United States Office of Water EPA~440/'5-80-074
Environmental Protection Regulations and Standards October 1980
Agency Criteria and Standards Division
Washington DC 20480
&EPA Ambient
Water Quality
Criteria for
Thallium
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AMBIENT WATER QUALITY CRITERIA FOR
THALLIUM
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.'
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including^ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
""n Natural Resources Defense Counci 1. et. al.. ys. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicity
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects
Paul B. Hammond (author)
University of Cincinnati *
Christopher DeRosa (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Thomas Clarkson
University of Rochester
Karl L. Gabriel
Medical College of Pennsylvania
John W. All is, HERL
U.S. Environmental Protection Agency
J.B. Lai
National Institute of Occupational
Safety and Health
Gordon Newell
National Academy of Sciences
Rolf Hartung
University of Michigan
John Carroll
U.S. Environmental Protection Agency
S.M. Charbonneau
Health and Welfare, Canada
Patrick Durkin
Syracuse Research Corporation
David H. Groth
National Institute of Occupational
Safety and Health
Terri Laird, ECAO-Cin
U.S. Environmental Protection Agency
Steven B. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
William W. Sutton, EMSL-Las Vegas
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell , T. Highland, R. Rubinstein.
IV
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction * B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-2
Plant Effects B-2
Residues B-3
Miscellaneous B-3
Summary B-3
Criteria B-4
References B-ll
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-3
Inhalation C-5
Dermal C-6
Exposure to Thallium from Food, Water, and Air as a
Basis for Estimating Daily Absorption C-6
Pharmacokinetics C-7
Absorption C-8
Distribution C-9
Excretion C-ll
Total Daily Excretion of Thallium as a Basis for
Estimating Daily Absorption C-18
Body Burden of Thallium as a Basis for Estimating
Daily Absorption C-22
Effects C-23
Acute, Subacute and Chronic Toxicity C-23
Synergism and/or Antagonism C-32
Teratogenicity C-33
Mutagenicity C-34
Carcinogenicity C-34
Criterion Formulation C-35
Existing Guidelines and Standards C-35
Current Levels of Exposure C-35
Special Groups at Risk C-37
Basis and Derivation of Criterion C-38
References C-42
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CRITERIA DOCUMENT
THALLIUM
CRITERIA
Aouatlc Life
The available data for thallium indicate that acute and chronic toxicity
to freshwater aauatic life occur at concentrations as low as 1,400 and 40
ug/1, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested. Toxicity to one species of fish
occurs at concentrations as low as 20 yg/1 after 2,600 hours of exposure.
The available data for thallium indicate that acute toxicity to salt-
water aauatic life occurs at concentrations as low as 2,130 ug/1 and would
occur at lower concentrations among species that are more sensitive than
those tested. No data are available concerning the chronic toxicity of
thallium to sensitive saltwater aquatic life.
Human Health
For the protection of human health from the toxic properties of thallium
ingested through water and contaminated aauatic organisms, the ambient water
criterion is determined to be 13 yg/1.
For the protection of human health from the toxic properties of thallium
ingested through contaminated aauatic organisms alone, the ambient water
criterion is determined to be 48 yg/1.
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INTRODUCTION
Thallium is an element having the chemical symbol Tl and is a soft, mal-
leable, heavy metal with a silver-white luster (Lee, 1971). Industrial uses
of thallium include the manufacture of alloys, electronic devices, and spe-
cial glass. Many thallium-containing catalysts have been patented for in-
dustrial organic reactions (Zitko, 1975).* Production and use of thallium
and its compounds approximated 680 kg in 1976 (U.S. Dept. Interior, 1977;
Zitko, 1975).
Thallium has an atomic weight of 204.37, a melting point of 303.5°C, a
boiling point of 1,457 ^ 10°C, and a specific gravity of 11.85 at 20°C
(Weast, 1975). Thallium exists in either tne monovalent (thallous) or tri-
valent (thailie) form, the former being the more common and stable and
therefore forming more numerous and stable salts (Hampel, 1968). Thai lie
salts are readily reduced by common reducing agents to the thallous salts
(Standen, 1967).
Thallium is chemically reactive with air and moisture, oxidizing slowly
in air at 20°C and more rapidly as the temperature increases, with the pre-
sence of moisture enhancing this reaction (Standen, 1967). Thallous oxide,
formed by oxidizing the metal at low temperature, is easily oxidized to
thallic oxide or reduced to thallium. Thallous oxide is a very hygroscopic
compound and has a vapor pressure of 1 mm Hg at 580°C (Lee, 1971). Thallous
hydroxide is formed when thallium contacts water containing oxygen (Hampel,
1968). While thallium itself is relatively insoluble in water (Windholz,
1976), thallium compounds exhibit a wide range of soluoilities, as shown in
Table 1.
7C-I"
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TABLE 1
Water Solubilities of some Thallium Compounds3
Compound
Thallium sulfide
Thallium bromide
Thallium chromate
Thallium chloride
Thallium sulfate
Thallium carbonate
Thallium bromide
Thallium hydroxide13
Thai lium fluoride
Molecular Formula
T12S
TIBr
Tl£Cr04
T1C1
T12S04
T12C03
TIBr
T10H
TIP
Solubility
(mg/1)
220
240
300
2,100
27,000
42,000
160,000
259,000
520,000
780,000
Temperature
(°C)
20
0
60
0
0
15
20
0
40
15
aSource: Standen, 1967
bWeast, 1975
A-2
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REFERENCES
Hampel, C.A. (ed.) 1968. The Encyclopedia of Chemical Elements. Reinhold
Publishers, New York.
Lee, A.G. 1971. The Chemistry of Thallium. Elsevier Publishing Co.,
Amsterdam. *
Standen, A. (ed.) 1967. Kirk-Othmer Encyclopedia of Chemical Technology.
Interscience Publishers, New York.
U.S. Department of the Interior. 1977. Commodity data summaries. Bur.
Mines.
Weast, R.C. (ed.) 1975. Handbook of Chemistry and Physics. 56th ed. CRC
Press, Cleveland, Ohio.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
Zitko, V. 1975. Toxicity and pollution potential of thallium. Sci. Total
Environ. 4: 185.
A-3
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Aquatic Life Toxicology*
INTRODUCTION
The data base for the effects of thallium on freshwater organisms does
not permit any determination of the effects of water quality on toxicity.
There are sufficient data to indicate that thallium is chronically toxic to
fish and invertebrate species at concentrations as low as approximately 20
ug/1. Algae are also sensitive with effects occurring at concentrations as
low as 100 ug/1-
There are a variety of results for thallium and saltwater organisms
from tests conducted using static test procedures. No adverse acute effects
were observed at concentrations lower than 2,130 ug/1. An embryo-larval
test with the sheepshead minnow resulted in adverse effects at concentra-
tions as low as 8,400 ug/1, a concentration about one-half of the 96-hour
LCgQ for that species.
EFFECTS
Acute Toxicity
Daphnia magna 48-hour 50 percent effect concentrations were 2,180 and
910 ug/1 (Table 1). The fathead minnow was of similar sensitivity with a
96-hour LC50 of 1,800 ug/1 (Table 1). Two 96-hour LC50 values for the
bluegill were 132,000 and 121,000 ug/1 which results indicate that this spe-
cies is rather insensitive to thallium.
The saltwater shrimp species, Mysidopsis bahia, was more sensitive than
the tested fish species with an LC5Q value of 2,130 ug/1 (Table 1). The
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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sheepshead minnow (U.S. EPA, 1978) and the tidewater silverside (Dawson, et
al. 1977) are similarly sensitive with LC5Q values of 20,900 and 24,000
ug/1, respectively (Table I).
Chronic Toxicity
A life cycle test with Daphnia magna (Kimball, Manuscript) has been
conducted and the chronic value was 130 ug/1 (Table 2). The acute-chronic
ratio for this species is 7.0. *
An embryo-larval test has been conducted (U.S. EPA, 1978) with the fat-
head minnow and adverse effects were observed at the lowest tested thallium
concentration of 40 ug/1 (Table 2). Kimball (Manuscript) also conducted an
embryo-larval test with the same species and observed adverse effects at 81
ug/1 but not at 40 ug/1 (Table 2). When the chronic value for this species
(57 wg/1) is divided into the 96-hour LC5Q, an acute-chronic ratio of 32
results.
The only chronic test with a saltwater species has been conducted with
the sheepshead minnow (U.S. EPA, 1978). No adverse effects during an
embryo-larval test were observed at 4,300 ug/1 (Table 2). At 8,400 ug/1 ad-
verse effects were detected. The acute-chronic ratio for the sheepshead
minnow is 3.5.
Species mean acute and chronic values are summarized in Table 3.
Plant Effects
There was a 40 percent inhibition of oxygen evolution by the freshwater
alga, Chlamydomonas reinhardi, exposed to a concentration of 40,800 ug/1
(Table 4). The 96-hour EC,-,, values for chlorophyll £ inhibition and cell
number of the alga, Selenastrum caporicornutum, was 110 and 100 ug/1, re-
spectively (U.S. EPA, 1978).
B-2
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There was a 50 percent inhibition of photosynthesis by two saltwater
algal species at thallium concentrations of 4,080 and 51,200 ug/1 (Table 4).
Residues
Muscle tissue of Atlantic salmon (Zitko, et al. 1975) bioconcentrated
thallium to a concentration 130 times that in the water (Table 5). The
bluegill (whole body) bioconcentrated thallium 34 times and the tissue half-
life was greater than 4 days (U.S. EPA, 1978).
Zitko and Carson (1975) observed bioconcentration factors of 18 and 12
for the soft shell clam and blue mussel, respectively (Table 5). These re-
sults indicate that saltwater clams and mussels do not bioconcentrate thal-
lium as much as freshwater fishes.
Miscellaneous
Zitko, et al. (1975) exposed Atlantic salmon for as long as 2,600 hours
and observed 40 and 70 percent mortality at approximately 20 and 45 wg/l»
respectively (Table 6). No effects were observed for other species at con-
centrations close to those affecting the salmon.
Early development of sea urchin eggs was inhibited at concentrations of
thallium between 41,000 and 204,000 wg/1 (Table 6).
Summary
Daphnia magna and the fathead minnow were of similar acute sensitivity
to thallium with LC^Q values in the range of concentrations from 910 to
2,180 yg/1. The bluegill LCgg values were about two orders of magnitude
higher. The chronic values for Daphnia magna and the fathead minnow were
also similar, 130 and 57 ug/1, respectively. There were 50 percent reduc-
tions in chlorophyll a_ and cell numbers of an alga at concentrations of 110
and 100 ug/l» respectively. The highest bioconcentration factor for fishes
B-3
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was' 130 for muscle tissue of Atlantic salmon. This species apparently is
rather sensitive to thallium with partial mortality after about 100 days ex-
posure to concentratons as low as 20 wg/1.
The sheepshead minnow and tidewater silverside were of similar sensi-
tivity to thallium with 96-hour LCgQ values of 20,900 and 24,000 wg/1, re-
spectively. The mysid shrimp was more sensitive with an lC,-n value of
2,130 wg/1. Chronic effects on the sheepshead minnow were observed at 8,400
wg/1. There was a 50 percent inhibition of photosynthesis in a saltwater
algal species at 4,080 ug/1. Two bivalve species were exposed for 40 and 88
days and the bioconcentration factors were less than 20.
CRITERIA
The available data for thallium indicate that acute and chronic tox-
icity to freshwater aquatic life occur at concentrations as low as 1,400 and
40 wg/1, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested. Toxicity to one species of fish
occurs at concentrations as low as 20 wg/1 after 2,600 hours of exposure.
The available data for thallium indicate that acute toxicity to salt-
water aquatic life occurs at concentrations as low as 2,130 wg/1 and would
occur at lower concentrations among species that are more sensitive than
those tested. No data are available concerning the chronic toxicity of
thallium to sensitive saltwater aquatic life.
B-4
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Table 1. Acute values for thai HIM
to
I
Species Mean
LC50/EC50 Acute Value
Species Method* (ua/D (W9/D
FRESHWATER SPECIES
Cladoceran, S, U 2,180
Daphnia magna
Cladoceran, S, H 910 1,400
Daphnia roagna
Fathead minnow, FT, M 1,800 1,800
Plmephales promelas
Blueglll, S, U 132,000
Lepofflls macrochlrus
Bluegill, S, U 121,000 126,000
Lepomis macroch i rus
SALTWATER SPECIES
Mysid shriRf>, S, U 2,130 2,130
Hysldopsls bah la
Sheepshead minnow, S, U 20,900 20,900
Cyprtnodon variegatus
Tidewater silverside, S, U 24,000 24,000
Henidia beryl Una
Reference
U.S. EPA, 1978
Klnball, Manuscript
Mwball, Manuscript
Oawson, et at. 1977
U.S. EPA, 1978
*
U.S. EPA, 1978
U.S. EPA, 1978
Dawson, et al. 1977
* S = static, FT = flow-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the mini gun data base requirements are not met.
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Table 2. Chronic values for thallium
Species
Cladoceran,
Daphnla magna
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
LlMltS
Method* (U9/I)
Species Mean
Chronic Value
(ug/l)
FRESHWATER SPECIES
LC 100-181 130
E-L <40
E-L 40-81 57
Reference
Kimbal I, Manuscript
U.S. EPA, 1978
KimbalI, Manuscript
CO
I
Sheepshead minnow,
Cyprlnodon varlegatus
SALTWATER SPECIES
E-L 4,300- 6,000
8,400
U.S. EPA, 1978
* E-L = embryo-larva I, LC = life cycle or partial life cycle
Acute-Chronic Ratios
Species
Cladoceran,
Daphnia magna
Fathead minnow,
Plmephales promelas
ChronIc
Value
(U9/I)
130
57
Sheepshead minnow, 6,000
Cyprlnodon varlegatus
Acute
Value
(ug/l)
910
1,800
20,900
Ratio
7.0
32
3.5
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Table 3. Species Mean acute and chronic values for thai HIM
I
-J
Nunber
3
2
1
3
2
1
Species
Blueglll,
Lepomls macrochlrus
Fathead minnow,
Plmephales prontelas
Cladoceran,
Daphnla magna
Tidewater sllverslde,
Menldia beryl Una
Sheepshead minnow,
Cyprlnodon varlegatus
Mysid shrimp,
Mysldopsls bah la
Species Mean Species Mean
Acute Value* Chronic Value
(ug/l) (ug/l)
FRESHWATER SPECIES
126,000
1,800 57
1,400 130
SALTWATER SPECIES
24,000
20,900 6,000
2,130
Acute-Chronic
Ratio"
32
7.0
3.5
* Rank from high concentration to low concentration by species mean acute value.
**See the Guidelines for derivation of this ratio.
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Table 4. Plant values for thai HUM
Species
Alga,
Ch 1 amydomonas relnhardl
Alga,
Selenastrum capr 1 cornutum
Alga,
Selenastrum capr 1 cornutum
Effect
FRESHWATER SPECIES
40? Inhibition of
oxygen evo 1 ut Ion
96-hr EC50 for
ch 1 orophy 1 1 a
Inhibition
96-hr EC50 for
eel 1 number
Result
(ug/l)
40,800
110
too
Reference
Overnel 1,
U.S. EPA,
U.S. EPA,
1975a
1978
1978
CO
I
oo
Alga,
Dunallella tertollecta
SALTWATER SPECIES
50J inhibition of 4,080 Overnel I, 1975b
photosynthesis „
Alga, 50* inhibition of 51,200 OvernelI, 1975b
Phaeodactylum trIcornutum photosynthesis
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Table 5. Residues for thallium
CD
1
VD
Species
Atlantic salmon
( juvenl le),
Sal mo salar
Bluegill,
Lepomis macrochirus
Soft shel 1 clam,
Mya arenaria
Blue mussel,
Myt i 1 us edu 1 i s
B locon cent rat Ion
T 1 ssue Factor
FRESHWATER
muscle tissue
whole body
SALTWATER
edible portion
edible portion
SPECIES
130
34
SPECIES
18
12
Duration
(days)
12.5
28
88
40
Reference
Zitko, et al.
U.S. EPA, 1978
Z 1 tko i Carson
Zltko & Carson
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Table 6. Otter data for thai HIM
I
H
O
Cladoceran,
Daphnla sp.
Rainbow trout,
Salmo galrdneri
Atlantic salmon
(juveni le),
Sal mo salar
Atlantic salmon
(juvenile),
Salmo salar
Fathead minnow,
Pltnephales promelas
Frog (embryo),
(unidentified)
Duration Effect
FRESHWATER SPECIES
3 days Initial effects
3 days Initial effects
2,600 hrs LC40
2,600 hrs
LC70
7 days LC50
56 days Mortality
Result
(U9/I)
2,000-
4,000
10,000-
15,000
20
Reference
Nehrlng, 1962
Nehrlng, 1962
Zltko, et al. 1975
45 Zltko, et al. 1975
800 U.S. EPA, t978
409 0111 ing & Healey,
1926
Sea urchin,
Paracentrotus llvldus
SALTWATER SPECIES
Cessation of early
development of
ferti I ized eggs:
4 eel I stage
8-16 eel I stage
Blastula
204,000
82,000
41,000
Lai Her, 1968
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REFERENCES
Dawson, C.W., et al. 1977. The acute toxicity of 47 industrial chemicals
to fresh and saltwater fishes. Jour. Hazard. Mater. 1: 303.
Dilling, W.J. and C.W. Healey. 1926. Influence of lead and the metallic
*
ions of copper, zinc, thorium, beryllium and thallium on the germination of
frogs' spawn and on the growth of tadpoles. Ann. Appl. Biol. 13: 177.
Kimball, G. The effects of lesser known metals and one organic to fathead
minnows (Pimephales promelas) and Daphnia magna. Manuscript.
Lallier, R. 1968. Investigation of the toxicity of thallium ions in the
eggs of the sea urchin, Paracentrotus lividus. C.R. Acad. Sci. Paris
267: 962.
Nehring, D. 1962. Experiments on the toxicological effect of thallium ions
on fish and fish-food organisms. Zeitz. Fisch. 11: 557.
Overnell, J. 1975a. Effect of some heavy metal ions on photosynthesis in a
freshwater alga. Pest. Biochem. Physiol. 5: 19.
Overnell, J. 1975b. The effect of heavy meals on photosynthesis and loss
of cell potassium in two species of marine algae, Dunaliella tertiolecta and
Phaedoctylum tricornutum. Mar. Biol. 29: 99.
B-ll
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U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-
4646.
Zitko, V. and W.V. Carson. 1975. Accumulation of thallium in clams and
mussels. Bull. Environ. Contam. Toxicol. 14: 530.
•&
Zitko, V., et al. 1975. Thallium: Occurrence in the environment and tox-
icity to fish. Bull. Environ. Contam. Toxicol. 13: 23.
B-12
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
The major problem in assessing the amount of thallium ingested
from water is the inadequate sensitivity of analytical methods for
thallium. An almost equally serious problem is the limited amount
of information available utilizing even the inadequate methodolo-
gies currently available. As a matter of fact, essentially all the
information available is to be found in two reports. The first of
these is a U.S. EPA study which was conducted in cooperation with
the National Heart and Lung Institute and the National Center for
Health Statistics. Its main purpose was to delineate the occur-
rence of inorganics in household tap water and relationships to
cardiovascular mortality rates (Greathouse, 1978). The second
study was not concerned with average or usual exposures. Rather,
it was concerned with worse situations, namely the concentration of
thallium in the run-off from slag heaps and holding ponds associ-
ated with ore processing and mining operations (U.S. EPA, 1977).
In the first study grab samples of tap water were taken from
3,834 homes. The study began in July 1974 and was completed in
December 1975. Multi-elemental analyses were conducted using pro-
ton-induced x-ray emission (PIXE). The procedure and its charac-
teristics of precision and sensitivity are described in a separate
report (U.S. EPA, 1978a). The limit of detectability as applied to
water was 0.3 ppb. Samples of tap water were collected from 3,834
households which were randomly selected from 35 geographic areas by
C-l
-------
the Bureau of Census to provide a "representative" sample of the
U.S. population. Thallium was detectable in only 0.68 percent of
the samples. The average thallium concentration, when detectable,
was 0.89 ppb. Assuming a water consumption of 2 1/d for the average
adult, over 99 percent of adults would consume <1 ug Tl per day.
So far as worse situations are concerned, the so-called Cal-
span Report (U.S. EPA, 1978a) reviews in great detail the basis for
concluding that the leaching of thallium from ore processing opera-
tions is the major source of elevated thallium concentrations in
water. Thallium is a trace metal associated with copper, gold,
zinc and cadmium. Thus, wherever these metals have been mined and
processed, an enrichment of the environment with thallium was also
suspected to occur. This led to analyses of run-offs from mining
and smelting operations involving these other metals. The sensiti-
vity of the analytical methodology for thallium was not as good as
for the tap water studies referred to earlier. The overall limit
of sensitivity was reported to be 10 ppb, but values as low as 3 ppb
are reported. It is not clear how this apparent shift in sensiti-
vity occurred. Mines and processing operations from Washington and
California to New Jersey and Pennsylvania were studied. The high-
est concentrations reported were 30 ppb in slag run-off near Kel-
logg, Idaho and 21 ppb in the Colorado River just below the Big Wil-
liams River which drains the Planet Mine, an operation in which
copper is extracted from iron ore. It is not at all clear as to how
much of the Colorado River thallium came from that particular mine,
since this was a generally ore-rich area. The only other source of
information as to discharges from Canadian ore operations into
C-2
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streams is a study by Zitko, et al. (1975) in which he indicates
concentrations of 0.7-88 ppb.
Ingestion from Food
Data concerning the intake of thallium from food are sparse.
So far as thallium in man's usual diet is concerned, only three
studies are available. They provide only a limited indication as
»
to what might constitute the total contribution of food to daily
intake under normal circumstances. Vegetables (lettuce, red cab-
bage, green cabbage, leek, and endive) averaged 68.2 ppb dry weight
(Geilmann, et al. 1960). Assuming 85 percent water content, this
would amount to 10 ppb, wet weight. From the same study, bread con-
tained 0.75 ppb, dry weight. The only data concerning thallium in
meat report that the concentration in rib eye beef and veal is
<0.5 ppm (Mitteldorf and Landon, 1952). Due to the poor analyti-
cal sensitivity, this study is not very helpful. It seems unlike-
ly, however, that meats contribute as much thallium to the total
diet as vegetables. This is based on two considerations: 1) vege-
tarians excrete in their urine four times as much thallium as non-
vegetarians (Weinig and Zink, 1967); and 2) the concentration of
thallium in human skeletal muscle is only approximately 1 ppb (Wei-
nig and Zink, 1967). This raises the interesting question as to
why vegetables should contain so much more thallium than meat. It
is possible that this is related to the relatively high concentra-
tion of thallium in fertilizer. Geilmann, et al. (1960) found 37-
230 ug Tl/kg in 4 samples of potash fertilizers containing 35 to 43
percent potassium. Since these studies were conducted on a very
limited number of vegetables and fertilizer samples in Germany, it
C-3
-------
is difficult to estimate just how representative these data are of
the situation in the U.S. In any event, if one accepts that most
dietary thallium is to be found in vegetables and that 10 ppb is the
average fresh weight concentration, an estimate can be made as to
the contribution of food to total intake of thallium in man. The
average adult consumption of vegetables in the U.S. is estimated at
*
0.38 kg/d (Toscano, 1975), and the total food consumption is 1.6
kg/d (U.S. Dep. of Agric., 1968). Assuming the cited concentration
figures are correct and they apply to the average diet of vegeta-
bles, the daily intake of thallium from vegetables would be (0.38)
X (10 jug) or 3.8 jag. As will be shown in the section on Criterion
Formulation, this is probably a high estimate. In all probability,
the data cited as to concentrations of thallium in a few selected
vegetables are really not representative of what is normally eaten
in the category of vegetables. Based on the solubility character-
istics of thallium, it is also possible that a good deal of thal-
lium is leached out during food preparation.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. An appropriate BCF can be used with data concern-
ing food intake to calculate the amount of thallium which might be
ingested from the consumption of fish and shellfish. Residue data
for a variety of inorganic compounds indicate that bioconcentration
factors for the edible portion of most aquatic animals is similar,
except that for some compounds bivalve molluscs (clams, oysters,
scallops, and mussels) should be considered a separate group. An
analysis (U.S. EPA, 1980) of data from a food survey was used to
C-4
-------
estimate that the per capita consumption of freshwater and estua-
rine fish and shellfish is 6.5 g/day (Stephan, 1980). The per
capita consumption of bivalve molluscs is 0.8 g/day and that of all
other freshwater and estuarine fish and shellfish is 5.7 g/day.
Zitko, et al. (1975) reported a BCP of 130 for thallium in
muscle of atlantic salmon, whereas Zitko and Carson (1975) found
BCP values of 18 and 12 for the edible portions of the soft shell
clam and blue mussel, respectively. If 130 and the geometric mean
of 18 and 12 are used with the consumption data, the weighted aver-
age bioconcentration factor for thallium and the edible portion of
all freshwater and estuarine aquatic organisms consumed by
Americans is calculated to be 116.
Inhalation
The concentration of thallium in ambient urban air from six
major U.S. cities was reported in a U.S. EPA study conducted by
Battelle Columbus Laboratories (U.S. EPA, 1971). The concentra-
tions of thallium were given as weighted averages from data from
all cities: low, ^_.02; high, 0.1 and typical, <^0.04.
The concentration of thallium in fly ash has been estimated,
however, and on this basis the ground level concentration of thal-
lium near a coal-fired plant might be 700 ug/m (Carson and Smith,
1977). This can hardly be used as a basis for judging usual expo-
sure for the general population, but it does suggest a worse case
situation. Assuming inhalation of 20 m /d and 35 percent retention
of the thallium-bearing aerosol, 700 ng Tl/m would result in the
daily absorption of 4.9 ug Tl. The air level in Chadron, Nebraska
is stated to be .04-.48 ng Tl/m . This may be the more typical level
C-5
-------
of exposure (Carson and Smith, 1977). Assuming 20 m /d inhalation
and 35 percent retention, 0.48 ng/m = 3.4 ng Tl/d from air.
Inhalation of thallium in cigarette smoke may, on the other
hand, be a very significant source. The urinary excretion of thal-
lium in smokers is about twice that in non-smokers (Weinig and
Zink, 1967) and the concentration in cigar stubs was shown to be
57-170 ng/g (Geilmann, et al. 1960f, about 20 times the concentra-
tion estimated for the diet.
Dermal
The dermal absorption of thallium presumably would normally
occur as a result of bathing and from contact with thallium in
clothing. It is virtually impossible to estimate the contribution
of these potential sources to total intake. Suffice it to say that
the concentration of thallium in tap water is less than in body
tissues (<0.3 tig/1 vs.—" 1 ug/kg in tissues). From this it would
seem that the net flux of thallium as a result of bathing would, if
anything, be outward rather than inward. As to thallium in cloth-
ing, there does not appear to be any information.
Exposure to Thallium from Food, Water and Air as a Basis for Es-
timating Daily Absorption
In summary, this section on various sources of exposure pro-
vides only a very broad perspective as to the relative contribu-
tions of known environmental media to which the general population
is exposed. The most reliable data, fortuitously, concern thal-
lium in drinking water. It is possible to state with reasonable
assurance that >99 percent of Americans probably absorb
-------
3.8 ug/day (see Ingestion from Foods) and air is probably an insig-
nificant source, being probably no more than 3.4 ng/day (see Inhal-
a tion). If foods other than vegetables are assumed to have a con-
centration of 1 jug/kg, then their contribution at approximate con-
sumption levels of 1.2 kg (total daily consumption of 1.6 kg minus
daily vegetable consumption of 0.38 kg) would be 1.2 ug/day, i.e.
(1.2 kg/day x 1 jug Tl/kg in non-vegetable food). Thus, the total
daily input based on data reviewed above is "Cl ug (water) + 3.8 ug
(vegetables) + .0034 ug (air) + 1.2 jug (non-vegetable food)
-------
which man is exposed via water, attention will be drawn wherever
possible to the distinction between the pharmacokinetics of massive
doses and the pharmacokinetics of small doses. Unfortunately, such
distinctions can be drawn only from consideration of animal data.
Absorption
The only study of gastrointestinal absorption in man was con-
ducted in a middle-aged woman with terminal osteogenic carcinoma
(Barclay, et al. 1953). Following oral administration of a single
204
tracer dose of Tl, only approximately 0.5 percent of the dose
was excreted in the feces during the succeeding 72 hours, while
urinary excretion rose dramatically. This suggests that no bolus
204
of Tl passed unabsorbed. Complete absorption of tracer doses of
204
Tl administered orally in rats is suggested by the data of Lie,
et al. (1960). They found approximately the same fraction of a
204
single tracer dose of Tl in various organs at 1, 2 and 7 days
regardless of whether the dose was given orally or by any one of
four parenteral routes. There is no information available concern-
ing the deposition and clearance of inhaled thallium aerosols. As
with almost all metallic salts, the pattern of deposition of thal-
lium aerosols would depend upon particle size (aerodynamic); and
the rate of clearance would depend upon the solubility of the salt.
From the report of the Task Group on Lung Dynamics it would be pre-
dicted, however, that all salts of thallium (oxide, hydroxide and
halide excepted) would be cleared rapidly (days) and that none
would be cleared slowly (years) (ICRP, 1966).
The skin as a route of absorption has not received much atten-
tion, as is the case with most metallic salts. At one time thallium
C-8
-------
was applied to the skin as an ointment containing 3 to 8 percent
thallous acetate. Numerous cases of systemic poisoning have been
documented to result from this practice (Munch, 1934). This does
not mean that skin is a significant portal of entry under usual ex-
posure conditions however. The net movement of thallium through
the skin is dependent on the concentration gradient, and the con-
*•
centration of thallium to which the skin is normally exposed is
miniscule in comparison to the concentration under which signifi-
cant absorption has been demonstrated.
As a summary statement it may be said with reasonable confi-
dence that thallium is completely absorbed from all the usual por-
tals of entry, with the possible exception of the skin.
Distribution
Thallium is widely distributed in the body. It is distributed
preferentially to the intracellular space. Based on tracer studies
in rats, the apparent volume of distribution has been calculated to
be 20 I/kg (Rauws, 1974). This indicates a high degree of concen-
tration in one or more parts of the body. To some extent at least,
this preferential intracellular distribution is analogous and re-
lated to mechanisms which favor the intracellular localization of
potassium. Active transport of thallium into erythrocytes, medi-
ated by (Na-K)ATPase, has been demonstrated by a number of investi-
gators (Gehring and Hammond, 1964; Cavieres and Ellroy, 1974). In
spite of the considerable avidity of erythrocytes for thallium,
Rauws (1974) estimated that, in rats at least, under steady state
conditions 61 percent was distributed to the blood cells as com-
pared to 39 percent in the plasma. Gibson and Becker (1970)
C-9
-------
similarly reported a cell-plasma ratio of 1.5-2 in rats. The very
minor degree of preferential thallium distribution to blood cells
is probably due to the very high concentration of potassium in the
blood, which competes with thallium for active transport. Factors
other than active transport into cells must be operative in the
localization of thallium in various organs and systems, since there
&
does exist some organ-specific concentration. Thus, in both condi-
tions of normal thallium exposure and fatal exposure in man, there
is a tendency for thallium to concentrate in the kidneys, colon and
hair (Weinig and Zink, 1967; Cavanagh, et al. 1974). In other re-
spects the distribution of thallium is not remarkable.
Thallium distributes rather freely from the maternal circula-
tion to the fetus. The fetal-maternal ratios of tracer doses of
O C\ A
Tl in rats and mice are reported to be, respectively, 0.84 and
0.46 under steady state conditions (Gibson, et al. 1967). These
observations were made on gestation days 18 and 19 for mice and
rats respectively. It was also found that thallium administered on
days 1 and 7 postnatally was distributed in a manner quite similar
to that for adult animals. In a later publication, Gibson and
Becker (1970) reported that simultaneous thallium ratios in whole
fetuses and in maternal rat blood plasma were approximately 0.07
over a wide range of thallium infusion rates (0.2-6.4 mg/min/kg),
indicating that dosage does not seem to alter the kinetics of dis-
tribution from mother to fetus. The fetal-maternal ratio in this
instance is not contradictory to the authors' earlier observation,
cited above, that fetal-maternal ratios in rats and mice are 0.84
and 0.46, respectively, since steady state conditions did not
C-10
-------
prevail in the latter study. Low dietary potassium did not signif-
icantly alter fetal-maternal distribution of thallium.
So far as distribution of thallium to the human fetus is con-
cerned, there is essentially no quantitative data. One report in-
dicates that no thallium was found in the 5-month fetus of a woman
who died of thallium poisoning. Thallium was demonstrated in vari-
**
ous tissues of the mother (Neal, et al. 1935). Absence of detect-
able thallium in this fetus does not rule out its presence, even at
abnormally high concentrations since the spectrographic method used
probably was neither very sensitive nor very precise. It is only
possible to surmise that fetal concentrations were lower than ma-
ternal concentrations. Richeson (1958) cites one report in which
thallium was found in the tissues of a baby whose mother had taken
1.2 g thallium at term. The infant died five days after birth.
Excretion
There have been numerous reports of the characteristics of
204
thallium excretion in animals using both tracer doses of Tl and
rather large (up to 10 mg/kg) carrier doses. By contrast, there
are only two studies reported of thallium excretion in man from
which may be derived any useful kinetic constants. Worse, each of
these two studies involved only a single subject. This serious
limitation must be remembered in judging the reliability of the
safety assessment which ultimately must be made in this document.
The first study traced the fate of an orally-administered
204
tracer dose of Tl given to a middle-age woman with osteogenic
carcinoma metastatic to the lungs (Barclay, et al. 1953). The
dose of thallium given was 0.5 mci, containing 2.3 mg total
Oil
-------
thallium. In addition, single oral doses of 45 mg non-radioactive
thallium sulfate (presumably » 8.7 mg Tl) were also given every 3
days until 225 mg had been administered. Excretion of radioacti-
vity in the urine and feces was determined for the succeeding 5.5
days. It is evident that fecal excretion was inconsequential as
compared to urinary excretion (Figure 1). Based on these data, a
& -. 1
first order rate constant of 0.032 day" was estimated for excre-
tion. The t^ for rate of excretion of the dose would therefore be
21.7 days. Based on a rate constant of 0.032 day , the amount of
thallium remaining in the body at the time of death (24 days after
204
administration of Tl) would have been 46.3 percent of the dose
from:
where:
A a percent dose in body at 24 d
AQ » 100 percent
k » 0.032
t • 24 d
The amount actually recovered in the body at the time of death
was stated to be 45 percent. It is not clear how this figure was
204
obtained. The cumulative urinary excretion of Tl, illustrated
in Figure 1 has a hyperbolic form during the first 48 hours, con-
sistent with a first order rate process. Subsequently, the cumula-
tive urinary excretion is linear with time. This is inconsistent
with animal studies and with the only other human study discussed.
In these studies a first order rate process prevails, even months
following dosing. The supplementary doses of thallium sulfate
C-12
-------
•S r
6 (2
2«
120 UZ
MOUJIS
FIGURE 1
204
The excretion of Tl by a human after oral administration of
500 JJG of activity plus five 45 mg doses of thallous sulfate oral-
7D4
ly. The level of Tl in the blood at 2, 4, 8, 24, and 48 hour
intervals after administration of the radioactive isotope is also
included.
Source: Barclay, et al. 1953
C-13
-------
204
given subsequent to the single dose of Tl would not likely have
altered the form of the excretion curve. These supplementary doses
no doubt increased total thallium excretion, but this would not
affect the rate of Tl excretion since dilution of the Tl pool
with "cold" thallium would precisely cancel any enhancement of
204
Tl excretion resulting from the increased total thallium concen-
*?•
tration presented to the kidney.
The only other paper which sheds light on the kinetics of
thallium excretion in man was a report of a single case of poison-
ing (Innis and Moses, 1978). Approximately four weeks following
the time of intoxication a series of urine analyses for thallium
were performed. These data are presented in graphic form
(Figure 2). The estimated t, for urinary excretion was 30 days
(k = .023 day"1).
The discrepancy in rate of urinary loss of the body burden in
the two above-described cases (k = .032 vs. k = .023) is not re-
markable. The rate constant calculated for the first subject was
based on excretion data which behaved in a kinetically anomalous
fashion. On the other hand, the rate constant calculated for the
second subject may have been influenced by the fact that she was
experiencing clinical manifestations of thallium poisoning. It is
known from experimental studies in rats that the rate of body
clearance of thallium is considerably slower following a toxic dose
than following a tracer dose. Thus, Gehring and Hammond (1967) re-
ported a rate constant for total thallium excretion of 0.0353 day
in rats receiving a single iv injection of 10 mg Tl/kg as compared
to a rate constant of 0.0790 day in rats receiving a tracer dose
C-14
-------
3.0
2.0
T1, mg/1
urine
1.0
0.5
0.2
\
X
30
60
days
90
FIGURE 2
The Excretion of Thallium in the Urine of a Patient, Beginning
Approximately Four Weeks after Thallium Intoxication.
Source: Innis and Moses, 1978
C-15
-------
«0.1 mg Tl/kg). These constants were for animals on low dietary
potassium. When dietary potassium was high, tracer doses were more
rapidly excreted (k = 0.146 day" ). In summary, for people not ex-
periencing overt signs of thallium poisoning, it seems that the ap-
propriate rate constant lies between 0.032 and 0.023 day~ . The
slower rate constant (0.023) will be assumed in the criteria formu-
lation for purposes of calculating the accumulation of thallium in
man, since this represents the more conservative approach.
It should be noted that excretion of thallium in animals dif-
fers from excretion in man in two respects. The rate of excretion
is much more rapid in animals. For example, in Gehring and Hammond
(1967) the rate constant for total excretion in rats on a high
potassium diet was 0.146 day~ . Lie, et al. (1960) calculated a
rate constant of 0.210 day for rats receiving single tracer doses
and Rauws (1974) calculated a rate constant of 0.173 day" in rats
receiving single doses of 10 mg/kg. The average rate from these
three studies was 0.18 day" . Another major difference between man
and animals is the relative contribution of fecal and urinary ex-
cretion. Whereas the gastrointestinal tract seems to be a very
minor excretory pathway in man, the rate of fecal excretion is
about 3 to 4 times the rate of urinary excretion in the rat (Gehring
and Hammond, 1967; Lie, et al. 1960). In the rabbit the contribu-
tion of the two routes of excretion is about equal (Truhaut, 1952).
The rate of urinary excretion under steady state conditions of
intake should reflect accurately the rate of total thallium absorp-
tion. This proves to be an extremely important consideration in
light of the fact that reliable estimates of intake based on known
C-16
-------
concentrations in food, air and water are virtually non-existent.
The only published estimate of total dietary intake is
-------
increase thallium excretion and perhaps dietary intake (Table 1).
In the second study (Goenechea and Sellier, 1967) no such distinc-
tion is made, and the average urinary concentration of thallium is
somewhat lower though similar (Table 2). From the data in the last
three papers it seems safe to assume that the concentration of
thallium in urine seldom exceeds 1.5 ug/1. The discrepancy between
the data in the last two studies, ©.81 vs. 0.23 jug/1, cannot be ex-
plained. Even if one assumes that the higher of the two figures is
correct and that average daily urinary excretion is 1.5 Jug/1, aver-
age daily thallium excretion in the urine would be 1.2 ug (0.81
ug/1 x 1.5 1).
Total Daily Excretion of Thallium as a Basis for Estimating Daily
Absorption
It is useful to estimate total daily excretion of thallium
since this can reasonably be assumed to be the same as total daily
absorption, at least under steady state conditions. To the daily
excretion via the urine must be added the following miscellaneous
routes:
1) gastrointestinal excretion (including cell exfoliation)
2) hair
3) exfoliating epithelium of the skin
4) sweat
The contribution of gastrointestinal excretion is probably
very minor in man, at least based on the data of Barclay, et al.
(1953). From Figure 1, it can be estimated that cumulative fecal
excretion was 0.5 percent of the dose of Tl at 72 hours, whereas
cumulative urinary excretion at the same time was approximately 11
percent of the dose. On this basis, one might add to the average
C-18
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TABLE 1
Thallium Concentration in the Morning Urine of Vegetarians,
Smokers and Non-smokers with Normal Diets*
Subject
Vegetarian
"
n
Smoker
n
n
Non-smoker
n
it
*Source: We
a
Sex Years of a
D Age Urine sp.g.
F
M
M
M
M
M
M
F
F
inig
C i — ,
40
43
12
28
25
24
26
60
48
and Zink,
.
1.024
1.034
1.032
1.019
1.023
1.018
1.008
1.025
1.030
overall
1967
Ave . Tl , ug/1
Tl, ng/g for group
1.34
1.69
0.92
1.42
0.40
0.69
0.13
0.39
0.53
average
1.28
0.82
0.34
0.81
calculated from the authors' data in the table
C-19
-------
TABLE 2
Naturally-Occurring Thallium Concentration in the Urine
and Feces of Humans Under Physiological Conditions*
Case
1
2
3
4
5
6
7
8
9
10
Urine,
jug/kg
0.1"
0.4
0.1
0.2
0.1
0.1
0.3
1.0
0.2
a
a
Feces,
ug/kg
0.6
3.0
b
b
b
b
0.1
b
b
a
0.1
average0 0.23
*Source: Goenechea and Sellier, 1967
abelow detectable limit, which is 0.02
not determined
^
assumes urine samples below detectable limit
= 0.02 jag/kg
C-20
-------
urinary excretion an additional increment of 1.2 x 0.5/11 = 0.06
ug/d.
So far as excretion via hair is concerned, it was reported by
Barclay, et al. (1953) that at autopsy 7 percent of the original
204
dose of Tl was localized in scalp hair. During this same period
55 percent of the original dose had been lost by other excretory
O f\ A
routes. Minor loss of ^U*T1 via fiair was also reported in rats
O f\ A
(Lie, et al. 1960). Seven days following a pulse dose of Tl,
approximately 75 percent of the radioactivity had been excreted in
the urine and feces. Only 1.56 percent of the residual amount was
localized in hair. Assuming that total excretion via hair = 2X
scalp hair excretion, 14 percent could conceivably have been re-
moved from the body in this manner. An additional increment of
1.26 >ug x 14/55 or 0.32 ug results.
Exfoliation of skin and sweat probably do not contribute sig-
nificantly to total thallium excretion, at least probably not more
so than the gastrointestinal tract which has a larger surface area
than the skin, a very rapid turnover rate of epithelium, and a high
rate of secretory activity. It would seem conservative to assign
the skin an excretory role similar to the role of the gastrointes-
tinal tract. In summary, total excretion of thallium per day in
adults not exposed to unusual sources of thallium is probably as
follows:
C-21
-------
Excretory route ug Tl/d
urine 1.20
feces 0.06
hair 0.32
skin and sweat 0.06
Total 1.64
Body Burden of Thallium as a Basis for Estimating Daily Absorption
There is an alternate basis for estimating daily absorption of
thallium. It begins with certain assumptions. First, it is as-
sumed that the excretory process is essentially first-order, where-
in the rate of excretion is proportional to the amount in the body
at that time. Second, it assumes that input is fairly constant -
essentially zero order. For the steady state condition, the fol-
lowing relationship exists:
A -tS.
B k where:
A_ = amount in the body
A, = amount absorbed per day
k = elimination constant (day~ )
The amount of thallium in the body (AB) of persons not unduly ex-
posed has been estimated to be 100 ug per 75 kg (Weinig and Zink,
1967). Using the elimination constant of Innis and Moses (1978),
k = 0.023, the daily absorption of thallium to attain a steady
state body burden of 100 ug would be:
100 ug = ~ or x = 2.3 wg.
That is approximately 1.4X the value obtained using the estimated
sum of excretion by all pathways, and approximately 0.4 times the
C-22
-------
intake value derived from estimates of input from food, water, and
air. Since the estimated body burden is based on data from only two
cadavers, the small difference in estimated daily absorption is not
surprising. Order-of-magnitude agreements using two different ap-
proaches to the problem of intake are about all one can expect
given the small amount of hard data available.
EFFECTS
Acute, Subacute, and Chronic Toxicity
The vast majority of the cases of adult human poisoning have
been acute, usually involving single doses, taken by reason of
homicidal or suicidal intent. Acute poisoning in children has
resulted from ingestion of thallium-containing rat and ant bait or
from thallium's therapeutic use as a depilatory agent. It is pos-
sible to estimate at least roughly the minimum lethal dose. As for
the minimally toxic dose, the former practice of using thallium as
a depilatory agent makes it possible to make an estimate, at least
for children.
Cavanagh, et al. (1974) investigated a homicidal attempt on
three men, two of whom died after being given 930 mg thallous ace-
tate (721 mg Tl). The third man survived a dose of 310 mg (240 mg
Tl). In another series of seven cases of suicidal attempts, four
survived the consumption of one tube of Zelio Paste (263 mg Tl)
with signs of poisoning, two survived after eating two tubes of
Zelio Paste (526 mg Tl), and one died after eating five tubes of
Zelio Paste (Grunfeld and Hinostroza, 1964). Assuming an average
weight of 70 kg, the average toxic, non-fatal dose for adults is
about 4-8 mg/kg and the minimal fatal dose is probably somewhat
C-23
-------
less than 10 mg/kg. The minimal acute lethal dose is quite similar
for a variety of animal species and the range from the highest non-
lethal dose to the lowest lethal dose also is quite narrow
(Table 3) (Downs, et al. 1960).
Based on the limited data available, children seem to be no
more sensitive to the acute toxic or lethal effects of thallium
<3*
than adults. In a series of 8,006 children estimated to have been
given single oral doses of 3.1-7.8 mg Tl per kilogram body weight
of thallous acetate as a depilatory, 447 (6 percent) became ill and
eight (0.1 percent) died (Munch, 1934). Given the imprecise nature
of reports as to incidence of toxic effects, it is of course quite
possible that substantially more than 6 percent of the children in
this series experienced signs or symptoms of poisoning. It is not
even known how consistently the therapeutic objective of alopecia
was attained in this series of cases.
Acute thallium poisoning is a disease entity which has been
widely described. The initial signs and symptoms involve primarily
the gastrointestinal tract and peripheral nervous system. Alopecia
does not generally occur until several weeks following intoxica-
tion. Indeed, in fatal cases death may supervene before alopecia
occurs. The detailed description of three cases of acute poisoning
by Cavanagh, et al. (1974) is rather typical of what has been de-
scribed by many other investigators (see, for example, Paulson, et
al. 1972; Papp, et al. 1969). Initially, the subject experiences
gastrointestinal pains, diarrhea, and vomiting. This is followed
by paresthesia of the upper and lower limbs, dizziness, and facial
weakness. These signs first appear in 2-5 days. A frequent
C-24
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TABLE 3
Acute Toxicity of Thallium Compounds*
n
KJ
cn
Thallous Acetate
Route
iv
ip
po
Species
rabbit
rabbit
guinea pig
rat
rabbit
guinea pig
rat
dog
1
7
9
25
41
4
4
37
3
Sex
F
F
M,F
F
F
M
F
M,F
lethal range**
mg Tl/kg
12-20
8-13
4-7
13-20
12-19
8-12
18-29
10-20
*
3
3
3
41
3
10
42
3
Thallic Oxide
Sex
F
M
F
F
M *
M,F
F
M
lethal range**
mg Tl/kg
24-39
30-60
10-30
62-92
10-30
3-5
9-20
20-30
*Source: Downs, et al. 1960
**lethal range = highest non-lethal dose - lowest dose showing any lethality during 14-day
period.
-------
complaint is pain and tenderness of the lower limbs, particularly
of the knees. Dysphagia and dyspnea also are commonly reported.
Sensory impairment occurs frequently. The cranial nerves as well
as the spinal nerves are affected. The central nervous system also
is affected to varying degrees. Attention span is reduced; somno-
lence and delerium or coma may occur. Various abnormalities of
&P
cardiac function have been reported, including sinus tachycardia
and flattening or inversion of the T-wave. These and other cardiac
effects have been variously attributed to vagus involvement and to
myocardial damage. The electroencephalogram is frequently abnormal
(Cavanagh, et al. 1974). These effects and others occur in vari-
ous combinations. Chamberlain, et al. (1958) summarized the inci-
dence of effects in their series of 14 cases in children
(Figure 3), as did Grunfeld and Hinostroza (1964) in a series of
adult cases (Figure 4).
Although acute poisoning is a somewhat protracted disease,
with effects lingering for several months, the prognosis for full
recovery in adults seems to be good. Such does not appear to be the
case in children. In a follow-up study of 72 cases, Reed, et al.
(1963) found that 26 of 48 had neurologic abnormalities when they
were followed up for an average of 4 years. The neurologic abnor-
malities found at follow-up usually represented persistence of
signs found during the initial stages of the disease (Table 4). It
should be noted that mental abnormalities and muscle weakness or
paralysis actually increased in incidence during the follow-up
period.
C-26
-------
Number of children
5
H
10
(Alopecia)
At aid a
Weakness
Somnolence
Trim or
Irritability
Headache
Coma
Hyperreftet
Convulsion!
Paresthesios
P to sis
Resp. Paralysis
Polh. ReHexes
Paralysis
23%
50%
75%
FIGURE 3
Incidence of Gastrointestinal (Top) and Neurologic Signs
and Symptoms of ThaliotOKicosis in Children
Source; Chamberlain et al., 1958
C-27
-------
Svmoton
tuicir of cam
FIGURE 4
Signs and Symptoms in Seven Cases of Thallotoxicosis
Source: Grunfeld and Hinostroza, 1964
C-28
-------
TABLE 4
Percent of 26 Patients with Abnormalities at Follow-up Stage
(Southern Texas Thallotoxicosis Study, 1954-1959)*
Symptoms
ataxia
tremor
abnormal reflexes
convulsions
abnormal vision
mental abnormalities
abnormal movements
muscle weakness
or paralysis
Acute Stage
of Illness, %
81
57
62
27
15
15
15
4
Follow-up
Stage, %
23
19
38
15
4
58
8
15
*Source: Reed et al., 1963
C-29
-------
It is not surprising that acute thallium poisoning should lead
to irreversible damage, or at least to only slowly-reversible dam-
age to the central and peripheral nervous system. Degeneration of
peripheral nerve fibers and chromatolysis of motor nerve cells were
frequently reported in man (Munch, et al. 1933; Gettler and Weiss,
1943), and in animals (Zook and Gilmore, 1967; Zook, et al. 1968).
^
So far as subacute and chronic thallium poisoning in man are
concerned, there are very few reports of any kind and those which
are available provide little information as to duration of expo-
sure, level of exposure as reflected in thallium concentrations, or
doses in either the external environment or in the affected sub-
jects. In one brief report concerning 13 men exposed 3-4 months,
the signs and symptoms were pains in the legs, weariness, loss of
hair, disturbance of sensation, psychic trouble, albuminuria and
nephritis (Meyer, 1928). Generally speaking, these findings corre-
spond to the usual description of acute poisoning. The author also
reports that lymphocytosis was a constant finding. Gettler and
Weiss (1943) reported that in two cases of chronic poisoning the
only symptoms observed were pain in the legs, mild symptoms resem-
bling those of encephalitis, alopecia, and oliguria. The sugges-
tion that renal damage is a feature of chronic poisoning is not
surprising. In the description of acute cases of poisoning, fre-
quent reference is made to manifestations of renal damage (Fischl,
1966). Postmortem evidence of renal damage, at least in acute poi-
soning, also has been reported (Gettler and Weiss, 1943*). Finally,
there also is one report of a case of chronic intoxication in a man
C-30
-------
exposed 24 years. The main effects were loss of hair, ascending
polyneuritis and disturbances of speech and vision (Egen, 1955).
Rats fed thallous acetate in their diet for 105 days experi-
enced no reduction in weight gains at concentrations of 5 and 15
ppm. Doses of 30 ppm for 105 days proved fatal to approximately
half of the animals. The only toxic effect noted at 15 ppm was loss
of hair (Downs, et al. 1960). It was first noted at two weeks. It
must be recognized, however, that there has been very little effort
to search for more subtle effects at exposure levels below those
causing alopecia. A study of the toxic effects of chronic admin-
istration of thallium in animals (>90 days) was reported by
Tikhonova (1967). In this instance, thallium administration in
rabbits resulted in paralysis and pathological changes in the
liver, kidneys and stomach mucosa.
It seems from the limited number of reports that regardless of
whether thallium intake occurs in one dose or over several months,
the effects are qualitatively very similar, if not identical. It
is not possible to state with any degree of certainty which of the
many effects reported is the one to which man is most sensitive. It
would seem that in cases of acute poisoning in man alopecia is the
most consistent effect among those surviving more than two weeks.
In the series of children studied by Chamberlain, et al. (1958),
this was clearly the case. In the series of adult cases reviewed by
Grunfeld and Hinostroza (1964), (see Figure 4), nausea and vomiting
occurred in one case where alopecia did not occur. That subject
survived only 5 days after ingesting thallium. Among documented
cases of chronic poisoning no specification as to the frequency of
C-31
-------
various signs and symptoms has been recorded. In summary, the most
consistently reported effect is alopecia. Unfortunately, consist-
ency cannot be equated a priori with sensitivity.
Synergism and/or Antagonism
Potassium has long been known to exhibit significant interac-
tions with thallium, both in the pharmacokinetic sense and in toxic
interactions. Lund (1956) first demonstrated that potassium in-
creases the renal clearance of thallium. Mullins and Moore (1960)
demonstrated that the influx and efflux patterns of thallium in
frog muscle were quite similar to the fluxes of potassium. Gehring
and Hammond (1967) extended these earlier observations to show that
potassium markedly enhanced the rate of thallium excretion in both
rats and dogs. The excretion occurred for the most part in the
urine. Salivary secretion of potassium, when stimulated with de-
oxycorticosterone, was accompanied by a corresponding increase in
thallium excretion. Potassium also increased somewhat the acute
LDj.. of thallium, suggesting that mobilization from the receptor
sites is responsible for the toxic effects.
As a result of these studies in animals, the use of potassium
was instituted in the management of thallotoxicosis in man. Re-
sults have been somewhat equivocal. The use of potassium in the
management of thallotoxicosis does result in some increase in the
urinary excretion of thallium, but this mobilization is accompanied
by a temporary accentuation of the neurological signs and symptoms
(Innis and Moses, 1978; Papp, et al. 1969).
Several other interactions have been reported, but their sig-
nificance is difficult to evaluate. Levkovitch (1938) reported
C-32
-------
that ambient temperature had an effect on thallium toxicity in
sheep and rabbits, and that confinement and dietary restriction en-
hanced toxicity. Levander and Argrett (1969) observed that thal-
lium reduced the exhalation of volatile selenium metabolites, an
action shared with mercury and arsenic. Unlike arsenic, however,
neither thallium nor mercury increased biliary excretion concomi-
tantly.
Teratogenicity
There are two reports in the literature which suggest a tera-
togenic effect of thallium. The first was a study of the effect on
chick embryos (Karnofsky, et al. 1950} in which T12SO. (0.4 - 0.7
mg/egg) was administered during incubation. The primary defect
produced was achondroplasia. Thallium also produced early embryon-
ic death and reduced embryonic size. Thus, the study did not ful-
fill the usual criteria for teratogenesis wherein the effect must
be evident at doses not otherwise grossly toxic.
Only one study of thallium teratogenesis in mammalian species
has been reported. Gibson and Becker (1970) studied the terato-
genic effects of thallium in rats under conditions of both low and
normal dietary potassium. Thallium administered intraperitoneally
to the mothers early (d. 8,9,10) at 2.5 mg/kg/dose, or late (d.
12,13,14) at 2.5 and 10 mg/kg, resulted in reduced fetal weight and
in increased incidence of teratologic effects (hydronephrosis and
missing or non-ossification of vertebrae). It was observed that at
both dosage levels thallium caused maternal toxicity as manifested
by diarrhea, lethargy, irritability, poor hair luster and body hair
loss. One interesting aspect of this study was in regard to the
C-33
-------
effects of dietary potassium deficiency. A low-potassium diet
increased the toxicity of thallium to the dams and was of itself
teratogenic, but it did not potentiate the teratogenic effect of
thallium. Given the types of malformation reported, the evidence
of maternal toxicity and the reduced fetal weights, it is quite
likely that these effects were due to delayed fetal maturation
(see, for example, Kimmel and Wilson, 1973). In both studies thal-
lium was administered by a parenteral route and in both cases gen-
eral fetotoxic effects were apparent. Thus, it is impossible to
distinguish teratogenicity from a more geasral toxic effect.
Mutagenicity
No pertinent information could be found in the available lit-
erature concerning the mutagenicity of thallium.
Carcinogenicity
There are no available published reports on the carcinogeni-
city of thallium; however, there are two carcinogenicity studies
on-going at the time of this document's preparation. Carcinogeni-
city/mutagenicity/teratogenicity evaluations of thallium sulfate
are being conducted by Litton Bionetics under EPA contract;
Sprague-Dawley rats are being fed thallium sulfate in the diet at
three dose levels. The National Institute for Occupational Safety
and Health (NIOSH) in Cincinnati, Ohio is investigating the carcin-
ogenicity of thallic oxide by inhalation in rodents.
Without any implications as to non-carcinogenicity it is of
interest to note that thallium has mild anti-carcinogenic effects,
along with other metals of Group Ilia (Adamson, et al. 1975).
C-34
-------
CRITERION FORMULATION
Existing Guidelines and Standards
There is a threshold limit value (TLV) of 0.1 mg/m for thal-
lium in workplace air (ACGIH, 1971). This value is based on anal-
ogy to other highly toxic metals. This standard has been adopted
by the Occupational Safety and Health Administration (OSHA), and is
the same as that for East Germany and* West Germany (Winell, 1975).
The U.S.S.R. standard is 0.01 mg/m . No criteria have been devel-
oped for thallium in irrigation water, drinking water, fresh water
or other media.
Current Levels of Exposure
It is extremely difficult to specify current levels of expo-
sure for either man or animals because of the scarcity of good
data. This is due to the fact that analytical methods which have
been applied to the problem have generally not been sufficiently
sensitive for determination of thallium in major media (air, food,
water) or in normal man. This is not to say that adequate methods
do not exist. For example, the mass spectroscopic-isotope dilution
procedure used by Weinig and Zink (1967) could detect thallium in
urine in the range of .01-0.1 ng/g. There probably has not been
sufficient motivation to develop alternate sensitive methodology to
define human exposure adequately in the normal range.
Certain approximations as to usual human exposure are possi-
ble. Thus, based on one extensive study it seems that tap water
seldom exceeds 0.3 ug Tl/1 (Greathouse, 1978). Assuming that the
average adult consumes 2 liters of water per day, total input would
be somewhat less than 1 ug/d.
C-35
-------
Even in the worst conditions of water pollution, the concen-
tration of thallium probably seldom exceeds 30 jug/1 (U.S. EPA,
1977). These conditions occur in the immediate vicinity of ore
processing operations and possibly in streams draining ore-rich
soils, e.g. the Colorado River as it courses through western
Arizona.
Limited data on thallium in vegetables suggest that, as a
class of food, these may have considerably higher concentrations of
thallium, perhaps 10 jug/kg wet weight, than other classes of foods
(Geilmann, et al. 1960). Bread and muscle, for example, contain
1 jag/kg or less. This may explain the observation that vegetarians
excrete considerably more thallium in the urine than non-vegetari-
ans. Assuming that total food consumption is 1.6 kg/d, (DSDA,
1968), that 0.38 kg is in the form of vegetables, and that the re-
mainder has a concentration of only 1 ug/kg, total daily thallium
intake would be (0.38) (10) + (1.2) (1) = 5 jug. This estimate prob-
ably is on the high side since prepared vegetables would likely
have less thallium than raw vegetables due to leaching of thallium
into water during cooking.
So far as ambient air as a source is concerned, the single
largest anthropogenic source of thallium is considered to be stack
emissions from coal-fired plants. It has been estimated that flue
gas would contain about 0.7 mg/m , with a likely ground level con-
centration of 0.7 ug/m . Given that a large factor of dilution
would result by dispersion from the base of a stack, it seems un-
likely that the contribution of coal combustion to thallium in
ambient air would be significant. The highest measurement of
C-36
-------
thallium reported in ambient air indicated a range of 0.04-0.48
ng/m (Carson and Smith, 1977).
Inhalation of thallium in cigarette smoke may, on the other
hand, be a very significant source. The urinary excretion of thal-
lium in smokers is about twice that in non-smokers (Weinig and
Zink, 1967) and the concentration in cigar stubs was shown to be
57-170 ng/g (Geilmann, et al. 1960),*about 20 times the concentra-
tion estimated for the diet.
Total intake in the general non-smoking adult population cal-
culated on the basis of exposure data thus would consist of no more
than 1.0 ug/d from water and no more than 5 ug/d from food, even
assuming that virtually all ingested thallium is absorbed.
The total daily assimilation of thallium by adults in the gen-
eral population has also been arrived at by consideration of excre-
tion data and estimated body burden. The estimated daily intake
arrived at by consideration of food and water exposure and by these
other two methods is as follows:
Basis Estimated Daily Adult Intake
Food, air and water exposure < 6
Excretion data 1.64 ug/d
Body burden data 2.30 ug/d
Special Groups at Risk
From the standpoint of age, there is no basis for believing
that children are more susceptible to thallium intoxication than
adults. Children, however, experience neurological sequelae, while
adults do not. There is no reason for suspecting that the fetus is
unusually sensitive. Essentially nothing is known regarding sex
C-37
-------
differences in susceptibility. One study in rats indicated that
females are more resistant to sub-chronic toxicity than males.
From the standpoint of exposure hazard, it would seem that smokers
may have twice as great a level of thallium intake as non-smokers.
This suggestion is based solely on data concerning urinary thallium
excretion in six people and on very limited information concerning
thallium in cigars. Obviously, people occupationally exposed to
thallium may constitute a special risk category. This matter has
received little attention because the total annual industrial pro-
duction of about 0.5 tons of thallium is so small. In the U.S., the
main source of poisoning, thallium-containing rodenticides and in-
secticides, has been terminated. The manufacture and distribution
of these products is no longer permitted.
Basis and Derivation of Criteria
The proposed criterion for thallium in water is derived from
1) estimated least toxic level on chronic intake in man, 2) intro-
duction of a margin of safety, and 3) relative contribution of
water and other media to total daily intake in the general popula-
tion.
In estimating the least toxic level of intake, the effect to
which man is most sensitive is probably alopecia. Loss of scalp
hair in man and of body fur in animals seems to occur at somewhat
lower levels of intake than any other known effects. This is not so
clearly the case in adults as in children and animals. There is,
however, no great difference between the acute or chronic dose
causing alopecia and the dose causing neurologic effects. The
least daily amount of thallium which, when taken for a lifetime, will
cause alopecia can only be estimated on the basis of sub-chronic
C-38
-------
animal exposure data combined with some kinetic considerations. In
the Downs, et al. (I960) study alopecia occurred in 2 weeks as a
result of the administration of thallium at 12 ppm in the diet. At
this dose level, either effects occurred within two weeks or they
did not occur with continued intake. This is consistent with the
rapid turnover of thallium in rats and the consequently rapid at-
tainment of a steady state level of thallium in the body. Within
two weeks, a steady state is virtually achieved since 14 days
represents more than three half-lives for thallium clearance from
the body. Rats at the next lowest dose (5 ppm thallous acetate or 4
ppm thallium) fed for 105 days showed no alopecia or other toxic
effects. Therefore, the highest no observable adverse effect level
(NOAEL) would be 4 ppm (4 jug/g) of thallium.
In the following calculation the average weight of rats, 0.075
kg, is derived from inspection of Figure 1 (male rats) in the
author's report; the average daily food intake is assumed to be 10
g at that weight. Therefore, the "safe" ADI for rats can be cal-
culated as:
(4.0 ug/g) (10 g) = 40 jug/0.075 kg = 533 jug/kg.
Conversion to an acceptable daily intake (ADI) for man would
be as follows:
ADI , 533 ug/kg x 70 kg = 37>1 yg
1,000
where:
70 kg = average weight of man
1,000 =safety factor as recommended by NAS (1977) for com-
pounds where there are: "No long term or acute human data.
Scanty results on experimental animals. No indication of
carcinogenicity."
C-39
-------
For the purpose of establishing a water quality criterion, human
exposure to thallium is considered to be based on ingestion of
2 liters of water and 6.5 g of fish/day. The bioaccumulation
factor for thallium has been established to be 119.
The criterion (C) is derived from this data as follows:
(C x 2 liters) -t- (C x 119 x 0.0065) = 37.3 jug.
Solving for C gives: C = 13.4 jag/liter. Thus, the recommended
water quality criterion for thallium is 13.4 ug/liter. The cri-
terion can alternatively be expressed, if exposure is assumed to be
only from ingestion of contaminated fish and shellfish, as 48 jug/1.
It is interesting to note the similarity between the minimal
body burden causing alopecia in rats (on chronic administration)
and the single dose causing alopecia, with moderate incidence of
other effects, in children. For the rat:
1.6 mg/kg/d = 8.88 mg Tl/kg
0.18 day"
For children, the average acute dose associated with alopecia is
3.1 to 7.8 mg/kg (Munch, 1934).
So far as a safe level of thallium in drinking water is con-
cerned, there does not seem to be any reasonable possibility that
even the most thallium-polluted waters would have a toxic effect.
In the worst case identified by Zitko, et al. (1975), the concen-
tration of thallium was 88 ug/1. Assuming that this were a human
water supply, the daily input at 2 liters per day would be only
176 jug Tl, 4.74 times the ADI calculated for man in the document
and well within the 1,000-fold safety factor.
The great difference between estimated minimally toxic expo-
sures and current total exposure in the general population is
C-40
-------
reassuring. One cannot be totally sanguine, however, since there
is a paucity of chronic data, including information on mutagenici-
ty, teratogenicity and carcinogenic!ty. For that reason it seems
prudent to keep levels of exposure at or below their present lev-
els. From the data available, it would seem that few if any public
water supplies would ever contain more than 4 pg/1. Thus, the cri-
terion of 13 pg/1 is approximately threefold greater than the
likely maximum in public water supplies.
In summary form, the dose and exposure parameters for man are
estimated to be:
minimally lethal single dose 4-10 ing/'kg
recommended criterion 13 pg/1 water
ADI for 70 kg/man 37.3
probable limit for ^> 99 percent , ,.
of U.S. tap waters L P9/L
probable current level of daily-
adult thallium consumption from <^~L pg/d
drinking water
C - 41
-------
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• U. S. GOVERNMENT PRINTING OFFICE : ! 9BO 72C-016/4396
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