8 c,d

150 ± 2.0 c,d 155 ± 2.5 c,d

152 ± 1.0 c,d

Blood sugar (mg/l00mL) 30
90 103 ± 23.9
110 ± 28.7 80 ± 13.3 c

89 ± 15.9 80 ± 9.0 c

103 ± 19.9 67 ± 20.0 c

88 ± 20.4 50 ± 11.8 c,d

70 ± 18.0 c

a MRI ( 1988 ) . Ta ble was obtained directly from Tabl e 4

- 4 in U.S. EPA ( 2009 )

. b Mean ± standard deviation of 7

– 10 rats.

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

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

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Thallium and Compounds 20 APPENDIX C. REFERENCES

Ammendola, A; Ammendola, E; Argenzio, F; Tedeschi, G. (2007). Clinical and electrodiagnostic follow -up of an adolescent poisoned with thallium. Neurol Sci 28: 205-
208. http://dx.doi.org/10.1007/s10072-007-0822-0

ATSDR (Agency for Toxic Substances and Disease Registry). (1992). Toxicological profile for thallium [ATSDR Tox Profile]. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. http://www.n tis.gov/search/product.aspx?ABBR=PB93110856

Atsmon, J; Taliansky, E; Landau, M; Neufeld, MY. (2000). Thallium poisoning in Israel. Am J
Med Sci 320: 327-330.

Brockhaus, A; Dolgner, R; Ewers, U; Krämer, U; Soddemann, H; Wiegand, H. (1981). Intake and health effects of thallium among a population living in the vicinit y of a cement plant emitting thallium containing dust. Int Arch Occup Environ Health 48: 375-389. http://dx.doi.org/10.1007/BF00378686

Cavanagh, JB; Fuller, NH; Johnson, HR; Rudge, P. (1974). The effects of thallium salts, with particular reference to the nervous system changes. A report of three cases. QJM 43: 293

- 319.

Davis, LE; Standefer, JC; Kornfeld, M; Abercrombie, DM; Butler, C. (1981). Acute thallium poisoning: Toxicological and morphological studies of the nervous system. Ann Neurol
10: 38-44. http://dx.doi.org/10.1002/ana.410100108

Dolgner, R; Brockhaus, A; Ewers, U; Wiegand, H; Majewski, F; Soddemann, H. (1983). Repeated surveillance of exposure to thallium in a population living in the vicinity of a cement plant emitting dust containing thallium. Int Arch Occup Environ Health 52: 79-
94. http://dx.doi.org/10.1007/BF00380610

Downs, AJ. (1993). Chemistry of aluminum, gallium, indium, and thallium. London, UK:
Blackie Academic & Professional.

Downs, WL; Scott, JK; Steadman, LT; Maynard, EA. (1960). Acute and sub- acute toxicity studies of thallium compounds. Am Ind Hyg Assoc J 21: 399-406. http://dx.doi.org/10.1080/00028896009344093

El

- Garawany, AA; Samaan, HA; Sadek, M. (1990). Comparative hepatorenal toxicity of some commonly used chemical environmental pollutants. Egypt J Pharmaceut Sci 31: 331-336.

Feldman, J; Levisohn, DR. (1993). Acute alop ecia: Clue to thallium toxicity. Pediatr Dermatol
10: 29-31. http://dx.doi.org/10.1111/j.1525-1470.1993.tb00007.x

Formigli, L; Scelsi, R; Poggi, P; Gregotti, C; Di Nucci, A; Sabbioni, E; Gottardi, L; Manzo, L. (1986). Thallium-induced testicular toxicity in the rat. Environ Res 40: 531-539. http://dx.doi.org/10.1016/S0013-9351(86)80128-1

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Thallium and Compounds 21 Gefel, A; Liron, M; Hirsch, W. (1970). Chronic thallium poisoning. Isr J Med Sci 6: 380-382.

Gosselin, RE; Smith, RP; Hodge, HC; Braddock, JE. (1984). Clinical toxicology of commercial products (5th ed.). Baltimore, MD: Williams and Wilkins.

Gregotti, C; Di Nucci, A; Formigli, L; Sabbioni, E; Manzo, L. (1985). Altered testicular enzyme patterns in rats after long -term exposure to thallium sulphate. J Toxicol Clin Exp 5: 265-
271.

Hantson, P; Desoir, R; Léonard, ED; Crutzen-Fayt, MC; Léonard, A; Mahieu, P. (1997). Cytogenetic observations following thallium poisoning. J Toxicol Environ Health A 50:
97-100. http://dx.doi.org/10.1080/009841097160500

Heyl, T; Barlow, RJ. (1989). Thallium poisoning: A dermatological perspective. Br J Dermatol
121: 787-791. http://dx.doi.org/10.1111/j.1365-2133.1989.tb08223.x

Hirata, M; Taoda, K; Ono

- Ogasawara, M; Takaya, M; Hisanaga, N. (1998). A probable case of chronic occupational thallium poisoning in a glass factory. Ind Health 36: 300-303. http://dx.doi.org/10.2486/indhealth.36.300

Hoffman, RS. (2000). Thallium poisoning during pregnancy: A case report and comprehensive
literature review [Review]. J Toxicol Clin Toxicol 38: 767-775. http://dx.doi.org/10.1081/CLT-100102390

IPCS (International Programme on Chemical Safety). (1996). Environmental health criteria: Thallium. Geneva, Switzerland. http://www.inchem.org/documents/ehc/ehc/ehc182.htm

Kazantzis, G. (2007). Thallium. In Handbook on the toxicology of metals. New York, NY:
Elsevier.

Kuo, HC; Huang, CC; Tsai, YT; Chu, CC; Hsieh, ST; Chu, NS. (2005). Acute painful neuropathy in thallium poisoning. Neurology 65: 302-304.

Leloux, MS; Lich, N; Claude, JR. (1987). Experimental studies on thallium toxicity in rats. I.
Localization and elimination of thallium after oral acute and sub -acute intoxication. J Toxicol Clin Exp 7: 247-257.

Limos, CL; Ohnishi, A; Suzuki, N; Kojima, N; Yoshimura, T; Goto, I; Kuroiwa, Y. (1982). Axonal degeneration and focal muscle fiber necrosis in human thallotoxicosis: Histopathological studies of nerve and musc le. Muscle Nerve 5: 698 -706. http://dx.doi.org/10.1002/mus.880050906

Lu, CI; Huang, CC; Chang, YC; Tsai, YT; Kuo, HC; Chuang, YH; Shih, TS. (2007). Short- term thallium intoxication: Dermatological findings correlated with thallium concentration.
Arch Dermatol 143: 93-98.

Ludolph, A; Elger, CE; Sennhenn, R; Bertram, HP. (1986). Chronic thallium exposure in cement plant workers: Clinical and electrophysiological data. Trace Elem Med 3: 121 -125.

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Thallium and Compounds 22 Manzo, L; Scelsi, R; Moglia, A. (1983). Long

- term toxicity of thallium in the rat. In Chemical toxicology and clinical chemistry of metals. London: London Academy Press.

Marcus, RL. (1985). Investigation of a working population exposed to thallium. Occup Med (Lond) 35: 4-9. http://dx.doi.org/10.1093/occmed/35.1.4

Midwest Research Institute. (1988). Toxicity of thallium (I) sulfate (CAS No. 7446-18-6) in Sprague -Dawley rats. Vol. 2. Subchronic (90-day) study. Rockville, MD: Dynamac Corporation.

Mourelle, M; Favari, L; Amezcua, JL. (1988). Protection against thallium hepatotoxicity by silymarin. J Appl Toxicol 8: 351-354. http://dx.doi.org/10.1002/jat.2550080503

Reed, D; Crawley, J; Faro, SN; Pieper, SJ; Kurland, LT. (1963). Thallotoxicosis. Acute manifestations and sequelae. JAMA 183: 516-522.

Roby, DS; Fein, AM; Bennett, RH; Morgan, LS; Zatuchni, J; Lippmann, ML. (1984). Cardiopulmonary effects of acute thallium poisoning. Chest 85: 236-240. http://dx.doi.org/10.1378/chest.85.2.236

Rossi, F; Marrazzo, R; Berrino, L; De Santis, D; Lisa, M; Susanna, V; Montanaro, C; Fici, F; Marmo, E. (1988). Prenatal and postnatal thallium exposure in rats: effect on development of vasomotor reactivity in pups. Teratog Carcinog Mutagen 8: 13-23. http://dx.doi.org/10.1002/tcm.1770080103

Rusyniak, DE; Furbee, RB; Kirk, MA. (2002). Thallium and arsenic poisoning in a small Midwestern town. Ann Emerg Med 39: 307-311. http://dx.doi.org/10.1067/mem.2002.122008

Saha, A; Sadhu, HG; Karnik, AB; Patel, TS; Sinha, SN; Saiyed, HN. (2004). Erosion of nails following thallium poisoning: A case report. Occup Environ Med 61: 640-642. http://dx.doi.org/10.1136/oem.2003.009464

Schaller, KH; Manke, G; Raithel, HJ; Bühlmeyer, G; Schmidt, M; Valentin, H. (1980). Investigation of thallium -exposed workers in cement factories. Int Arch Occup Environ
Health 47: 223-231. http://dx.doi.org/10.1007/BF00381680

Schoer, J. (1984). Thallium. In The handbook of environmental chemistry. Berlin: SpringerVerlag.

Sharma, AN; Nelson, LS; Hoffman, RS. (2004). Cerebrospinal fluid analysis in fatal thallium poisoning: evidence for delayed distribution into the central nervous system. Am J
Forensic Med Pathol 25: 156-158.

Tsai, YT; Huang, CC; Kuo, HC; Wang, HM; Shen, WS; Shih, TS; Chu, NS. (2006). Central nervous system effects in acute thallium poisoning. Neurotoxicology 27: 291-295. http://dx.doi.org/10.1016/j.neuro.2005.10.009

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9-19-2012

Thallium and Compounds 23 U.S. EPA (U.S. Environmental Protection Agency). (2009). Toxicological review of thallium and compounds [EPA Report]. Washington, DC.

Wei, QY. (1987). Studies on spermotoxicity of thallium carbonate in drinking water and its effect on reproductive function of mice. Zhonghua Yufang Yixue Zazhi 21: 141-143.

Yokoyama, K; Araki, S; Abe, H. (1990). Distribution of nerve conduction velocities in acute thallium poisoning. Muscle Nerve 13: 117-120. http://dx.doi.org/10.1002/mus.880130205

Zasukhina, GD; Vasilyeva, IM; Sdirkova, NI; Krasovsky, GN; Vasyukovich, LY; Kenesariev, UI; Butenko, PG. (1983). Mutagenic effect of thallium and mercury salts on rodent cells

w ith different repair activities. Mutat Res 124: 163 -173. http://dx.doi.org/10.1016/0165- 1218(83)90176-3