EPA-600/1-71 922
May 1977
Environmental Health Effects Research Series
Triangle Park, North
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5 Socioeconomc Environmental Studies
6. Scientific and Technical Assessment Reports (STAR)
7. Interagency Energy-Environment Research and Development
8. "Special" Reports
9. Miscellaneous Reports
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
ances of man for unhealthful substances or conditions. This work is generally
assessed from a medical viewpoint, including physiological or psychological
studies. In addition to toxicology and other medical specialities, study areas in-
clude biomedical instrumentation and health research techniques utilizing ani-
mals — but always with intended application to human health measures.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.
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EPA-600/1-77-022
May 1977
TOXICOLOGY OF METALS - Volume II
By
Subcommittee on the Toxicology of Metals
Permanent Commission and International Association of
Occupational Health
Prof. Lars Friberg, Chairman
in cooperation with
The Swedish Environmental Protection Board, and
The Karolinska Institute
Contract No. 68-02-1287
Project Officer
Robert J. M. Horton
Criteria and Special Studies Office
Health Effects Research Laboratory
Research Triangle Park, N. C. 27711
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
iiiu-.L,.,AL PROTECTION
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DISCLAIMER
This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication. Approval
does not signify that the contents necessarily reflect the views and policies
of the U.S. Environmental Protection Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation for use.
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TABLE OF CONTENTS
Introduction 1
Aluminum 4
Antimony 15
Arsenic 30
Barium 71
Beryl 1 i urn 85
Bismuth 110
Cadmium 124
Cnrorni urn 164
Cobalt 188
Copper 206
Germanium 222
Indium 234
tead 242
Mercury 301
Molybdenum 345
Si 1 ver 358
Tellurium 370
Thallium 388
Tin 405
Titanium 427
Tungsten 442
Uranium 454
Zinc 473
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INTRODUCTION
Introduction to Volume I:
At the time of the XVIth International Congress on Occupational Health
in Tokyo in 1969 the Permanent Commission and International Association of
Occupational Health decided to form a subcommittee on the toxicology of metals.
The need for such a group had been recognized during an international meeting
on mercury toxicology in 1968. The subcommittee was formed with Prof. Lars
Friberg of Stockholm as chairman. The program developed by this group consisted
of exploration and documentation of the general principles of metal toxicology
by means of symposia and workshops of experts in the field. A broad approach
was selected including general environmental exposures as well as those related
to occupation. Emphasis was placed on greater depth and precision of understanding
in terms of metabolic processes and dose-effect relationships. The Permanent
Commission, the Swedish Environmental Protection Board, and the Karolinska
Institute have supported the committee in carrying out this program. Two workshops
were conducted, one in conjunction with the meeting of the Permanent Commission
in 1971, and another in conjunction with the XVIIth International Congress on
Occupation Health in 1972.
Recently the subcommittee has decided to broaden its work by preparing a
handbook on metal toxicology which will contain the general material being
developed in its workshops and also specific information on a large number of
metals for use by toxicologists and occupational and environmental health workers.
The Environmental Protection Agency is cooperating with the other sponsors in
supporting this phase of the subcommittee's work. As information is developed
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on the subject it will be collected in three annual progress reports. The first
of these is contained in this volume. It consists of the conclusions of the
subcommittee's third workshop which was held in Tokyo in 1974. Since the three
workshops which have been held constitute a cumulative series, with frequent
reference back to previous definitions and statements, it was thought best on
this occasion to reproduce all of them together as a unit.
Introduction to Volume II:
This second volume on Toxicology of Metals contains material prepared
for the Handbook on the Toxicology of Metals - Environmental and Occupational
Aspects which is being prepared by the Scientific Committee on the Toxicology
of Metals of the Permanent Commission and International Association of
Occupational Health. It is intended to have chapters on thirty metals in the
completed handbook. Twenty-three of these are available at this time and
make up the contents of this volume. Although these are finished chapters,
it has occurred to the authors and editors that publication at this time
offers the opportunity to solicit comments and suggestions from the scientific
community which might be helpful in improving these texts before final
publication in the handbook. Readers who know of additional pertinent
material which should be included, or have other suggestions for improvements
are urged to communicate directly as soon as convenient with the responsible
senior authors whose addresses are given below:
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List of Senior Authors
Matns Berlin, M.D.
Department of Environmental Health
University of Lund
Box 2009
S-220 02 Lund 2, Sweden
Bruce Fowler, Ph.D.
Senior Staff Fellow
Environmental Toxicology Branch
National Institute of Environmental Health Sciences
P. 0. Box 12233
Research Triangle Park, N. C. 27709, U.S.A.
Lars Friberg, M.D.
Department of Environmental Hygiene
The Karolinska Institute
S-104 01 Stockholm 60, Sweden
George Kazantzis, M.D.
Department of Community Medicine
The Middlesex Hospital Medical School
London WIN 8AA, England
Gunnar Nordberg, M.D.
Department of Environmental Hygiene
The Karolinska Institute
S-104 01 Stockholm 60, Sweden
Tor Norseth, M.D.
Institute of Occupational Health
Gydas Vei 8, Box 81 49
Oslo 1, Norway
Magnus Piscator, M.D.
Department of Environmental Hygiene
The Karolinska Institute
S-104 01 Stockholm 60, Sweden
Andrew Reeves, Ph.D.
Department of Occupational and Environmental Health
Wayne State University School of Medicine
1400 Chrysler Expressway
Detroit, Michigan 48207, U.S.A.
Kenzaburo Tsuchiya, M.D.
Department of Preventive Medicine and Public Health
School of Medicine
Keio University
35 Shinanomachi, Shinjuku-ku
Tokyo, Japan
Velimir B. Vouk, Ph.D.
Control of Environmental Pollution and Hazards
Environmental Pollution
Division of Environmental Health
World Health Organization
1211 Geneva 27, Switzerland
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ALUMINUM
Tor Norseth
1. Abstract
No reliable data exist on absorption of aluminum. Some absorption
should occur as aluminum is found in human organs, The lungs
invariably show the highest concentration. Aluminum is found in
the fetus. The biological half-time is not known but there is no
tendency toward an increase of aluminum concentrations in organs
with age. It has been suggested that aluminum is an essential
metal, but a final answer to this question can not be given at
present. Pulmonary fibrosis has been described after inhalation
of aluminum in certain industrial operations. Aluminum may
cause hypophosphatemia by forming insoluble phosphate complexes
in the gastrointestinal tract.
A review of environmental and health aspects of aluminum has
been given by Sorensen et al. (1974).
2. Physical and chemical properties
Aluminum, Al, atomic weight 27.0; atomic number 13; density
2.7; melting point 660.4°C; boiling point 2467°C; crystalline
form silver-white ductile metal, cubic; oxidation state 3.
Some compounds of interest are aluminum oxide, aluminum sul-
fate, aluminum hydroxide, aluminum fluoride, aluminum chloride
and aluminum-glycole complex.
Technical aluminum oxide, which is used in the industrial pro-
duction of aluminum metal, consists of two main crystal modifica-
tions, a-A!20 and y-AI O of different toxicological importance.
Aluminum forms highly reactive organic compounds, some of which
become hot and fume violently when exposed to air.
3. Methods and problems of analysis
Colorimetric and fluorescence methods as well as titrimetric
methods for aluminum suffer the drawback of interference from
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other substances present in biological materials. Separation
ana preconcentration of samples present definite problems as
no reagent specific to aluminum exists. Emission spectroscopy
is a specific and sensitive method in which preparation and
manipulation of the samples are kept to a minimum. This is
an important consideration since the abundance of aluminum
in the environment can easily lead to contamination of samples.
A detection limit of 1 to 0 .1 ,149 has been reported (Lander
et al., 19 71).
Atomic absorption seems today to be the method favored for
routine analytical determination of aluminum in biological
materials. A reported detection limit of ,1 mg/1 can be improved
to 0.01 mg/1 with benzene extraction (Hsu and Pipes, 1972).
Using fiameless atomic absorption, a detection limit of about
0.03 ng with a coefficient of variation of about 5 % has
been obtained (Fuchs et al., 1974).
Neutron activation, polarography and X-ray fluorescence have
been used for aluminum analysis, but these methods do not seem
to possess special advantages. Even if neutron activation seems
to offer the best detection limit, other methods are sufficient
for most toxicological work.
A review of analytical methods for the determination of
aluminum has been given by Sorensen et al. (1974), but no
comparison of the different methods has been published.
4. Production and uses
4.1 Production
Aluminum is the most common metal in the earth's crust (8.13 %) .
Aluminum is not found in an uncombined state in nature, but
mostly in the form of various silicates. Important aluminum-
containing silicates are bauxite and cryolite. The raw material
for the aluminum oxide is usually bauxite, the oxide being
produced by sedimentation of aluminum hydroxide after caustic
treatment of the raw material, followed by calcination. Aluminum
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metal is produced by the electrolysis of aluminum oxide in
smelted cryolite at a temperature of about 970°C. Aluminum
Iluoride and calcium fluoride are added to the bath in addition
to the fluoride-containing cryolite. The main component of technical
aluminum oxide is a-Al 0_; the amount of Y~A1_O depends on
4. 3 2. j
the calcinating temperature used. The ^-modification is con-
o
verted to the a-modification at temperatures higher than 900 C.
The world production of aluminum has increased from 602 thousand
tons in 1938 to about 14 million tons in 1974 (Baudart, 1975).
4.2 Uses
Aluminum has a variety of industrial uses, the most important
being electrical engineering, household utensils and appliances,
the transport and building industry, and as packaging material.
About one third of the: world production of aluminum is now
(1973) used in the transport industry, and about half that amount
in electrical engineering. The building industry in various
industrialized countries utilizes from 10 to 20 % of the world
production; from 10 to 15 % is utilized in packaging (Baudart,
1975). Aluminum compounds are utilized in the processing,
packaging and preservation of food and as food additives for
various purposes. Aluminum sulfate is widely utilized for
sedimenting particles in the treatment of drinking water.
Aluminum and aluminum compounds are used therapeutically to
prevent hyperphosphatemia in renal disease, and in the prev-
ention of silicosis. Other therapeutic uses of aluminum
compounds are as an antacide, as an antidote, as an antiper-
spirant and as an adjuvant for vaccines, toxoids and for
aluminum penicilline.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Most unprocessed food items contain less than 10 mg Al/kg.
Use of aluminum in the processing and storing of food increases
the aluminum content, but not to a toxicologically significant
extent. Some vegetables and fruits may contain up to about
150 mg Al/kg. The daily intake of aluminum from food may thus
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show a considerable variation dependent on the diet (Schlettwein-
Gseii and Mommsen-Straub, 1973} Sorensen et al., 1974). Total
daily intake_ of aluminum may amount to about 80 mg/day, as
reviewed by Sorensen et al. (1974).
5.1.2 Water, soil and ambient air
Aluminum in ocean water generally is reported up to about 1
mg/i, this value being one-tenth of the concentration reported
in rivers and lakes. The activities of man increase the aluminum
content in surface water, but aluminum is generally not regarded
as a water pollution problem. Concentrations of aluminum as
high as 150-600 g/kg have been reported in soil. Aluminum con-
tent in urban air is reported up to about 10/ug/m-; in non-urban
3
areas values lower than 0.5,ug/m are usually reported (Sorensen
et al., 1974) .
5.2 Working environment
Occupational exposure to aluminum and aluminum compounds is
widespread, but the exposure has only to a limited degree
turned out to be of toxicological importance. Exposure to
aluminum oxide-containing dust in the production of abrasives
from bauxite has been described as a hazard (Shaver and Ridell,
1947), but exposure levels have not been reported.
6. Metabolism
6.1 Absorption
The presence of aluminum in human organs indicates some absorp-
tion of ingested aluminum. Different opinions exist as to the
degree of absorption.
Ondreicka et al. (1966) found no increase in the urinary excretion
of aluminum or in aluminum deposition in the organs of rats when
twice the normal aluminum concentration was given as chloride or
sulfate in food. When the concentration was increased to about
15 times the normal, both urinary excretion and organ deposition
were enhanced.
In man absorption from the gastrointestinal tract has been dis-
cussed in relation to the use of aluminum hydroxide for the
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treatment of hyperphosphatemia in renal failure. About 15 %
absorption was found in uremic patients, with a considerable
variation among individuals (Clarkson et al., 1972). Other in-
vestigators assume a much lower absorption in uremic patients
(Berlyne et al., 1970;, Thurston et al., 1972). Estimates of
absorption of aluminum compounds other than the hydroxide or
with normal kidney function have not been published. Homeostatic
regulation of aluminum absorption has been suggested (Sorensen
et al., 1974).
There are no data for aluminum absorption from the respiratory
tract.
6 . 2 Pis tr ibu t ion
Aluminum has been demonstrated in all human organs analyzed, but
the lungs invariably show the highest concentration, about
200 to 300 g/kg.Most other organs are reported to contain one-tenth
or less of the aluminum concentration of lung tissue. Aluminum
in the lung is probably a result of local deposition from in-
haled air.
Increased concentrations of aluminum in food did not increase
aluminum in the lungs of rats. There was a prominent increase
in the liver, brain, testes and blood (Ondreicka et al., 1966).
After parenteral administration to rats, increased concentrations
of aluminum were found in all organs analyzed, with the highest
concentration in the brain (Berlyne et al., 1972).
The fetus contains aluminum, but there is no indication that
the body burden of aluminum increases with age. Various diseases
influence-the, aluminum concentration of'orga'ns {Sorensen et
al., 1974).
6.3 •Excretion
Parenteral administration of aluminum to experimental animals
increases urinary excretion of aluminum. After peroral admin-
istration increased urinary excretion is found infrequently,
probably due to a limited absorption.
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In pa-events with renal failure, Berlyne et al. (1970) observed
aluminum clearance of from 0.11 to 0.42 ml/min. These values
correspond to about 5 % of the urea clearance and to 10 % of
the creatinine clearance in these patients.
Aluminum in feces probably reflects the amount ingested. Lig-
ating the bile duct in experimental animals increases urinary
excretion of aluminum, indicating that biliary excretion may
be of importance in gastrointestinal excretion (Soroka, 1966).
Increased concentration of aluminum in bile after peroral or
parenteral administration of aluminum salts has not been con-
clusively demonstrated.
Aluminum is a normal constituent of cow and human milkj values
in the range of 1-2 mg/1 are given (Schlettwein-Gsell and
Mommsen-Straub, 1973).
7. Normal, levels in tissues and biological fluids
Normal values of aluminum in whole blood determined by emission
spectroscopy have been reported from 0.14-6.24 mg/1, plasma
values from 0.13-0.16 mg/1 (Sorensen et al., 1974). Berlyne et
al. (1970) reported 1.46 mg/1 and 0.24 mg/1 as normal values
in serum using neutron activation and atomic absorption, res-
pectively. Fuchs et al. (1974), using a flameless atomic absorp-
tion technique, reported 0.037 mg/1 as a normal value in serum.
Tipton et al. (1966) in a balance study found less than 1
mg/1 in the urine. Kehoe et al. (1940) reported a low value
of 0.05 mg/1. These low values are in accordance with the
assumed limited absorption of aluminum.
8. Effects and dose-response relationships
The biological role of aluminum has not been clearly estab-
lished, and a definitive answer to the question of essential-
ity cannot be given. Failure to produce a diet free of alum-
inum has hampered the tests to date. A disease state caused
by lack of aluminum has not been described.
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8.1 Local effects and dose-response relationships
8.1.1 Animals.
By intratracheal instillation both salts of aluminum and metallic
aluminum powder have been found to produce pulmonary fibroses
(Stacy et al., 1959; Corrin, 1963). Aluminum silicate minerals
cause a limited fibrous reaction. The y-oxides seem to produce
the fibrous reaction to a greater extent than the a-oxide.
In a recent paper Gross et al. (1973) could not demonstrate
fibrosis following inhalation of metallic aluminum powders
in hamsters, guinea pigs or rats, but fibrosis was demonstrated
after intratracheal injections of high doses. No such reaction
was found with lower closes. They assume that fibrosis after
intratracheal injection is caused by the injection procedure
combined with high doses of dust. Pulmonary proteinosis was,
however, demonstrated with both inhalation and intratracheal
injection. Acute pulmonary reactions have been demonstrated
with a number of aluminum compounds, among which were also
more complex aluminum compounds, such as a glycole complex
used as an antiperspirant (Drew et al., 1974).
Intraperitoneally injected, aluminum compounds generate fib-
rotic peritonitis.
8.1.2 Humans
A fibrotic lung disease in workers exposed to fine powdered
aluminum metal has been clearly documented, but the mean
exposure level recorded for time periods of 30 to 90 minutes
per shift was 95 mg/m respirable dust. Severe and sometimes
fatal lung damage has been reported in workers exposed to
10-50 mg/m respirable dust of aluminum metal in the production
of explosives and fireworks (Mitchell et al., 1961). Human
pulmonary fibrotic reaction caused specifically by other
aluminum-containing dusts such as aluminum oxide has yet
to be documented properly. The condition reported by Shaver
and Ridell (1947) was probably a result of a combined exposure
to aluminum oxide end silica, and the disease reported by
Kubic (1960) may have been caused by accompanying chromate
10
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exposure. When used for the prevention of silicosis, aluminum
itself has given rise to fibrosis.
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
A picture of severe aluminum intoxication characterized by
lethargia, anorexia and death has been described after parent-
eral and oral administration of aluminum hydroxide, chloride
and sulfate to rats (Berlyne et al., 1972). These results have
been disputed by others who claim aluminum hydroxide to be
relatively non-toxic, and the toxic symptoms to be related to
phosphate depletion (Thurston et al., 1972). Experimental
animals fed 100 to 200 mg/kg aluminum chloride in long term
experiments show retardation of growth and disturbances of
phosphate and carbohydrate metabolism (Sorensen et al., 1974).
Some aluminum compounds have been studied as food additives.
In small amounts (1% - 2%) they stimulated growth, but it was
reported that higher amounts gave rise to retardation of growth
with grave disturbances of phosphate and calcium metabolism
(Sorensen et al., 1974).
8.2.2 Humans
Excessive occupational exposure leads to increased aluminum
uptake with recorded changes in some serum enzymes, the rel-
evance of which to health is uncertain. Most experience with
the toxicity of aluminum in man comes from the use of aluminum
hydroxide in the prevention of phosphate retention in uremic
patients. It must be assumed that the administration of aluminum
to these patients leads to an increased absorption.
To what extent the kidney damage causes increased retention
is uncertain. On the basis of an increased retention of alum-
inum in uremic patients maintained on aluminum hydroxide
treatment, Alfrey et al. (1976) suggested that the dialysis
encephalopathy syndrome is caused by an aluminum intoxication.
Otherwise, no systemic effects except those caused by hypophos-
phatemia have been described in such patients. Hypophosphatemia
11
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may also be induced by using aluminum hydroxide as an antacide.
8.3 Carcinogenic effects
Carcinogenicity studies have failed to produce cancer in ex-
perimental animals.
8.4 Interaction with phosphorus metabolism; aluminum and fluorides
Aluminum compounds form insoluble salts with phosphorus in the
gastrointestinal tract and large amounts given perorally may
thus induce a phosphorus depletion syndrome with depletion
of red cell ATP. Other changes in phosphorus metabolism with
unknown mechanisms which may not be related to the complex
formation have also been reported (Sorensen et al., 1974).
The main health hazard in primary aluminum production is
fluoride exposure/ not exposure to aluminum or aluminum oxide.
Both gaseous and particulate fluorides are found in the working
atmosphere as well as in the emissions. Exposure levels of up
to 20 mg/m of total dust have been reported in modern plants;
fluoride levels were mostly below 2.5 mg/m (Gylseth and Jahr,
1975).
12
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Alfrey, A.C., Le Gendre, G.R. and Kaehny, W.D. (1976).
l\ew Engi. J. Med. 294, 184-189.
Baudart, G.-A. (1975). Rev. Alum. No. 438, 121-123.
Berlyne, G.M., Ben-Ari, J., Pest, D., Weinberger, J.,
Stern, M. , Gilmore, G.R. and Levine, R. (1970). Lancet 2,
494-496. ~
Berlyne, G.M., Yagil, R., Ben-Ari, J., Weinberger, G., Knopf,
E.-and Danovitch, G.M. (1972). Lancet 3., 564-568.
Clarkson, E.M., Luch, V.A., Hynson, W.V., Bailey, R.R.,
Eastwood, J.B., Woodhead, J.S., Clements, V.R., O'Riodan,
J.L.H. and DeWardener, H.E. (1972). Clin. Sci. 43, 519-531.
Corrin, B. (1963). Brit. J. Ind. Med. 20, 268-276.
Drew, R.T., Gupta, B.N., Bend, J.R. and Hook, G.E.R (1974).
Arch. Environ. Health 28, 321-326.
Fuchs, C., Bransche, M., Paschen, K., Nordbeck, H. and
Quellhorst, E. (1974). Clin. Chem. Acta _52_, 71-80.
Gross, P., Hariey, R.A. and de Treville, R.T.P. (1973).
Arch. Environ. Health 26>, 227-236.
Gylseth, B. and Jahr, J. (1975). Undersjrfkelse av arbeids-
forholdene i aluminiumselektrolysehallene ved Norsk Hydro
A/S, Karm^y fabrikker under bruk av henholdsvis ren oksyd
og gjennvinningsoksyd, Yrkeshygienisk institutt, Oslo,
HD 515, 27 p.
Hsu, D.Y. and Pipes W.O. (1972). Environ. Sci. Technol.
j5, 645-647.
Kehoe, R.A., Cholak, J. and Story, R.V. (1940). J. Nutr.
19_, 579-592.
Kubik, S. (1960). Prac. Lek. 12, 458-464. Trans. National
Translations Center. NTC-73-11444.
Lander, D.W., Steiner, R.L., Anderson, D.H. and Dehm, R.L.
(1971). Appl. Spectrosc. ^5, 270-275.
Mitchell, J., Manning, B.B., Molyneux, M. and Lane, R.E.
(1961). Brit. J. Ind. Med. 18, 10-20.
Ondreicka, R., Ginter, E. and Kortus, J. (1966). Brit. J. Ind.
Med. 2J3, 305-312.
Schlettwein-Gsell, D. and Mommsen-Straub, S. (1973). Int. Z.
Vitam. Ernahrungsforsch, Beiheft 13, 176-188.
Shaver, C.G. and Riddell, A.R. (1947). J. Ind. Hyg. Toxicol.
29, 145-157.
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Sorensen, J.R.J., Campbell, I.R., Tapper, L.B. and Ling, R.D.
(1974). Environ. Health Perspect. 1_, 3-95.
Soroka, V.R. (1962). Ukr. Biokhim. Zh. 3±, 834-838. Chem.
Abstr. (1963). 58, 8296-8297.
Stacy, B.D., King, E.J., Harrison, C.V., Nagelschmidtf G. and
Nelson, S. (1959). J. Pathol. Bacteriol. 77, 417-426.
Tipton, I.,Stewart, P.L. and Martin, P.G. (1966). Health
Phys. 12, 1683-1689.
Thurston, H., Gilmore, G.R. and Swales, J.D. (1972).
Lancet 1, 881-883.
14
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ANTIMONY
Carl-Gustav Elinder and Lars Friberg
i. Abstract:
Antimony has two valences, 3 and 5. Most absorbed antimony is
excreted rapidly via urine and feces. Elimination and route
of excretion are dependent on the type of antimony compound.
The urinary excretion seems to be higher for pentavalent than
for trivalent antimony compounds. Gastrointestinal excretion
is higher for trivalent than for pentavalent antimony. Some data
on humans indicate that a small part of absorbed antimony may
have a long biological half-time. After acute or chronic exposure
to antimony the highest concentrations will be found in thyroid,
adrenals, liver, and kidney.
Industrial exposure may give rise to irritative symptoms from the
respiratory tract. After long-term exposure, pneumoconiosis, some-
times with obstructive lung diseases, has been observed. Heart
effects, even fatal, have been observed as a result of long-term
industrial exposure to antimony trioxide, and as side effects in
connection with treatment of parasitic diseases with antimony
compounds. Cardiovascular effects have been observed also in ani-
mal experiments.
The primary route of exposure for normal people is usually via
food.
2. Physical and chemical properties
Antimony, Sb, atomic weight 121.8; atomic number 51; density 6.7;
melting point 631°C; boiling point 1750°C; crystalline form
silver-white metal, hexagonal; oxidation state 3, 5. Compounds
to be mentioned in this chapter are antimony trioxide, antimony
trisulfide, antimony trichloride, antimony pentasulfide, antimony
potassium tartrate, antimony pentoxide, stibine, sodium antimony
dimercaptosuccinate.
15
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Antimony belongs to the same periodic group as arsenic, which
it resembles both chemically and biologically. It exists in
both organic and inorganic complexes. Stibine is an odorless,
highly toxic gas.
3. Methods and problems of analysis
Antimony in air and biological materials has been determined
polarographically, spectrographically and colorimetrically using
Rhodamine B (Tabor et al., 1970). Neutron activation and atomic
absorption spectrophotometry are now the chief methods used.
Kennedy et al. (1962) reported a detection limit of 1.8yug/kg
lung tissue employing neutron activation and Dams et al. (1970)
using the same principles could detect 1 ng Sb/m air. AAS
had a detection limit around 0.5 mg Sb/1 in a water solution
(Christian and Feldman, 1970). Recently a hydride generation
technique with subsequent atomic fluorescence determination
was reported to have a detection limit of 0.1,ug Sb/1 in con-
centrated hydrochloric acid (Thompson, 1975).
Precision and accuracy of the methods for different materials
have not been studied.
A colorimetric method used for determination of stibine (SbH_)
3
in air had a detection limit of 50 ,ug Sb/m (Short and Wheatley,
1962).
4- Production and uses
4.1 Production
In nature antimony occurs in association with sulfur, forming
stibnite. Other minerals containing antimony are cervanite,
valentinite and kermesite.
The world production of antimony, which has generally increased
at a rate of about 3 % per annum, was 69,400 metric tons in 1973.
The leading producers were South Africa with 15,483 tons, Bolivia
with 14,719 tons and the People's Republic of China with 12,000
tons.
16
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4.2 uses
An-ci^ony is a common constituent of alloys with other metals,
oucn as lead and copper. Antimony compounds are used for pro-
ducing fireproofing chemicals and textiles.
In the USA antimonial lead accounts for 38 %, fireproofing
chemicals and compounds for 14 % and ceramics and glassware
for 11 % of the industrial consumption. Other important in-
dustrial uses are in bearing metals and pigments (Wyche, 1972).
Some antimony compounds, particularly tartar emetic, are used
against parasitic diseases and infections (Goodman and Gilman,
1941; Liu et al., 1958; Ciplea et al., 1966; Arfaa et al., 1967;
Pedrigue et al., 1970).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food _and daily intake
Data on daily intake are controversial. Reports range from about
10 ,ug in a Swedish balance study using neutron activation on four
subjects (Wester, 1974) to 250-1250 ,ug in a USA study on institu-
tional diets for children, using atomic absorption spectrophotom-
etry without extraction (Murthy et al., 1971). In fresh water
fish antimony concentrations have been reported to be in the
order of 3yug/kg wet weight (Uthe and Bligh, 1971)
5.1.2 Water, soil and ambient air
In the Rhine River, antimony averages 0.1,ug/l; 0.2,ug/l has been
reported from the northeastern Pacific Ocean (Schmidt, 1968;
Spencer et al., 1970).
In soil antimony usually ranges from 0.1 to 10 mg/kg dry weight
(Bowen, 1961; Khatamov et al., 1967).
Brar et al. (1970) and Dams et al. (1970) using neutron activation
reported concentrations of antimony in Chicago air ranging from
1.4 to 55 ng/m and an average of 32 ng/m , respectively.
17
-------
5.1.3 Cigarettes
Antimony in cigarettes has been studied by means of neutron
activation by Nadkarni and Ehman (1970). The tobacco, on the
average, contained 0.1 rag Sb/kg dry weight. The amount of
inhaled antimony was estimated to 20 %.
5.2 Working environment
Air concentrations of antimony in the order of 1 to 10 Sb
mg/m have been reported from different smelter operations.
Renes (1953) found average working zone concentrations of
antimony ranging from 4.7 to 10.2 mg/m in smelting works.
In an abrasives plant studied by Brieger et al. (1954), the
average air concentration was 3.0 mg/m .
Stibine (SbH_) was found to have evolved during charging of
lead storage batteries in which antimony was a compound of
the negative grid (Haring and Compton, 1935).
6. Metabolism
Antimony is considered a non-essential metal.
6 ••*• Absorption
6.1.1 Inhalation
Data on respiratory absorption of antimony are lacking.
6.1.2 Ingestion
About 15 % of a single oral dose of labelled antimony potassium
tartrate to mice is absorbed, i.e. recovered in urine and tissues
(Waitz et al., 1965). The absorption might, however, be higher
since simultaneous gastrointestinal excretion takes place. Thus,
Gellhorn et al. (1946), following intraperitoneal administration
of antimony potassium tartrate to hamsters, observed a fecal
excretion of 50 % of the given dose (0.43 mg)in 24 hours.
6.2 Distribution
6.2.1 Animals
Antimony given as a single dose or by repeated injections is
found in kidney, liver (Boyd et al., 1931: pentavalent antimony
to monkeys; Hassan, 1938: trivalent antimony to dogs and monk-
18
-------
eysj Goodwin and Page, 1943: pentavalent antimony to mice)
and thyroid (Brady et al., 1945: trivaient antimony to dogs).
In rats fed a diet containing 2 % antimony trioxide for 1 1/2
months, the highest concentrations of antimony were found in
the thyroid and adrenals, with 88.9 and 67.8 mg/kg, respectively
(wet or dry weight not stated). Spleen, lungs, liver, and
kidneys had concentrations between 6.7 and 18.9 mg/kg (VJesterick,
1953} .
6.2.2 Humans
By surface body scanning of persons given intravenous injec-
tions of labelled antimony, as sodium antimony dimercaptosuccinate,
liver, thyroid and heart were seen to receive the highest
amounts. Forty-three days after the last injection, the liver
still showed values of about 1/6 of the maximum, which had
been reached one day after the last injection (Abdallah and
Saif, 1962; Abdel-Wahab et al., 1974).
6.3 Excretion
With a few exceptions data exist only for antimony salts used
in medicine.
6.3.1 Animals
Rate and route of excretion are dependent on the valence of
the compound. Certain species differences are also seen. In
general pentavalent organic antimony is mainly excreted in
urine, trivaient mainly in feces (Otto and Maren, 1950).
Six hours after intravenous and intraperitoneal injections of
pentavalent antimony compounds to mice about 50 to 60 % will be
found in urine. The initial excretion rate is less rapid for the
trivaient form, but after 48 hours the differences between the
forms decline; total urinary excretion in 48 hours is around 70 %
(Goodwin and Page, 1943).
Twenty-four hours after intraperitoneal administration of
tri- and pentavalent antimony to hamsters about 50 % of the -
trivaient and less than 10 % of the pentavalent antimony were
19
-------
found in feces. Corresponding excretion in urine was about
15 % and 70 % respectively (Gellhorn et al., 1946).
6.3.2 Humans
Single intravenous or intramuscular injections to volunteers
produced higher 24-hour urinary excretion of pentavalent (80
%) than of trivalent (25 %) antimony compounds, a pattern
similar to the one found in animals (Boyd and Roy, 1929;
Goodwin and Page, 1943-, Abdallah and Saif, 1962) .
Out of a single intravenous dose of labelled antimony potassium
tartrate (trivalent) about 80 % of excretion will take place
via urine and 20 % via feces (Bartter et al., 1947). In one
patient studied 73 % of the total single dose was eliminated
in four weeks.
In workers exposed to air containing around 3 mg Sb/m , a
colorimetric method showed urinary values ranging from 0.8
to 9.6 mg (Brieger et al., 1954), thus highly elevated compared
to normals; see section 7.
6.4 Biological half-time
6.4.1 Animals
6.4.1.1 Inhalation
A study on beagles exposed to labelled antimony aerosols in-
dicates an initial fast clearance, a few days, of up to 80
% of the initially deposited material (whole-body measurements),
This fast excretion phase was followed by a slow clearance
with a half-time in whole-body on the order of 36 to 100 days
(Felicetti et al., 1974). The retention in lung in percent
of initial lung burden after 4 months ranged from 0.0 to 6
% depending on type of particles. Excretion of antimony took
place via urine and feces, with a ratio of 0.8. The particles
had been nebulized from an antimony potassium tartrate solution
passing through a heating column at 100, 500 and 1,000°C which
yielded particles with aerodynamic diameters of 0.3, 1.0 and
1.3 mm.
20
-------
6.4.1.2 Parenteral administration
Sorae animal data indicate an initial rapid clearance of antimony,
involving gastrointestinal and urinary excretion. Twenty-
four nours subsequent to an intraperitoneal injection given
to hamsters, Gellhorn et al. (1946) found about 65 % of tri-
valent and pentavalent antimony compounds in feces and urine
combined.
6.4.2 Humans
The initial excretion of antimony in humans is fast (see section
6.3.2). There might be a long-term component according to
a study by Mansour et al. (1967). They studied antimony in
oiood and urine (neutron activation) in patients who, one
year earlier, had been treated with antimony for bilharzia.
They found averages of 6.7,ug/l and 27,6,ug/l in three persons"
blood and urine respectively. Three untreated subjects had
3.4yug/1 and 6.2,ug/l in blood and urine.
7. Normal levels in tissues and biological fluids
The highest antimony concentration, around 0.5 mg/kg dry weight
(about 0.1 mg/kg wet weight), is found in the lung. Liver
and kidney contain about one third of the lung concentration
(Kennedy, 1966; Nixon, 1967; Shicka et al., 1972, all employing
neutron activation). Recently, based on Japanese autopsies,
it has been reported that skin and adrenals contain slightly
higher concentrations of antimony than lung and liver, 0.1
mg/kg and 0.07 mg/kg wet weight compared to 0.06 mg/kg and
0.02 mg/kg. The total body burden of antimony in an average
Japanese was estimated to be about 1 mg (Sumino et al., 1975,
employing the Rhodamine B method).
Blood and serum concentrations of antimony in normal subjects
have been reported to be 3.ug/l and 0.8,ug/l respectively
(Mansour et al., 1967; Wester, 1973, both employing neutron
activation). The 24 hour urinary excretion in 16 subjects
ranged from 0.5 to 2.6,.ug (Wester, 1973).
21
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8. Effects and dose-response relationships
8.1 Animals
In peroral exposure, acute and chronic, antimony potassium
tartrate is more toxic than antimony tri- and pentoxide. In
dogs and cats, acute symptoms such as vomiting and diarrhea
were produced by antimony potassium tartrate in doses on the
order of 10 mg/kg. Antimony tri- and pentoxide could be given
to the same animals in doses above 100 mg/kg for months without
toxic manifestations (Flury, 1927).
In a long-term study, rats given 5 mg/kg as aatimony potassium
tartrate in drinking water showed a significantly shortened
survival and average length of life (about 15 %) compared
with controls (Schroeder et al., 1970).
8.1.1 Local effects and dose-response relationships
After inhalation of antimony trioxide in an average concentra-
3
tion of 45 mg/m for 33 to 609 hours, guinea pigs showed signs
of interstitial pneumonitis (Dernehl et al., 1945). Rats exposed
to antimony trioxide, dose not stated, for periods up to 14
months showed, in addition to pneumonitis, lipoid pneumonia,
fibrous thickening of alveolar walls and focal fibrosis (Gross
et al., 1951).
8.1.2 Systemic effects and dose-response relationships
8.1.2.1 Circulatory system effects
Intravenous injections of antimony produce an acute circulatory
response with fall in blood pressure (Chopra, 1927; Gotten and
Logan, 1966). Pathological ECG changes have been observed. In
dogs injected for four days with 5 mg of antimony potassium
tartrate one of the most prominent features was inversion of
the T-wave (Girgis et al., 1970).
Chronic effects with parenchymatous degeneration in the myo-
cardium were observed upon histopathological examination of
3
hearts from rats and rabbits exposed to 3.1 and 5.6 mg/m
as antimony trisulfide for six weeks (Brieger et al., 1954).
22
-------
8.1.2.2 Liver and kidney effects
Fatty degeneration occurred in the convoluted tubules of the
kidney and the liver after a single administration of 60 mg
antimony potassium tartrate solution to rabbits. The kidney
changes appeared a few hours after the administration, preceding
the ones in the liver (Franz, 1937; Dernehl et al., 1945).
8.2 Humans
Data on acute and chronic toxicity of antimony to be given
here come essentially from industrial airborne exposure. Adverse
effects from treatment of tropical diseases with antimony
compounds will be discussed only to a limited extent.
Stibine, like arsine, attacks the circulatory and the central
nervous systems. Acute poisoning gives rise to headache, nausea,
weakness, slow breathing and weak pulse (Stokinger, 1963).
8.2.1 Local effects and dose-response relationships
8.2.1.1 Respiratory system effects
3
Acute respiratory exposure to antimony trichloride (73 mg/m )
caused irritation and soreness of the upper respiratory tract
in 7 workers (Taylor, 1966). Three cases, two of them fatal,
of severe pulmonary edema evoked by antimony pentachloride
are described by Cordasco and Stone (1973); air concentrations
were not available.
Chronic effects of antimony have been studied by Renes (1953).
He examined 78 workers engaged in smelting procedures, for
periods exceeding two weeks. Exposure concentrations ranged
from 4.7 to 11.8 mg/m ; 20 % of the workers suffered from
rhinitis, 8 % from pharyngitis, 5.5 % from pneumonitis, and
1 % from tracheitis. Soreness and nosebleeds were experienced
by more than 70 %. Brieger et al. (1954) did not mention ob-
serving respiratory tract irritation in their extensive study,
discussed in section 8.2.2.1, where workers were exposed to
antimony trisulfide ranging from 0.6 to 5.5 mg Sb/m .
Several authors have remarked upon pneumoconiosis-like X-ray
pictures obtained from workers with long-term occupational
23
-------
exposure to antimony (Karajovic, 1958; McCallum, 1963; Browne,
1968; Cooper et al., 1968; Le Gall, 1969).
Two investigators have also observed obstructive lung changes
and emphysema among antimony workers (Karajovic, 1958; Klucik
et al., 1962). Klucik et al. (1962) reported on workers exposed
to antimony trioxide for up to 28 years (concentration and
number of workers were not given). The incidence rates of
pneumoconiosis and symptoms of emphysema were 21 % and 42
% respectively.McCallum et al. (1970) have developed an X-
ray method for measurement of inhaled antimory trioxiae. Upon
examination of 1.13 antimony process workers, they found a
significant correlation between estimated lung antimony and
period of employment.
8.2.1.2 Skin effects
Pustular skin eruptions, "antimony spots", are common among
persons working with antimony and antimony salts. These erup-
tions are transient and mainly affect skin areas exposed to
heat and those where sweating occurs (Renes, 1953; McCallum,
1963; Pashoud, 1964; Stevenson, 1965).
8.2.2 Systemic effects and dose-response relationships
8.2.2.1.Circulatory system effects
Brieger et al. (1954) reported hypermortality and morbidity
among workers in an abrasives industry. 124 workers were exposed
to air concentrations of antimony trisulfide ranging from
0.6 to 5.5 mg/m for 8 to 24 months. During this period 6
workers died suddenly and two others died of chronic heart
disease. Four of the deceased were under 45 years of age.
EGG changes, mostly of the T-wave, were seen in 37 out of
75 examined. During the preceding 16 years, one death had
occurred in this department. No control group was examined.
8.2.2.2 Gastrointestinal effects
Acute antimony poisoning manifested as vomiting, nausea and
diarrhea was reported in 150 children who drank a contaminated
lemon drink (about 30 mg/1) (Werrin, 1963).
24
-------
Renes (1953) reported abdominal cramps, diarrhea and vomiting
arfiong- certain workers who had heavy exposures to antimony fumes
in a smelter. A higher incidence of ulcer, 6 % of 111 examined
antimony workers compared to that of the total plant population,
1.5 % of 3,912 employees, was seen by Brieger et al. (1954).
8.2.3 Adverse effects during antimony treatment
Various side effects and in several studies cases of sudden
death nave been recorded in connection with clinical treatment
with antimony (El Halawani, 1968). Nausea and vomiting are
common features during such treatment (Zaki et al., 1964;
Hamad, 1969; Pedrique et al., 1970). Liver effects, with rises
in serum GOT and GPT at the onset of therapy, were reported
by Woodruff (1969). As in animal studies, EGG changes, partic-
ularly in the T-wave, are frequently reported during long-
term treatment (Mainzer and Krause, 1940; Schroeder et al.,
1946; Davis, 1961; Abdalla and Badran, 1963; Sapire and Silverman,
1970). Mansour and Reese (1965) have proposed that tartar
emetic is an augmenting factor in the development of schistosomal
myopathy.
25
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29
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ARSENIC
Kenzaburo Tsuchiya, Noburu Ishinishi and Bruce A. Fowler
1. Abstract
Absorbed arsenic is distributed to various tissues and
organs but is mainly excreted in the urine and feces. It has
a high affinity for sulfhydryl groups in the skin, hair, and
nails. Most probably because of this affinity, arser.ic seems
to concentrate in these tissues.
The main source of arsenic exposure in the general population
is food. According to various authors, the daily intake of
arsenic in the "normal" population has been reported to be
from 0.07 to 0.9 mg per person. As reported in a study from
the U.S.A., the body burden of arsenic is 14-20 mg and the
biological half-time is relatively short. Although arsenic
has not been confirmed as an essential element for human
life, there is evidence that arsenic is required for the
growth of some species of animals.
A number of episodes of arsenic poisoning caused by medica-
tion or contaminated food and drinking water have been
reported. Skin lesions such as dermatoses, which include
eruption, pigmentation, or leukodermal hyperkeratosis, may
finally lead to development of a cancerous stage known as
Bowen's disease. Angiosarcoma of the liver has also been
reported in cases of chronic exposure to arsenic. Hemotolo-
gical changes caused by arsenic poisoning have not been well
documented, although anemia has been reported in some studies,
Typical arsenic poisoning among industrial workers is charac-
terized by the perforation of the nasal septum, skin changes,
and peripheral neuritis. An excessive risk of lung cancer in
the production of arsenic trioxide has been observed in many
studies. Workers in copper refineries, insecticide factories,
30
-------
and mines may also be subjected to a high risk of lung
cancer.
Epidemiological evidence indicates a cause-effect relationship
between arsenic exposure and lung cancer, skin cancer, and
angiosarcoma of the liver in human beings, but animal experi-
ments have thus far failed to substantiate this relation-
ship.
Arsine gas is a powerful hemolytic poison.
2. Physical and chemical properties
Arsenic, As; atomic weight 74.9; atomic number 33; density
5.1; melting point 817°C; boiling point 613°C sublimes;
crystalline form gray metalloid, hexagonal-rhombic; oxida-
tion state -3,0,3,5. The inorganic compounds to be taken up
specifically here are the two most common ones, arsenic
trioxide and arsenic pentoxide, as well as arsenic trichloride,
lead arsenate, calcium arsenate, sodium arsenate, copper
aceto-arsenite and arsine. Organic compounds to be mentioned
include arsanilic acid, methylarsonic acid, dimethylarsinic
acid and cacodylic acid.
From the viewpoint of biology and toxicology, the compounds
of arsenic are classified into three major groups (Vallee et
al., 1960): (1) inorganic arsenicals, consisting of trivalent
arsenicals, arsenic trioxide, arsenite salts, and pentavalent
arsenate salts; (2) organic arsenals and (3) gaseous arsenic
or arsine (AsH., , hydrogen arsenite) . The toxicology of this
last compound will be dealt with in Section 11 of this
chapter. The chemical structures of more prominent arsenicals
are shown in Figure 1.
3• Methods and problems of analysis
Until a few decades ago analytical methods for arsenic,
which could involve procedures such as Reinsch's method,
Marsh's test, and Gutzeit's test were qualitative rather
than quantitative. Because of this inadequacy, analytical
-------
conclusions based on these methods have to be carefully
evaluated. The heteropoly molybdenum blue method and the
silver diethyldithiocarbamate method are two fairly good
quantitative colorimetric methods which have a limit of
detection in the range of 1-50 mg/1 in a 5 1 solution (Sandell,
1959) .
Introduced by Holak (1969) atomic absorption spectrophotometric
measurement of generated arsine gas has the potential detection
limit of 0.04/ug of arsenic. Neutron activation analysis has
10
a detection limit of 10 grams for arsenic ind makes possible
the accurate quantitative determination of arsenic in samples
such as a single strand of hair (Smith, 1959, 1964; Liebscher
and Smith, 1968) . Proton-induced X-ray emission analysis
(PIXEA) with a detection limit of 0.1 mg/kg has been used
for the simultaneous determination of arsenic and a number
of other elements in biological tissues (Walter et al.,
1974; Fowler et al., 1975).
In the past few years several methods for the quantitative
determination of the various valence states and chemical
forms of arsenic have been reported. Pulse polarography,
which has a detection limit of 0.3 /ug/1 for arsenic in
water, is capable of distinguishing the polarographically
+ 3 +5
active As from the inactive As (Meyers and Osteryoung,
1973) . A differential capture method with a detection limit
on the order of 1 ng is capable of distinguishing As ,
+ 5
As methylarsonic acid, and dimethylarsinic acids (Braman
and Foreback, 1973) . Gas chromatography and atomic absorption
spectroscopy have been used to distinguish various organoarsenicals
from inorganic arsenic (Daughtrey et al., 1975; Fitchett et
al., 1975). A number of methods for arsenic analysis have
recently been reviewed by Braman (1977).
4. Production and uses
4.1 Production
Arsenic usually exists in nature as an oxide in the trivalent
state. Arsenic is obtained principally as a by-product in
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the smelting of copper, lead, and gold ores. When these ores
are smelted, the arsenic becomes gaseous and is caught by
electrostatic precipitators as a crude dust which contains
relatively large amounts of arsenic trioxide. The crude dusts
are roasted and the arsenic trioxide is driven off. Arsenic
trioxide is collected in a cooling chamber, or arsenic kitchen,
and is prepared for shipment as a material containing approxi-
mately 97% As^O,., the principal impurity being Sb~CU (Pinto
and McGill, 1953). The world production of arsenic from 1911-
1972 is shown in Table 1.
4.2 Uses
Arsenic was known as a therapeutic agent as early as 400 B.C.
and has since been widely used as such. From the 19th century
until about 20 years ago, Fowler's solution in the inorganic
form was used for the treatment of dermatoses. The organic
arsenical compounds have been used for syphilis and treponema-
tosis.
Arsenic was one of the most common homocidal poisons during
the Middle Ages. Arsenicals which have been used throughout
the world as agricultural chemicals include lead arsenate,
calcium arsenate, copper aceto-arsenite ("Paris Green"),
sodium arsenate ("Wolman Salts") and cacodylic acid.
The currently important uses of arsenic include the production
of insecticides, herbicides, fungicides, and wood preservatives,
It is also used in the manufacture of glass, as a bronzing
or decolorizing agent, and in fabricating opal glass and
enamels. Arsenicals have been used in the manufacture of
dyestuffs and chemical warfare gases and in the thylox
purification of industrial gases. Elemental arsenic in con-
centrations of 0.3% to 0.5% is utilized as an additive in
the production of several alloys in order to increase hard-
ness and heat resistance. In the livestock industry,
arsanilic acid is sometimes added to swine and poultry feed
as a growth promoting agent.
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5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Some kinds of food plants contain extremely small or non-
detectable amounts of arsenic, whereas others grown in the
same soil contain the element in measurable amounts. The
degree of arsenic uptake by plants is apparently related to
the concentration of soluble arsenic in soil, chemical
composition of the soil and species of plant (Walshetal, 1977).
Arsenic concentrations in food in USA and Japan which had not
come into contact with arsenical insecticides are shown
in Table 2.
Marine organisms as well as seaweed contain roughly 10 times
higher arsenic concentrations than other foods. Many species
of bony fish contain 2 to 8 mg/kg, oysters 3 to 10 mg/kg,
mussels 120 mg/kg, clams around 11.6 mg/kg, whale meat about
0.36 mg/kg, prawns from the coastal waters of Britain up to
174 mg/kg and shrimps from the southeastern coastal waters of
the USA up to 42 mg/kg (Underwood, 1971). The arsenic content
of commercial fishmeals in animal feed ranges from 2.6 to
19.1 mg/kg with a mean of 6 mg/kg. Arsenic seems to be present
as a highly stable organoarsenical in marine fish (Lunde,
1975, 1977; Penrose, 1977). A comparison of the arsenic
levels in fish reported in 919 with those of 1970 failed
to show any significant increase (International Atomic Energy
Agency, 1970).
The amounts of arsenic ingested daily via food are greatly
influenced by the amount of seafood in the diet. A special
diet in the USA which excluded seafood contained 0.4 mg of
arsenic per person per day, while an average USA diet consisted
of 0.19 mg per person per day (Schroeder and Balassa, 1966).
According to another study, the daily intake of arsenic as
arsenic trioxide in the same country was calculated to be
0.137 to 0.330 mg per person (Duggan and Lipscombe, 1969,
34
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Cited in IARC, 1973). Other sources indicate that arsenic is
present in the diet at levels from 0.05 to 0.16 mg/kg per
day, corresponding to an intake of 0.15 to 0.40 mg per
person per day (Sommers and Smith, 1971, cited in IARC,
1973; Schroeder and Balassa, 1966). The daily intake of
total arsenic in Japan was reported to be from 0.07 to 0.17
mg per person in 1960 (Nakao, 1960), and the daily intake in
Fukuoka in 1974 was measured from 0.069 to 0.365 mg per
person (Ishinishi et al., 1974).
5.1,2 Water and soil
Traces of arsenic can be detected almost everywhere. In most
parts of the world, the arsenic content of river water
averages 0.0004 mg/1 and ranges from nondetectable to 0.23
mg/1 (Bowen, 1966) . Sea water ordinarily contains 2-5 /ug/1
of arsenic (Johnson, 1972). Arsenic contents of natural
water in several areas of the world have been reviewed by
Ferguson and Gavis (1972). The concentrations of arsenic in
surface waters of the United States were found to vary from
less than detectable to 1.1 mg/1 (Durum et al., 1971) .
Methylated species of arsenic have been measured in both
fresh and salt water (Braman and Foreback, 1973; Crecelius
et al., 1975) .
High carbonate spring waters in California, Romania, Kamchatka
in the USSR, and New Zealand have been reported to contain
0.4 to 1.3 mg/1 of arsenic (Schroeder and Balassa, 1966). In
Japan, hot-spring water has also been found to contain rela-
tively high concentrations of arsenic, ranging from 0.0 to
10.3,ug/1 in Beppu City, Oita Prefecture, to 1.62/ug/l in
Oninuki Town, Miyagi Prefecture, in one study (Kawakami,
1967) .
The mean arsenic content of crystalline rock is about 2
mg/kg, while soil usually contains from 1 to 40 mg/kg. In
general, arsenic tends to remain in surface layers of soil
and may render it temporarily sterile to the growth of some
plants, particularly legumes. It should be noted that arsenic
is contained in the phosphate rock currently used to manufacture
35
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fertilizers and detergents (Vallee et al., 1960; Bowen,
1966; Schroeder and Balassa, 1966).
5.1.3 Ambient air
Major sources of arsenic air pollution are the smelting of
metals, burning of coal, and use of arsenicals as pesticides.
Soils are not a significant source of air pollution. Arsenic
in ambient e;r occurs mainly in particulate form as arsenic
trioxide aiiu m^tal arsenites.
The 133 stations of Hche U.S. National Air Sampling Network
reported in 1964 that the annual average concentrations of
arsenic in air ran9ed from nondetectable to 0.75/ug/m . The
3
overall average was approximately 0.02 ,ug/m (Sullivan,
1969). The highest value, which was a quarterly average in El
Paso, Texas in 1964, was 1.40 /ug/m . In Anaconda, Montana,
which had local air pollution from a metal mine and refinery,
the highest ambient air concentration was 2.5 ,ug/m in 1961
and 1962.
Coal contains 0.08 to 16 mg/kg of arsenic. In Czechoslovakia,
emissions of approximately one ton of arsenic per day were
reported around the Novaky power station, which burned coal
containing up to 1.53 mg/kg of arsenic. In the power station
flue dust, the arsenic concentration varied from 43.0 to
113.4 mg/kg (Bencko et c.1., 1971; Long-Term Programme,
1973) .
5.1.4 Tobacco
Arsenic in tobacco originates from insecticides, especially
lead arsenite. The arsenic content of various popular brands
of American cigarettes averages 12.6 ,ug per cigarette in
1932-33 and had increased to 42 ,ug per cigarette in 1950-51
(Satterlee, 1956). The concentration of arsenious oxide in
cigarette smoke was reported to range from 3.3 to 10.5 mg/m
(Thomas and Collier, 1945). Arsenic concentrations in tobacco
have been reported to have declined during the last twenty
years due to decreased use of arsenical pesticides (Frost,
1967) .
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5 .2 Working environment:
Studies on the measurement of arsenic concentrations in
cases of occupational exposure are rare. According to Patty
(1962) the highest exposure in insecticide manufacturing is
usually found in the mixing, screening, drying, bagging, and
drum-filling operations. He gave concentrations of arsenic
in the air ranging from 0.5 to 45 mg/m during such operations,
A high exposure to arsenic fumes and dusts may occur in
factories which manufacture As~0.,, in smelters of copper,
lead, zinc, iron, and other ores, as well as in factories
which manufacture and use herbicides. According to more
recent reports from Japan, arsenic concentrations in the air
of well-controlled workshops in a copper refinery were 0.07
to 0.11 mg/m under normally ventilated conditions, and
0.077 to 0.194 in a nonventilated condition. Kodama et al.
(1975) reported average arsenic concentrations in air of
0.01 to 0.12 mg/m around a furnace in a copper smelter and
0.01 to 0.07 mg/m near a furnace in a ferro-nickel smelter.
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
Arsenic exposure through inhalation usually occurs in the
form of arsenic oxide, particularly arsenic trioxide, and
arsenate compounds. In a review on size frequency distribution
of arsenic trioxide dust, more than 23% of the particles
were reported to be larger than 5.5 ,um (Pinto and McGill,
1953). Sieve analyses of the final product of the arsenic
trioxides showed that over 98% (by weight) remained on a
325-mesh sieve. This characteristic of arsenic trioxide dust
causes its deposition in nasal and mouth cavities and in the
upper respiratory tract. More recent analytical data on air
samples collected near a copper smelter have indicated a
high concentration of arsenic in particles of less than 1 ,um
diameter.
37
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There are few human data which lend themselves to an exact
calculation of the absorption of inhaled arsenic. One study
which does include r_ ach data is that conducted by Holland et
al. (1959). Eight persons weie studied, and uptakes ranged
from 2.2% to 8.6% of the total arsenic that had been
injected into cigarettes. Holland et al. concluded that if a
cigarette contained 30 ,ug of arsenic trioxide in the portion
smoked, the 'v^rage =• noker would take up 2.5/ug of arsenic
trioxide in u^s respiratory tract per cigarette.
6.1.2 Ingestion
Absorption of arsenic through food is the most significant
route of exposure for the nonindustrially exposed. Coulson
et al. (1935) found that of 17.9 mg/kg arsenic (assumed to
be pentavalent) in shrimp fed to rats, a minimum of 0.7% was
retained in the tissue, whereas of the same concentration of
arsenic trioxide 18% was retained during a three-month
period. The absorption of arsenic from the gut is apparently
influenced by the chemical form of the arsenical involved
and dietary composition (Morgareidge, 1963; Tamura, 1972).
6.2 Transport and distribution
After absorption by the lungs or the alimentary tract,
arsenic is transported via the blood to other parts of the
body. Hunter et al. (1942) studied the distribution of
radioactive arsenical compounds after oral and parenteral
administration and found arsenic in the liver, kidney,
lungs, spleen, and skin during the first 24 hours after
administration. Arsenic concentration in the skin increased
for several days after a single administration, while in the
liver and kidneys it decreased after 24 hours. Small concentrations
were found in the brain, heart, and uterus. Bone and muscle
concentrations of arsenic were low, but the overall amounts
of arsenic in these tissues may be high due to their mass.
In conjunction with the skin, they comprise the major depots
of arsenic in the body. Vallee et al. (1960) noted that
small quantities of arsenic, even when the dose is low, may
be detected in tissues of ectodermal origin such as the
hair and nails many months after it has disappeared from the
urine and feces.
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Inorganic arsenic does not cross the blood-brain barrier in
humans, although it may do so in some anthropoids. In man
and rats, arsenic is transferred across the placenta (Vallee
et al., 1960). In radioactive tracer studies on arsenic in
rats, 95% to 99% of the arsenic in the whole blood was
detected in erythrocytes whereas in humans, monkeys and
rabbits, arsenic was more equally distributed between blood
cells and plasma proteins. The form of the arsenic administered,
arsenate or arsenite, played a role in this distribution
(Hunter et al., 1942; Hogan and Eagle, 1944; Mealy et al.,
1959). In various mammalian tissue fractions, the greater
part of the injected radio-arsenic is found in the protein
fractions; small amounts are present in the acid-soluble
portions of the tissue, and insignificant amounts are found
in lipids (Lowry et al., 1942). Nucleoproteins do not combine
with arsenic more than do proteins in general. The major
carriers of arsenic in the plasma of mice are alpha-1 globulins.
In each organ or tissue, it is known that arsenic can chemically
combine with sulfhydryl groups. It has been demonstrated
that trivalent arsenical toxicity can be reversed by thiol
compounds of the reduced type, e.g., glutathione and cysteine
(Vallee et al., 1960).
6.3 Accumulation and biological half-time
Bencko and Symon (1970) administered arsenic trioxide by
inhalation or drinking water to animals and found that
arsenic accumulation was biphasic and that it did not have
the character of a simple saturation curve. In the first
phase, the arsenic concentration increased in all organs and
tissues which were investigated, and in the second phase it
decreased. They concluded that the decrease of arsenic
concentrations in internal organs, for example, the liver,
was probably dependent on the activation or enhancement of
an arsenical excretion mechanism.
About 80% of the absorbed arsenic is retained and widely
distributed in tissues, such as the liver, kidney, spleen,
bone marrow, skin, and the hair and nails. The biological
39
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half-times in the blood of chickens given a single oral dose
of arsanilic acia or sodium arsenate were 36 hours and 60
hours respectively (Overby and Fredrickson, 1963).
Crecelius (1975, 1977) has reported biological half-times of
10 hours for As and 30 hours for methylated forms of
arsenic in a person who drank wine containing As
6.4 Excretion
Arsenic is excreted mainly in urine, to some extent in the
feces (Hunter et al., 1942) and through nornril hair loss and
skin shedding. The available evidence indicates that ingested
inorganic arsenate is excreted from the body mainly in the
pentavalent form but some percentage may be reduced (Lanz et
al., 1950; Ginsburg and Lotspeich, 1964; Ginsburg, 1965).
Trivalent arsenic appears to be primarily methylated in vivo
to methylarsonic acid and dimethylarsinic acid (Braman and
Foreback, 1973; Crecelius, 1975, 1977). Excretion of methylated
arsenic following exposure to airborne arsenic has been
recently reported (Smith and Crecelius, 1977).
7' Levels in tissues and biological fluids, normally and as
indices of exposure, intoxication and concentrations in
critical organs
Studies which quantitatively indicate the relationship
between arsenic concentrations in air and critical organs
such as the skin are rather limited. The critical effects in
these organs usually develop following a long incubation
period after the cessation of exposure. Also, arsenic concentrations
in critical organs are not easily measured.
Arsenic concentration in urine has been used as an index of
exposure but a number of complexities such as diet and
chemical forms of excreted arsenic affect this parameter.
The normal body burden of arsenic in humans in the USA was
concluded to be 14-21 mg based on calculations of daily
intake (Schroeder and Balassa, 1966). Arsenic concentrations
in organs of healthy persons from Scotland who died in
40
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accidents ranged from 0.012 mg/kg in brain to 0.460 mg/kg in
hair (Liebscher and Smith, 1968). Concentrations in persons
from Japan who consumed relatively high amounts of seafood
ranged from 0.020 mg/kg dry weight in the pancreas to 0.892
mg/kg in the nails (Kadowaki, 1960). The former authors used
neutron activation analysis and the latter polarography.
Values for all organs analyzed in the two studies are shown
in Table 3.
7.1 Arsenic in urine
In a study of arsenic trioxide exposure, Pinto and McGill
(1953) found an average urinary arsenic concentration of
0.13 mg/1 and a median of 0.10 mg/1 in 147 urine samples
taken from 124 workers who had not been exposed to arsenic.
The average arsenic concentration in urine in 835 spot
samples taken from 348 men who were exposed to arsenic in
the same factory as the control group was 0.82 mg/1 and the
median concentration was 0.58 mg/1.
Schrenk and Schreibeis (1958) reported that the average
arsenic concentration in urine among 756 people without any
particular exposure to arsenic was 0.08 mg/1 with a range
from 0.02 to 2.0 mg/1. In other studies, the concentration
of urinary arsenic in persons with no known exposure has
been reported as follows: 0.003-0.150 mg/1 or 12-260,ug/day
(Vallee et al., 1960) ; and 0.138 mg/1 or 12-927/ug/day as
the mean in a Japanese population sample (Iwataki and Horiuchi,
1959). Schrenk and Schreibeis (1958) found that ingestion of
marine shellfish caused marked elevation of total urinary
arsenic concentrations in humans. Crecelius (1977) ;;as
reported that the chemical form of urinary arsenic following
ingestion of shellfish is markedly different from the methylated
form observed after exposure to inorganic arsenic. Dietary
habits should be thoroughly examined when using urinary
arsenic concentrations as an index of exposure.
7.2 Blood
In general there are technical difficulties in the measurement
of arsenic concentrations in the blood. According to Liebsc.-,,-
41
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and Smith (1968) , the1, concentration of arsenic in the whole
blood averages 0.147 mg/1, with a range of 0.001 to 0.92
mg/1. Vallee et al. (1960) reported that the range of the
arsenic concentration in whole blood was from 0.0 to 0.37
mg/1. Heydorn (1970) reported mean arsenic concentrations in
whole blood of 0.022 mg/1 in Taiwanese subjects using neutron
activation analysis.
7.3 Hair
Normal concentrations of arsenic in hair are as follows:
Smith (1964) reported that 80% of 1,000 people had below 1
mg/kg of arsenic in the hair, with an average of 0.81 mg/kg
and a median of 0.51 mg/kg. He stated that hair concentrations
of arsenic above 3 mg/kg should always be suspect, those
that are 2-3 mg/kg require further examination, and those
that are less than 2 mg/kg should not be dismissed when
arsenic poisoning or heavy exposure to arsenic is suspected.
Liebscher and Smith (1968) reported 0.02 to 8.17 mg/kg as
the normal range for arsenic concentrations in the hair
based on 1,250 persons.
The relationship between arsenic concentrations in hair and
those in ambient air have been studied by Bencko et al.
(1971) and Hammer et al. (1971) who reported that the mean
concentration of arsenic in hair significantly reflected the
degree of arsenic air pollution in communities. Hair concentrations
of arsenic were found to increase depending on the magnitude
of arsenic exposure via any route of entry. However, soon
after arsenic exposure ceases, the hair concentration rapidly
decreases and returns to a normal level within a relatively
short period. Arsenic hair concentrations among retired
workers who had extensive arsenic exposure may be within a
normal range in spite of the fact that some of them may have
other symptoms of chronic arsenic poisoning, such as arsenomeianosis,
polyneuropathy, or sequelae of the poisoning (Ishinishi et
al., 1973).
42
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Lander et ai. (1965) reported that the arsenic concentration
of scaj.p hair was below 4 mg/kg (a normal value, according
to them) in 6 out of 18 persons who developed acute arsenic
poisoning within 24 hours of the ingestion of arsenic. The
other 12 persons showed values ranging from 5 to 700 mg/kg.
The distribution of arsenic along the shaft of the hair was
also examined. In 8 out of 12 persons with abnormal values
the highest levels were found near the hair root, while the
other 4 had the highest levels near the tip. Analysis of
hair offers no reliable method of distinguishing between
acute and chronic intoxication. Terada et al. (1960) described
an investigation of the arsenic concentration of hair in 39
cases with chronic arsenic poisoning caused by ingestion of
contaminated well water for about 10 years or more. Twenty-
eight percent of the total cases had 5-10 mg/kg arsenic in
the hair, 26% showed below 5 mg/kg, 13% revealed either 15-
20 mg/kg or 10-15 mg/kg, and the highest concentration was
85 mg/kg. There was no correlation between arsenical toxicity
and arsenic concentration in the hair. Caution must be
exercised in using hair concentrations of arsenic as an
index of exposure following atmospheric exposure due to
absorption of particles on hair shafts.
8. Effects
Arsenic may cause both acute and chronic types of poisoning.
Acute poisoning by arsenic is currently rare. Both subacute
and chronic poisoning usually occur because of exposure to
contaminated air or drinking water. The following review
will describe symptoms and signs in human beings suffering
from arsenic poisoning. It will also refer to animal data,
because these data may be helpful in the interpretation of
effects observed in humans both from a clinical and industrial
point of view and in the establishment of dose-response
relationships.
8 .1 Acute effects
Irritant and vesicant arsenical compounds, such as arsenic
trioxide, arsenic trichloride, and the arsenical war gases,
43
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have been known to cause severe damage to the respiratory
system upon inhalation. Symptoms of respiratory irritation
are cough, dyspnea, and pain in the chest, especially upon
inspiration. Other symptoms include giddiness, headache,
extreme general weakness, and later, nausea, vomiting,
colic, diarrhea, porathesis, and pains throughout the body.
In addition, acute poisoning from exposure to airborne dust
is frequently accompanied by irritation of any exposed skin
or mucous membrane, e.g., dermatitis, nasal mucosal irritation,
laryngitis, mild bronchitis, and conjunctivitis.
Cases of suicidal, homocidal, or accidental arsenical poisoning
by ingestion have been frequently reported. The last may be
a result of the consumption of food and liquids contaminated
by food additives containing arsenic. The most common chemical
form of arsenic in such cases is usually arsenic trioxide. A
fatal dose of ingested arsenic trioxide for humans has been
reported to range from 70 to 180 mg. Smaller amounts may
cause less severe symptoms of arsenic intoxication (Vallee
et al., 1960).
8.2 Chronic effects
8.2.1 General aspects; large-scale episodes and endemics
Chronic arsenic poisoning in workers after long-term exposure
via inhalation is manifested in abnormalities of the skin
and mucous membranes, as we .1 as in symptoms of the gastro-
intestinal and nervous systems. In a few cases, disorders of
the circulatory system and the liver have been recorded. A
number of studies have also disclosed systemic poisoning
caused by exposure to arsenical insecticides which were
mainly in the form of lead arsenate.
An episode of chronic arsenic poisoning in people living
near an arsenic trioxide refinery has been reported in
Japan. Victims showed several symptoms and signs of systemic
arsenic poisoning, including: skin lesions and signs and
symptoms of peripheral neuropathy. Since these chronic
44
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poisoning cases were discovered a number of years after the
closure of the refinery, the concentration of arsenic in the
ambient air of the community at the time the factory was
operating is unknown. Furthermore, many inhabitants of the
area with symptoms of systemic arsenic poisoning were also
working in the refinery at the time, so it is difficult to
distinguish whether those inhabitants were exposed occupa-
tional ly or environmentally. A high incidence of chronic
respiratory diseases was also observed in the same area. It
is not known whether these diseases were caused by inhalation
of air with high concentrations of arsenic or of high con-
centrations of sulfur dioxide (SO,-,) , which may have also
been present before closure of the refinery. According to a
case control study by Kuratsune (1973) , a significantly
higher incidence of lung cancer was also observed among the
inhabitants. However, most cases of lung cancer were related
to occupational exposure, and it was not elucidated whether
exposure to the community's ambient air alone could be a
contributory cause.
Certain respiratory and nervous symptoms (moderate hearing
impairment) have been reported in children living near the
Novaky power plant in Czechoslovakia mentioned in Section
5.1.2 (Symon and Bencko, 1973). Cmarko (1963, cited by
Wickstrom, 1972) stated that loss of working capacity was
significantly greater in the area of the power station than
in other industrial areas.
Chronic arsenic poisoning from ingestion of contaminated
food, beverages, and water has been reported in many countries
A report from the United Kingdom involved 6,000 people who
had ingested beer contaminated by arsenic (Kelynack et al.,
1900). Reports of "regional endemic chronic arsenicism"
caused by drinking water with high concentrations of arsenic
in and around Cordoba, Argentina, have been published oy
Manyano and Tello (1955) and Bergoglio (1964) (both ci^c by
Wickstrom, 1972) . These reports describe periods c.3.ti
far back as 1913. The primary criteria for diagnosis cf
45
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chronic poisoning were symmetrical palmar and plantar hyper-
keratosis. Excess death from cancer was seen during the
period 1949-1959. Hyperkeratotic skin lesions have also been
observed in populations exposed to arsenic-contaminated
drinking water in Chile (Borgono and Greiber, 1972; Borgono
et al., 1977). An endemic disease, also associated with
arsenic in drinking water, was discovered in Taiwan in 1963
(Yeh and How, 1963; Yeh, 1963; Tseng et al., 1968; Tseng,
1977). The major manifestation was a vascular disorder
resulting in gangrene of the lower extremities, commonly
called Blackfoot disease. Hyperkeratotic skin lesions were
also noted among the Taiwan population in question. Blackfoot
disease, in contrast, was not observed among the persons
with skin lesions in Chile.
The area around the Novaky power station in Czechoslovakia
also contained elevated concentrations of arsenic in drinking
and surface water (Somolnokyova, 1963, cited by Wickstrom,
1972). A large scale arsenic poisoning incident occurred in
Japan in infants who drank powdered milk contaminated with
arsenic containing phosphates in the blending process
(Hamamoto, 1955). This and similar incidents in Japan have
been recently reviewed in detail (Tsuchiya, 1977).
8.2.2 Skin lesions
Skin is a common critical organ in people exposed to inorganic
arsenical compounds (Buchanan, 1962; Nakamura et al., 1973).
Symptoms consist of eczematoid features of varying degrees
of severity, but vesicular lesions tend to predominate.
These latter lesions mature into more active and severe
types. In occupational exposure, the lesions in the initial
stage may result from local irritation and not necessarily
systemic poisoning. These lesions are frequently found in
areas of the skin which contain numerous moist creases, e.g.
the palm of the hand and sole of the foot. An allergic type
of contact dermatitis is also frequently seen among workers
who are exposed to white arsenic (arsenic trioxide). Chronic
dermal lesions may follow this type of initial reaction,
46
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depending on the concentration and duration of exposure.
These dermal lesions can be a result of occupational exposure,
environmental exposure via drinking water, or prolonged
therapeutic administration of arsenical compounds particularly
Fowler's solution. Hyperkeratosis, warts, and melanosis of
the skin are the most commonly observed lesions following
chronic exposure.
Melanosis of the skin is a common affliction after many
years' exposure to arsenic either medicinally or occupationally,
It is seen most often on the upper and lower eyelids, around
the temples, and on the neck, areolae of the nipples, and in
the folds of the axillae. In severe cases, arsenomelanosis
is observed on the abdomen, chest, back, and scrotum, along
with hyperkeratosis and warts. Chronic arsenic poisoning is
also characterized by depigmentation, i.e. leukodermia,
especially on the pigmented areas, commonly called "raindrop"
pigmentation. These skin lesions, particularly hyperkeratosis,
may be related to cancer of the skin (See Section 8.3).
Another characteristic of chronic arsenic poisoning is the
presence of white striae in the fingernails, first described
by Mees (1919). The accumulation of arsenic in skin is
probably related to the abundance of proteins containing
sulfhydryl (SH) groups with which arsenic readily reacts. It
should even be noted that the adverse effects on the skin
may develop long after the cessation of exposure when arsenic
concentrations have decreased to normal levels (Pinto and
McGill, 1953; Vallee et al., 1960j Buchanan, 1962).
8.2.3 Mucous membrane lesions
In the subchronic stage, dermatitis of the face and eyelids
is sometimes accompanied by conjunctivitis, characterized by
redness, swelling, and pain. Keratoconjunctivitis, a severe
type, was reported following exposure to calcium arsenate as
an insecticide. Corneal anaesthesia accompanied by a corneal
ulcer has also been reported, but this may have been a very
rare case. There may be irritation of the nose and pharynx
in the subchronic stage, causing acute or chronic rhinitis
as well as irritation of the bronchial passages.
47
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As a result of irritation of the upper respiratory organs by
arsenic dust, perforation of the nasal septum is a common
finding among workers who have been occupationally exposed.
The perforation, as with similar lesions caused by other
chemical irritants such as chromium, is confined to the
cartilagnous portion of the septum (Kiesselbach1s area) and
does not lead to deformity of the nose or other apparent
subjective symptoms once inflammation has subsided. Many of
the people who have this perforation are unaware of its
presence.
8.2.4 Gastrointestinal disturbance
Chronic arsenic intoxication by ingestion has been recognized
for many years and is usually characterized by weakness,
loss of appetite, gastrointestinal disturbances, and on
occasion, peripheral neuritis, hepatitis, keratitis, and
pigmentation. However, gastroenteritis in relation to arsenic
poisoning is not a common occurrence (Buchanan, 1962).
8.2.5 Peripheral nervous disturbance
Peripheral neuritis affecting mainly the upper and lower
extremities is one of the symptoms of chronic arsenical
poisoning. The neuritis caused by arsenic poisoning is
symmetrical, widespread, and painful, aspects which do not
characterize peripheral neuritis caused by lead poisoning.
In severe cases of arsenic poisoning, personality alterations
may occur along with headache, drowsiness, aphasia, and
disorientation. Nerve biopsies from patients with such
symptoms showed neuronal degeneration thought to result from
inhibition of the pyruvate oxidase complex (Vallee et al.,
1960). Among patients with chronic arsenic poisoning, not
only bilateral polyneuropathy but also unilateral polyneuropathy
without any motor paralysis has occurred. These cases showed
a diminishing sensation of touch with numbness of extremities,
and a "pins and needles" sensation (parathesias). These
symptoms were observed among retired workers who had been
heavily exposed to arsenicals and who also revealed skin
lesions or perforation of the nasal septum. Takahashi (1974)
48
-------
reported abnormal electromyograms (EMG) among people who had
lived near en arsenic mine and smelter and who were without
subjective symptoms. Typical arsenical skin lesions among
these inhabitants have not been confirmed.
8.2.6 Anemia
Anemia and disturbance of the hematopoietic system are not
common in chronic arsenical poisoning caused by industrial
exposure but anemia has been observed in chronic arsenic
poisoning caused by long-term ingestion. Cases of chronic
arsenic poisoning with skin lesions are often accompanied by
moderate anemia and leukopenia. This type of anemia is not
considered to be due to the deficiency of iron but thought to
be similar to aplastic anemia from a hematological viewpoint
(Terada et al., 1960; Yoshikawa et al., 1960; Terada, 1973).
Anemia caused by arsine is due to hemolysis and it quite
different in nature from arsenical poisoning (See Section 11).
8.2.7 Liver disturbance
Inorganic arsenical compounds have long been considered
capable of damaging the liver under certain circumstances.
However, this has not occurred with any reported frequency among
industrial workers. On the other hand, as a sequela of arsenical
medication, jaundice sometimes accompanied by ascites has
been reported. One of the first records of cirrhosis among
vineyard workers who used arsenic as a pesticide was reported
by Dorle and Ziegler (1930). This report mentioned that
arsenic poisoning was not caused by inhalation nor by skin
contact, but most probably by the ingestion of wine
contaminated by arsenic. More recently, similar cirrhotic
changes have been noted in livers of other vintners (Butzenge iger,
1940, 1949; Luchtrath, 1972). Similar findings have also
been observed among Japanese following outbreaks of mass
arsenic poisoning (Tsuchiya, 1977). In addition, liver
disturbances from long-term arsenic ingestion are frequently
complicated by chronic hepatitis, an enlarged tender liver,
and ascites.
49
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The cellular mechanisms of arsenic hepatotoxicity appear to
involve mitochondria! damage with subsequent impairment of
tissue respiration (Fowler et al., 1977; Schiller et al.,
1977; Woods et al., 1977).
Finally, primary liver cancer and hepatobiliary cancer caused
by arsenicals have been reported as a result of either
medication or industrial exposure (See Section 8.3).
8.2.8 Disorder of the heart and circulation
The epidemiological and clinical evidence for primary cardiac
injury in arsenic workers is not very definite, but electro-
cardiograms have revealed abnormalities (Barry and Herndon,
1962; Glazener, 1968). Abnormal electrocardiograms indicating
a toxic myocardial effect were found among vineyard workers
with chronic arsenical poisoning who used arsenical insecticides
These cases showed other symptoms of the poisoning as well.
Some of the workers with severe myocardial injury also suffered
from peripheral vascular disturbances, endo-angitis,
gangrene of the extremities, atrophic acrodermatitis, and other
less severe symptoms of peripheral blood vessel damage
(Butzengeiger, 1940, 1949; Hadjioloff, 1940). As mentioned
earlier, the Blackfoot disease in an arsenic-exposed
population in Taiwan is due to peripheral vascular disorders
(Yeh and How, 1963; Yeh, 1963).
8.3 Carcinogenic, teratogenic and genetic effects
8.3.1 Carcinogenic effects
Epidemiological studies indicate an apparent causal relation-
ship between skin cancer and heavy exposure to inorganic
arsenic via medication, contaminated well water, or
occupational exposure. Skin cancer as a result of arsenical
poisoning is characterized by multifocal lesions over the
entire body, especially in the palms and soles (Borgono,
1977; Ishinishi et al., 1977; Tsuchiya, 1977; Tseng, 1977).
50
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Among the several types of skin cancer, epithelioma developing
on the site of keratoses is the most common. The keratic
lesions may exist for many years before they change to a
malignant form of epithelioma which is usually of the
squamous type. Basal cell carcinoma of a low-grade malignancy,
j_n situ, accompanied by chronic "precancerous dermatitis"
(Bowen's disease) is also found in cases of chronic arsenical
dermatitis (Neubauer, 1946; Hill and Farring, 1948; Sommers and
McManus, 1953; Roth, 1957; Braun, 1958; Fierz, 1965; Tseng et al.,
1968; Nakamura et al., 1973).
The causal relationship between exposure to arsenical dust and
lung cancer had not been confirmed by epidemiological
observations until recently. Studies on hand now show a
higher risk of lung cancer among workers exposed to arsenic
trioxide in smelters and insecticide factories (Ott et al.,
1974; Pinto, 1977). An increased relative frequency of deaths
from lung cancer has been reported among vineyard workers
(Ref?) and in the population exposed to arsenic in drinking
water in Cordoba, Argentina (Bergoglio, 1964, cited by
Wickstrom, 1972) .
The development of tumors of other organs, frequently accompanied
by skin cancers, has been reported in cases which were
exposed to inorganic arsenic as medication, as an insecticide,
as contaminated wine and in drinking water (Sommers and
McManus, 1953; Roth, 1957; Braun, 1958; Bergoglio, 1964,
cited by Wickstrom, 1972). However, the relationship between
arsenic exposure and a higher risk of cancer in organs other
than skin and lungs has not been confirmed (IARC, 1973).
Nevertheless, it is important to note that hemangio-endothelial
sarcoma, often complicated by liver cirrhosis and splenomegaly,
has been reported (Roth, 1957; Braun, 1958; Regelson et al.,
1968; Popper and Thomas, 1975).
In spite of the epidemiological association between exposure
to arsenic and cancer of the skin and lungs as well as
angiosarcoma of the liver in man, a reliable and consistent
-------
induction of cancers in animals via arsenic exposure has not
been achieved as yet (Hueper, 1966; IARC, 1973). A preliminary
report by Osswald and Goerttler (1971) has suggested possible
carcinogenic effects (induction of lymphoma) in mice which
were exposed to several arsenical compounds by several
routes.
8.3.2 Teratogenic effects
Teratogenic effects have been shown after a single administra-
tion of sodium arsenate to pregnant golden hamsters (Ferm
and Carpenter, 1968; Ferm et al., 1971; Ferm, 1977). The
dose of dibasic sodium arsenate was from 15 to 25 mg/kg body
weight. The compound was given to the hamsters on the 8th
day of gestation with intravenous injection (Ferm et al.,
1971). Both the reabsorption and malformation rates in the
fetus increased with increasing doses of the arsenate. The
teratogenic effects were characterized by anencephaly, renal
agenesis, and rib malformations. Similar teratogenic effects
have been reported in mice (Hood and Bishop, 1972) at 25
mg/kg dose levels and in rats (Beaudoin, 1975) at 30 mg/kg
dose levels. The comparative teratogenic effects of arsenate
on rats and mice have been discussed in relation to protection
by BAL (Hood et al., 1977).
8.3.3 Genetic effects
An increased incidence of chromosome abnormalities has been
observed in lymphocytes of workers exposed to arsenic (Beckman
et al., 1977) and patients therapeutically treated with
arsenicals (Petres and Hagedorn, 1977). Arsenical interference
with normal DNA repair processes has also been noted (Jung,
1969, 1971; Rossman et al., 1977) suggesting that damage to
cellular genomes may occur through this mechanism.
8.4 Interaction between arsenic and other metals
According to Holmberg and Ferm (1969), sodium selenite
(which is not teratogenic), when injected simultaneously
with sodium arsenate, provided significant protection in an
animal experiment against the malformations induced by
arsenic.
52
-------
Interactions between arsenic and selenium have also been described
by Levander (1977) . A study on the simultaneous exposure to
arsenic and lead revealed that this combination had additive
effects on the levels of sulfhydryl groups, tissue respiration,
and functional changes in the central nervous system in
experimental animals (Novakova, 1969). Arsenical interactions
with lead or cadmium have also been described by Mahaffey and
Fowler (1977) .
9. Dose-effect and dose-response relationships in chronic
poisoning
The dose-effect relationship in chronic arsenic poisoning in
Japanese infants may be estimated from the report by Hamamoto
(1955) who observed that the victims ingested 90 to 150 g
of dried milk per day which contained from 25-28 mg/kg of As-0-,.
They developed symptoms of arsenic poisoning, including pigmenta-
tion, swelling of the liver and anemia, when a total of
about 115 mg of arsenic trioxide had been ingested. This means
that these patients ingested an average of about 3.5 mg of
arsenic trioxide daily over a period of 33 days. A total of 12,083
cases of poisoning with 128 deaths were reported as a result of
this incident. Residual impairment of learning and of clinical
function has been described among those who survived (Yamashita et
al. , 1972) .
There is one report by Fierz (1965) concerning the dose-
response relationship between skin cancer and the total dose
of Fowler's solution ingested as medication. He reviewed 262
patients who had been treated for weeks or even for several
years with Fowler's solution for various chronic dermatoses.
Ten to 2600 ml of the solution were administered to the
patients. Among those patients who developed late effects
from this treatment, 40% had hyperkeratosis and 8% had
skin cancer. A clear relationship between the increase in the
incidence of both hyperkeratosis and cancer and the increased
dosage of arsenic was indicated, as shown in Figure 2 (Fierz,
1965). The minimal dose of Fowler's solution for the develop-
ment of hyperkeratosis was 60 ml and for skin cancer approximo.-
tely 75 ml.
53
-------
In areas in Cordoba, Argentina, in which chronic arsenic
intoxication, the main symptoms being symmetrical palmar and
plantar hyperkeratosis, has resulted from exposure to arsenic
in drinking water, concentrations in the water have been
variously reported as 2.8, 1.1, 3.8, and 4.5 rag As2O3/l
(Wickstrom, 1972). For comparison, the national standard of
0.5 mg arsenite salt per liter drinking water may be
mentioned.
In the arsenic polluted area in Czechoslovakia where nervous
and respiratory effects have been observed the maximum
concentrations of arsenic in drinking water were 0.070 mg/1
and in surface water 0.210 mg/1 (Somolnokyova, 1963, quoted
by Wickstrom, 1972).
In the episode of arsenic poisoning reported in Taiwan, the
dose-response relationship between skin cancer and arsenic
concentrations in well water was described by Tseng et al.
(1968). Out of the total population of 40,421, arsenical
skin cancer was found in 428 people (10.6/1000 people).
There were no patients under 20 years of age. The villages
surveyed were divided into 4 groups according to the arsenic
concentration in the well water (See Figure 3): (1) below
0.3 mg/1, (2) 0.3-0.6 mg/1, (3) above 0.6 mg/1, and (4)
undetermined. It was estimated that the minimal amount of
arsenic in well water necessary for inducing skin cancer was
less than 0.29 mg/1.
There are a few reports regarding the dose-response relation-
ship of chronic arsenic poisoning by inhalation and by
occupational exposure. Pinto and McGill (1953) reported the
relationship between the urinary arsenic level ranges and
the percentage of dermatitis among workers exposed to arsenic
trioxide. Out of those workers excreting 0.3 mg/1 arsenic in
urine, 35% suffered from arsenical dermatitis, while of
those workers excreting 3.0 mg/1 and above, all suffered
from dermatitis. More studies are required in order to
establish a dose-response and dose-effect relationship
between the concentration of arsenic in air and in urine and
the symptoms of arsenic poisoning.
54
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10. Diagnosis, treatment, and prognosis
10.I Acute poisoning
10.1.1 Inhalation
10.1.1.1 Diagnosis
Acute arsenic intoxication via inhalation usually does not
occur except for acute arsine poisoning, although respiratory
symptoms may occur among those who are suddenly exposed to
high concentrations of arsenic in smelters. Acute skin
lesions such as contact dermatitis may be observed around
the eyes and mouth, as well as on the face and neck. The
diagnosis of such cases is based upon the history of arsenic
exposure. The measurement of arsenic in urine is useful
provided the specimen is taken within a few weeks after
exposure and provided no recent consumption of marine fish
or shellfish has taken place.
10.1.1.2 Treatment and prognosis
A conservative treatment is usually applied to the skin
lesions. British antilewisite (BAL) may be given in cases of
severe symptoms of the respiratory system or the skin.
10.1.2 Ingestion
10.1.2.1 Diagnosis
The determination of arsenic in the hair, urine, blood, or
stomach contents is useful for diagnosis if exposure to
arsenic is not readily identified.
10.1.2.2 Treatment and prognosis
The treatment for acute arsenic poisoning by ingestion is
referred to in medical textbooks, e.g. Krupp and Chatton's
"Current Diagnosis and Treatment" (1974). Prognosis will
depend upon both dosage and time of initiation of the treatment
after ingestion. In some cases where recovery from acute
poisoning has occurred, dermatitis and peripheral neuritis
55
-------
may persist for a relatively long time. The possible development
of secondary liver impairment after acute or chronic poisoning
has also been discussed (See Section 8.2.7).
10.2 Chronic poisoning
10.2.1 Diagnosis
In chronic arsenic poisoning, the differentiation between
senile pigmentation, senile leukodermia, and arsenical
dermatoses is extremely important for diagnostic purposes.
The characteristics of the skin lesions resulting from
arsenic poisoning have been described in Section 8.2.2.
However, it is not necessarily easy to determine whether
skin changes in older persons are of arsenical origin or are
simply senile skin changes. This problem is especially
evident in persons exposed to arsenic via ingestion.
Concentrations of arsenic in biological tissues may be
within the normal range at the time a diagnosis is made. In
such cases, a well-designed epidemiological study may be
required if it is thought that a group of people might have
been exposed to arsenic. The presence of white striae in the
fingernails is a useful tool in the diagnosis of arsenical
polyneuritis, because arsenic concentrations may be within
normal limits during this condition (Heyman et al., 1956).
Recognition of damage to the upper respiratory tract, specifi-
cally perforation of the nasal septum, may be quite helpful
for the diagnosis of chronic arsenic poisoning.
Liver damage, including such impairments as cirrhosis and
angiosarcoma, which may be seen in the exposed person, may
require differentiation in terms of the cause-effect relation-
ship.
10.2.2 Treatment and prognosis
BAL has been used for the treatment of chronic arsenic
poisoning, in particular in cases of dermatosis. Pinto and
56
-------
McGilI (1953) administered BAL to persons with arsenic
dermati-cis . They succeeded in augmenting the excretion of
arsenic into the urine but not in improving skin changes such
as melanosis and keratosis. Apart from the debatable treatment with
BAL, the treatment of chronic arsenic poisoning may be mainly
a conservative one.
Skin changes and neuropathy may be persistent over a long
period of years. The skin changes seen in simple keratosis
may progress into Bowen's disease, which will spread over the
entire body in multiple forms.
11. Arsine
Arsine (hydrogen arsenide, AsHO is a colorless, inflammable
gas with a slight garlic odor and is generated whenever
nascent hydrogen is liberated in material containing arsenic.
Since arsenic is present as a contaminant in many metal
ores, the generation of arsine may occur in metal industries,
nonferrous metal refineries, and in the manufacture of
silicone steel, if these ores accidently come into contact
with acid. It may also occur when the hydrogen ion is formed
by hydrolysis, as in the reaction of moisture with a dross
containing arsenic.
The toxicity and toxicological mechanism of arsine are quite
different from those of other inorganic or organic arsenic
compounds. Arsine is a well-known highly toxic gas and a
powerful hemolytic poison in cases of both acute and chronic
exposure.
Henderson and Haggard (1943) stated that the lethal dose of
arsine for humans was 250 mg/kg for 30 minutes, and that
poisoning symptoms would occur after a few hours of exposure
to 3 to 10 mg/kg. Elkins(1959) reported a serious, nonfatal,
acute case in a person who had worked in an atmosphere con-
taining an average of 0.5 mg/kg arsine. Five workers, reported
by Kipling and Fothergill (1964) , developed typical arsine
poisoning from exposure in a plant where an acetylene-like
-------
odor was detected during the slag-dissolving process in the
rotating drum. The concentration of arsine in this factory
was 5 mg/kg.
Morse and Setterling (1950) studied 2 fatal cases of arsine
poisoning where aluminum had been used to remove arsenic.
The concentration of arsine in this instance was 70 to
300 mg/kg.
Arsine poisoning is characterized by nausea, abdominal colic,
vomiting, backache, and shortness of breath, followed by
red urine and jaundice (Kipling and Fothergill, 1964).
According to Bulmer et al. (1940), the following symptoms
occurred after various lengths of exposure to arsine: shortness
of breath on exertion, general malaise, nausea, poor appetite,
palpitation on exertion, and headache. In some groups of
workers a tingling sensation in the feet, chills, garlic
breath, changes in the complexion, weakness, vomiting, and
drowsiness were observed. Jaundice was also recognized in
some workers. Among workers with the longest exposure, anemia
was present. Arsenic trioxide in urine was elevated in almost
all groups of workers, ranging from 0.04 to 4.3 mg/1.
Even after the workers had left the arsine-contaminated .
area, arsenic trioxide in urine ranged from 0.04 to 0.1
mg/1. Peripheral neuritis was also reported by Dudley
(1919). Liver disturbances may also accompany poisoning. In
most fatal cases renal failure due to blockage of the
renal tubules by hemoglobin casts seems to be the usual
cause of death (Fowler and Weissberg, 1974). Residual
functional impairment of the kidneys has been reported in
one person following an acute episode of arsine poisoning
(Muehrcke and Pirani, 1968).
The use of BAL for arsine poisoning is not promising, but
symptomatic therapy is more reliable, particularly in the
treatment of anuria. Blood transfusions may be necessary for
severe anemia. Arsine toxicity and treatment have been
recently reviewed (Fowler and Weissberg, 1974) .
58
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Table 1. World Production of Arsenic from 1911-1970
(From Ferguson and Gavis, 1972).
Average Yearly Production
Decade Metric Tons
1911-1920 12,600
1921-1930 21,700
1931-1940 39,400
1941-1950 44,000
1951-1960 34,400
1961-1970 42,700*
* Excludes U.S. production
-------
Table 2. Arsenic Concentrations in some Foods not Sprayed
with Arsenicals in the USA and Japan (Compiled
from Schroeder and Balassa, 1966, and Nakao,
1960, respectively).
Concentration
of arsenic
mg/kg wet weight
Food in USA
Winter rye
Corn
Barley
Spinach
White onions
Tomatoes
Grean beans
Wheat*
Corn*
Tomatoes*
2.40
0.00
0.85
1.10
0.18
0.00
0.09
0.17
0.11
0.10
Food in Japan
Rice
Rice without bran
Wheat
Beef
Pork
Whale meat
Eggs
Gray mullet
Tuna fish
Red snapper
Sardine
Apple
Grape
Pear
White onions
Spinach
Tomatoes
Milk
Dehydrated milk
0.033-0.045
0.027-0.036
0.020-0.034
0.100-0.190
0.135-0.205
0.150-0.250
0.008-0.012
0.325-0.585
0.315-0.585
0.310-0.425
0.390-0.550
0.020-0.022
0.015-0.075
0.012-0.073
0.005-0.033
0.000-0.030
0.007-0.012
0.002-0.017
0.008-0.037
* Commercially available vegetables and grains
60
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Table 3. Arsenic Concentrations in Human Organs and Tissues
in Scotland
Smith, 1968,
Tissue/Organ
Adrenal
Aorta
Whole blood
Bone
Bone
Brain
Hair
Heart
Intestine, large
Intestine, small
Kidney
Liver
Lung
Muscle
Nail
Ovary
Pancreas
Prostate
Skin
Spleen
Stomach
Teeth
Thymus
Thyroid
Uterus
and Japan (Compiled from Liebscher and
and Kadowaki, 1960, respectively).
Arsenic concentration
mg/kg dry weight
Scotland Japan
0.029
0.035
0.036
0.053
0.012
0.460
0.021
0.026
0.034
0.078
0.062 (pectoral)
0.283
0.048
0.047
0.039
0.080
0.017
0.022
0.049
0.019
0.042
0.037
0.118 (femur)
0.074 (rib)
0.034
0.174
0.041
0.025
0.022
0.041
0.042
0.047
0.029
0,892
0.020
0.064
0.021
0.022
0.078
0.036
61
-------
L AiS. A»4S4 2.
Sutfurft
Orpimcnt
4. CI-CH-CH-A»-CI2 5.
Arwnous ond**
Whit* ori«mc
A.-0
^X.
^. >NHZ
3. r.A.s
- Vtntnopyrit*
Arsenic
r
A» - At
dH
Phanyl Ar&omc Acid
10.
HjN
A» » Af
II.
12.
13.
HO • tti
ArtpKtianint H606" Salvanan
O j x O
Ai-/ VNH-CHZ-c - NH^
OH \*=/
Tryporsomidt
(pNa
NoO - A> = 0
HCI
NH
I
N* N
Mclarten
Figure 1. Arsenicals with biologic action (From Vallee et
al.f 1960).
62
-------
^
Q)
O
C
(0
0
M-l
O
U)
Cn
4->
C
0)
U
ju,
0)
w
C
O
to
0)
£4
^
0)
C
•H
e
fd
X
0)
tn
C
O
e
"1
i
30 1
25-
20-
15-
10-
5 •
0 200 400 600 800 1000 1TJ.J -»i:00
Concentration of arsenic in
Fowler's solution, cm
Figure 2. The relative frequency of skin cancer with
increasing doses of arsenic (From Fierz, 1965)
Both Sexes
200
ISO
100
i
1000
IIJ
H
J
no
H
i t
U
M
Age 20-39
40-59
Arxnie Conctntration(ppm) in V/ell Wot«r
H High 0.6O 8 Over
U Mid 0.3O - 0.39
L Lew 0.00 - 0.29
, U Undttcrmined
me
M
60 a Over
Totol
Figure 3. Age-specific and sex-specific prevalence rate
(1/1000) for skin cancer by arsenic concentration
in well water (From Tseng et al., 1968).
63
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BARIUM
Andrew L. Reeves
1. Abstract
Soluble forms of barium are readily absorbed after inhalation.
After ingestion barium sulfate remains essentially unabsorbed.
Soluble barium salts such as barium chloride are absorbed to
10-30 % in hamsters. After absorption barium accumulates in
the skeleton. An accumulation also takes place in the pigmented
parts of the eye.
Poisoning with soluble barium compounds has resulted from acci-
dental or suicidal ingestion. The Ba ion is a muscle poison,
causing gastrointestinal, cardiac, and skeletomuscular stimula-
tion followed by paralysis. In Szechuan province of China, a
subacute form of barium poisoning ("pa-ping") was endemic due
to use of contaminated table salt.
The mechanism of action of barium is based on its physiological
antagonism to potassium, and cases of barium poisoning are
accompanied by severe hypokaleiuia. Potassium infusion is an
effective antidote.
Inhalation of barium sulfate dust causes a benign pneumoconiosis
("baritosis") with conspicuous radiographic manifestations but no
impairment of pulmonary function. The condition has been repro-
duced in rats.
The primary route of exposure for the general population is
usually via food.
Reviews on barium toxicology and metabolism have been written
by Schroeder et al. (1972) and Marshall et al. (1973).
71
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2• Physical and chemical properties
Barium, Ba, atomic weight 137.3; atomic number 56; density 3.5;
melting point 725 Cj boiling point 1,640°C; crystalline form
yellowish-silver metal; oxidation state 2. The compounds to
be taken up here are barium chloride, barium sulfate, barium
carbonate, barium nitrate, barium sulfide, barium acetate,
barium hydroxide.
Barium is the heaviest of the stable alkaline earths. The free
element oxidizes readily in moist air and reacts with water or
with dilute acids under evolution of hydrogen gas.
In its compounds, barium is a colorless divalent positive ion.
Barium sulfate is one of the least soluble compounds known,
in any medium. Volatile compounds of barium (especially halide
salts) give the Bunsen flame a pale green color.
3. Methods and problems of analysis
Determination of barium with conventional analytical reagents
is unsatisfactory for micro-quantities. Procedures in current
favor include neutron activation analysis, limit of detection
about 1 rag/kg (Sowden and Stitch, 1957); emission spectrography,
limit of detection about 0.1 mg/kg (Gabrowski and Unice, 1958);
and atomic absorption spectrophotometry, limit of detection
about 0.01 mg/kg {Edelbeck and West, 1970). Several of these
are specifically adapted for assay in biological material.
4. Production and uses
4.1 Production
Barium occurs chiefly as the mineral barite. Much smaller
amounts are also mined as witherite. The United States, the
Federal Republic of Germany, and the Soviet Union are the
leading producers, the total world production being in the
range of 4 million tons per annum. For the manufacture of
barium chemicals, barite is reduced to the much more reactive
barium sulfide through high-temperature sintering with charcoal.
Similar treatment converts witherite to the water-soluble bari-
72
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4.2 uses
In recent years, about 80 % of ground and crushed barite sold
has been used directly as a weighting agent in oil- and gas-well
drilling muds.
The remainder of barite and all witherite are used in the man-
ufacture of glass, ceramics, television picture tubes, brick
and tile refractories, plastic stabilizers, railroad flares,
fireworks, fine chemicals, lubricating oil additives, permanent
magnets, as well as in sugar refining, paper coating, steel
hardening, and as pigment in paint (lithophone).
Barium-containing household and consumer products constitute
a minuscule part of barium consumption, but have the greatest
toxicological significance. They include rodenticides, insecti-
cides and depilatories.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Barium content in edible crops ranges from about 10 mg/kg in
wheat and corn grain to several thousand mg/kg in brazil nuts
(Beeson, 1941). Generally, barium content of food parallels
2 5
calcium content, in a ratio of 1:10 -10 . Expressed as mg
Ba/kg Ca, typical values in milk were 45-136; wheat flour
contained 1300 and oatmeal, 2320-8290 mg/kg (Henderson et
al., 1962).
In an American hospital diet the daily intake of barium was
estimated at 0.375 mg while in the diet of the general population
it may be as high as 1.33 mg (Schroeder et al., 1972). Grummitt
(1961) estimated that average dietary barium intake originated
25 % from milk, 25 % from flour, 25 % from potatoes and 25'
% from miscellaneous high-barium foods consumed in minor quan-
tities, especially nuts.
73
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5.1.2 Water, soil, plants and ambient air
Barium constitutes about 0.04 % of the earth's crust, mostly
confined to certain rock types. Agricultural soils contain
Ba in the mg/kg range. Concentration of the element in
sea water is 0.006 mg/1 and in fresh waters, 0.007-15.0
(average 0.05) mg/1 (Schroeder et al., 1972). Municipal wat-
ers of the United States ranged 0.0017-0.38 (average 0.043)
and of Sweden, 0.001-0.02 mg/1 (Bostrom and Wester, 1967). In
urban air, the average concentration was 5 (range 0-1500) ng
3
per m in 18 U.S. cities (Schroeder et al., 1972).
Barium has been found in all biological material where assayed.
Marine animals concentrate the element 7-100 times and marine
plants 1000 times from sea water. Among land plants, oak, ash,
Douglas fir, walnut, and particularly brazil nuts are the
strongest accumulators of soil barium. Soybeans and tomatoes
also accumulate soil barium 2-20 times (Robinson et al.,
1950) .
5.1.3 Cigarettes
Barium content of dry tobacco leaves was found as 88-293
mg/kg by McHargue (1913); more recent measurements yielded
24-170 (average 105) mg/kg (Voss and Nicol, 1960). Most of
this barium content is likely to remain in the ash during burning.
There are no values reported on smoke.
5.2 Working environment
The industrial uses of soluble barium are such that hazardous
conditions from atmospheric contamination are uncommon. Hyatt
(1971) has applied a limit of 0.5 mg Ba/m for a number of
years at the Los Alamos Laboratories with satisfactory re-
sults for the control of exposure to barium nitrate. It is
not known what degree of added safety this limit incorporates.
6. Metabolism
6.1 Absorption
6.1.1 .Inhalation
Soluble forms of barium are readily absorbed from all segments
74
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133
or the respiratory tract. Nasal absorption of Bad was
estimated at 60-80 % of the dose at 4 hours after dosing
(Cuddihy and Ozog, 1973) and alveolar absorption is of sim-
ilar magnitude. According to measurements at tracer levels,
even BaSO. was found to be cleared from the lungs, with a
biological half-time of 8-9 days (Morrow et al., 1964). This
indicated some solubility of BaSO. in body fluids, possibly
in colloidal form.
Clearance of various forms of barium after inhalation exposure
was studied by Einbrodt et al. (1972) and by Cuddihy et al.
(1974). Different compounds of barium were cleared from the
lungs in proportion to their solubilities; in the case of
BaSO., the clearance rate depended on the specific surface
area of the inhaled particles, and was lower for heat-treated
than for untreated particles. Barium in fused montmorillonite
clay had the lowest clearance rate.
6.1.2 Ingestion
Barium sulfate can be used as X-ray contrast material for gas-
trointestinal examinations, because during the relatively
brief period of passage through the alimentary canal BaSO
remains essentially unabsorbed. Soluble barium salts do become
133
absorbed, and in hamsters receiving EaCl by intragastric
intubation, absorption was 10-30 % of the dose (Cuddihy and
Ozog, 1973).
Sutton et al. (1972) and Sutton and Shepherd (1973) found that
addition of sodium alginate to the diet reduced intestinal ab-
sorption of barium in rats and man to 42-75% (average 64%)
of control.
6.1.3 Parenteral administration
Thomas et al. (1973) measured the in vivo solubility of 4 barium
salts after intramuscular deposition. Chloride and carbonate
were about equally diffusible and left the injection site very
rapidly. The sulfate showed a biological half-time of 26 days,
and a fused aluminosilicate clay, 1400 days.
75
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6.2 Transport and distribution
All alkaline earths have a tendency to accumulate in the skel-
eton, and the degree of osseous uptake for circulating barium
was found to be 3 to 5 times that for calcium or strontium.
Elsasser et al. (1969) found this preference for barium to
be due to uptake on bone surfaces rather than to diffuse up-
take. After intravenous injection of Ba into beagle dogs,
specific activity was highest in the sternum, followed by
sacrum and coccyx, vertebrae, ribs, humerus and femur. In the
skull, mandible, radius, ulna and fibia-fibula, the specific
activity was less than whole-body specific activity.
In most soft tissues, barium accumulation after intravenous in-
jection is slight and in proportion to their calcium content.
An exception is the submaxillary gland of the rat which was
found to concentrate barium from serum in preference to the
other alkaline earths (Bligh and Taylor, 1962) and the eye, in
which extremely high concentrations of barium are sometimes
found (Sowden and Pirie, 1958). The pigmented parts of the
eye (iris, sclera, and especially the choroid) are the strongest
accumulators of circulating barium with concentrations reaching
the 100 mg/kg (wet weight) level.
After inhalation exposure to 40 mg BaSO./m 5 hours daily
for 2 months, lymphatic transport was slight in rats. The
skeletal concentration of Ba was 800-1,500 mg/kg dry substance
(10-100 times the pulmonary concentration). Skeletal uptake
decreased somewhat with advancing age (Einbrodt et al., 1972).
6.3 Excretion
Normal humans in a state of barium equilibrium (with virtually
all of the intake occurring per ps) excreted about 91 % of
the total output in feces, 6 % in sweat and 3 % in urine
(Schroeder et al., 1972).
Barium excretion at 3-6 hours after intravenous administration
of a soluble salt was measured in saliva and seminal fluid of
a healthy man, yielding values of 0.22-0.33 and 0.81 % of the
76
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aose, respectively (Harrison et al., 1967). In lactating
cows, excretion in milk during the first 8 days after dosing
was 0.6 % of an oral dose and 10 % of an intravenously admin-
istered dose (Garner et al., 1960).
7. Normal levels in tissues and biological fluids
Scnroeder et al. (1972) published levels for barium in various
organs of unexposed persons. The total amount in the skeleton
of a 70 kg American adult was estimated at 2 mg/kg or about
90 % of total body barium. Other organs with measurable levels
included the eye (330 /ug/kg), lungs (160,ug/kg), connective
tissue (125/ug/kg) skin (50 ,ug/kg) and adipose tissue (36
,ug/kg) . In other internal organs, barium concentration was
slight. Among various parts of the eye, choroid had the highest
barium level, reaching 600 mg/kg in the cow and 10 mg/kg in
man (Sowden and Pirie, 1958).
Normal human blood contains 0.08-0.4 mg Ba/1 (Gooddy et al.,
1975); most or all is in the plasma fraction (Schroeder et
al., 1972). Urinary excretion in unexposed persons averaged
26,ug Ba/day (Tipton et al., 1969).
8. Effects and dose-response relationships
8.1 Humans
Occupational intoxications with soluble barium salts are vir-
tually unknown, but accidental or suicidal poisonings with
barium-containing household and medicinal products have been
reported. The compounds included the nitrate (Lydtin et al.,
1965), sulfide (Jobba and Rengei, 1971; Gould et al., 1973)
and carbonate (Morton, 1945; Maretic et al., 1957; Lewi and
Bar-Khayim, 1964). In the Chinese province of Szechuan, an
endemic condition resembling familial periodic paralysis
("pa-ping") has been described, which eventually turned out
to be food poisoning from the very high proportion of barium
in the table salt mined there (Allen, 1943).
The barium ion is essentially a muscle poison causing first
stimulation and then paralysis. The symptoms usually begin
77
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with the gastrointestinal muscles and acute barium poisoning
manifests itself rapidly after ingestion of a toxic dose, with
nausea, vomiting, colic, and diarrhea. Skeletomuscular and
cardiac symptoms follow with myocardial and general muscular
stimulation and tingling of the extremities. Severe cases of
poisoning progress to loss of tendon reflexes, heart fibrilla-
tion, and general muscular paralysis including the respiratory
muscles, leading to death.
Electrocardiographic tracings of barium-induced cardiomyo-
pathies were given by Sassine (1970)and Habicht et al. (1970).
Threshold of a toxic dose in adult humans is about 0.2-0.5 g
Ba, lethal in untreated cases is 3-4 g Ba. These figures apply
to the portion absorbed from the gut.
The barium ion is a physiological antagonist of potassium, and
it appears that the symptoms of barium poisoning are attributa-
ble to Ba -induced hypokalemia. The effect is probably due to
a transfer of potassium from extracellular to intracellular
compartments rather than to urinary or gastrointestinal losses
(Roza and Berman, 1971). Serum potassium in acute cases of
barium poisoning may decrease from the normal range of 3.5-5.0
m Eq/1 to 1.5-3.0 m Eq/1, and the symptoms and signs are
promptly relieved by intra'
al., 1964; Berning, 1975).
promptly relieved by intravenous infusion of K (Diengott et
latrogenic mishaps during the application of X-ray contrast
materials have occasionally caused barium sulfate to enter the
interstitial spaces and blood vessels, causing foreign-body
granuloma or embolism, respectively. Inhalation of barium
sulfate dust causes a pulmonary reaction with mobilization
of polymorphonuclear leucocytes and macrophages, and char-
acteristic radiographic changes with dense, discrete, small
opacities distributed throughout the lung fields ("baritosis").
However, the shadows appear to be due to the radioopacity of
barium sulfate itself rather than to any tissue lesions, and
the condition is symptomless with no abnormality of pulmonary
-------
function (Wende, 1956; Levi-Vallensi et al., 1966).
8.2 Animals
Long-term feeding studies in rats, with the drinking water
containing 5 mg/1 Ba (as acetate), caused no measurable
toxic effects (Schroeder and Mitchener, 1975). Chickens were
found to tolerate 1000 mg/1 Ba in their diet; 2000 mg/1
caused slight depression of growth; 4000 mg/1 caused substan-
tial depression of growth but no increase in mortality.
The results were similar with barium hydroxide and acetate
(Johnson et al., 1960).
The human symptoms and signs of barium toxicity have been well
reproduced in animal experiments. The cardiomyopathies in dogs
and guinea pigs included ectopic ventricular contractions,
ventricular tachycardia, and, finally, ventricular fibrillation.
The non-cardiac effects were salivation, diarrhea, hypertension,
skeletomuscular- paralysis and respiratory paralysis (Schott and
McArdle, 1974). Infusion of barium chloride into anesthetized
dogs produced all of the above, plus a prompt and substantial
hypokalemia. Potassium administration prevented or reversed all
of these effects except the hypertension which appeared to have
a different etiology not connected to the Ba -K antagonism
(Roza and Herman, 1971). In denervated cats, barium exerted a
stimulant action on the adrenal medulla, attributed to an in-
crease in the permeability of chromaffin cell membranes and
resulting in release of catecholamines (Douglas and Rubin,
1964) .
Baritosis from inhalation of BaSO. dust was successfully _ .-
produced in rats (Helusa et al., 1973). The lack of fibrotic
reaction was confirmed, and response was confined to accumula-
tion of alveolar macrophages and a reversible hyperplasia of
the bronchial epithelium.
9. Medical aspects
Treatment of poisoning by soluble barium salts may be prev-
entive or curative. Preventive treatment entails inhibi ~iw.-.
79
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of absorption, by administration of sodium sulfate or sodium
alginate (Sutton et al., 1972; Button and Shepherd, 1973).
Curative treatment entails counteracting the paralytic ef-
fect of the Ba ion on muscle, by intravenous infusion of
a potassium salt (Diengott et al., 1964; Berning, 1975).
Prompt administration of a soluble sulfate (e.g. Glauber
salt) causes precipitation of barium sulfate in the alimentary
tract and thus stops intestinal absorption.
80
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Ri. Jr. RECCES
Alien, A.S. (1943). Chin. Med. J. 61, 296-301.
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BERYLLIUM
Andrew L. Reeves
I. Abstract
Compounds of beryllium are not readily absorbed from the
gastrointestinal tract or skin; they tend to form insoluble
precipitates at physiological pH. Trace amounts which
circulate in blood or body fluids tend to accumulate in
the liver on a short-term basis and in bone on a long-
terra basis. Urinary excretion is irregular and not useful
as diagnostic criterion.
Inhaled beryllium has an initial pulmonary half-time of
about 2-3 weeks, but a particulate residuum tends to
remain in the lungs for long periods. There is also some
accumulation in the tracheobronchial lymph nodes. Pulmonary
deposition and clearance may come to an equilibrium.
Cheiation therapy for the purpose of enhancing excretion has
been largely unsuccessful.
Exposure to compounds of beryllium has caused dermatitis,
acute pneumonitis, and chronic pulmonary granulomatosis
("berylliosis") in humans. The dermatitis is of the allergic
type with edematous lesions following contact with soluble
salts, or with granulomatous ulcerations following the cutaneous
imbedding of insoluble compounds. Acute pneumonitis followed
inhalation of soluble salts in high concentration; typical
attacks resolved with complete recovery within several months.
The chronic granulomatosis is an insidious and slowly developing
disease with considerable mortality. It is associated with
inhalation of various types of beryllium compounds, especially
the "low-fired" oxide (calcined at about 500°C), sometimes
in very low concentrations. Occupational as well as "
cases are on record.
85
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In animal experiments, inhalation of beryllium compounds also
caused osteosarcoma in rabbits and pulmonary adenocarcinoma
in monkeys and rats. There is no epidemiological confirmation
to date that these conditions are also caused by beryllium
in humans. Other conditions associated with oral or parenteral
administration of beryllium to animals include osteosclerosis,
rickets, liver and kidney necrosis, anemia, and adrenal
imbalance.
Beryllium is an inhibitor of numerous enzymes, especially alkaline
phosphatase. It also interferes with DNA replication. Beryllium-
protein complexes formed in vivo are antigenic and provoke
a cell-mediated immune response in guinea pigs as well as in
man. The immune status appears to influence the development
of pulmonary berylliosis in beryllium-exposed subjects.
Beryllium is a light metal widely used in fatigue-resistant
alloys, nuclear reactors, space vehicle, missile parts, electronics
and for other specialized purposes, Industrial as well as
general environmental exposure may occur in connection with
these uses.
Reviews on beryllium toxicology were written by Kimmerle
(1966) and Tepper (1972). Pertinent symposium volumes are
"Pneumoconiosis - Leroy U. Gardner Memorial Volume" 1950
(Proceedings of the Sixth Saranac Symposium); and "Beryllium
- Its Industrial Hygiene Aspects" 1966 (AIHA-USAEC monograph).
2. Physical and chemical properties
Beryllium, Be, atomic weight 9.0; atomic number 4; density
1.9 (at 20°C); melting point 1,278°C; boiling point 2,970°C;
crystalline form gray metal, hexagonal; oxidation state 2.
Compounds to be taken up here are beryllium oxide, beryllium
sulfate, beryllium hydroxide, berylliun fluoride, beryllium
chloride, beryllium citrate, beryllium phosphate, beryllium
silicate and zinc beryllium silicate.
Beryllium is one of the lightest elements. It differs signifi-
cantly from the other alkaline earths in that its oxide is
86
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amphoteric. In that regard, beryllium shows similarity to
aluminum and the two metals have a number of other chemical
properties in common.
Beryllium is the lightest of all solid and chemically stable
substances. The metal has very high specific heat, heat of
fusion, sound conductance, and stiffness-to-weight ratio.
In alloys, it confers on other metals improved resistance to
fatigue, vibration, and shock. It also has extreme hardness
and resistance to corrosion, probably attributable to the thin
film of beryllium oxide rapidly forming on the surface of bare
metal upon exposure to air.
Cationic beryllium salts when dissolved in water undergo hy-
drolysis and the pH of these solutions is acidic: 2.7 for
iso-osmolar(0.154 M) beryllium sulfate (Reeves and Vorwald,
1961). At pH values between 5 and 8, the element tends to
form insoluble hydroxides or hydrated complexes, and at
pH values above 8, beryHates.
3. Methods and problems of analysis
At one time, widely used reagents were alkannin, naphthazarin,
naphthochrome green G, and chrome azurol S. The limit of
detection with these methods was 10-100 ug Be/1, but cumbersome
preparatory procedures have rendered them obsolete. The same may
be said of the method based on the fluorescent dye morin,
which had a limit of detection of 0.02 ug Be/1.
Spectrographic methods include direct current arc (Cholak and
Hubbard, 1952) , alternating current arc (Keenan and Holtz,
1964) and alternating current spark (Smith et al., 1952).
These have limits of detection in the range of 0.5-5.0 ng
Be/sample. An atomic absorption spectrophotometric method has
been described by Bokowski (1968), with a limit of detection
of 40/ug/l. The most sensitive method for beryllium analyses
is gas chromatography coupled with an electron capture detectcr
(Frame et al., 1974) or a mass spectrometer (Wolf et al., 1972,.
87
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4. Production and uses
4.1 Production
Most beryllium is present in localized deposits of beryl. The
highly treasured gemstones, emerald and aquamarine, are colored
variants of beryl. Other beryllium-containing minerals number
about 30 and include such other semi-precious stones as euclas,
phenakite and chrysoberyl. Most beryllium is mined as the mineral
beryl; other sources are bertrandite and helvite. Total world
production is presently at about 10,000 tons per annum. Leading
producers are Brazil and the Soviet Union; other deposits are
widespread around the world, including the U.S.A. and various
countries in Africa.
The ores are first converted to beryllium hydroxide by roasting
or sintering, leaching, and precipitation. Beryllium hydroxide is
then (1) converted to fluoride and reduced with magnesium to
obtain beryllium metal; (2) reacted with carbon and melted with
copper to obtain the master alloy.
Beryllium oxide ("beryllia") is prepared commercially by calcining
beryllium hydroxide at temperatures ranging from about 500 to
1750°C. There is ample evidence that all chemical reactivity,
including toxicity, of beryllium oxide is inversely related to
the temperature of firing (Spencer et al., 1965). This correla-
tion is apparently due to differences in crystallite size.
4.2 Uses
About 20% of world production is presently used as the free
metal. Applications include missile and nuclear reactor com-
ponents, rocket nozzles, aircraft brakes, electrical relays,
space optics, space vehicle reentry cones, X-ray windows,
inertial guidance parts, and a number of classified weapons
parts. Beryllium alloys account for about 72% of the total
production. The master alloy is 96% Cu, 4% Be. It can be
remelted to obtain a family of dilute beryllium-copper alloys
ranging from 0.5 to 2.75% Be. These are used as current-
carrying springs, welding components, bearing sleeves, non-
sparking tools and dies, and as underseas cable repeater
and amplifier housing. A beryllium-nickel alloy is used
88
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in diamond dr_-^ o^c ;..aL_..xes, A^-ch balance-wneeis , and aircratt
ana spacecraft parts. The remaining 8% of beryllium produced
^.s ^scc as -_-.he oxide in ceramic formulations for resistor
cores, integrated circuit chip carriers, and radio and laser
vaoes . An early major use of beryllia in fluorescent tube
phosphors has now largely been abandoned.
5 . Environmental levels and exposures
5 . 1 General en v i r onme n t
ana Zorn (1974) have recently measured beryllium concen-
trations in food in Western Germany. They found in polished
ric2 G.Ctt, in toasted bread 0.12, in potatoes 0.17, in tomatoes
0.24 and in head lettuce 0.33 rng Be/kg substance (dry weight
basis). Total intake figures for beryllium have not been published,
but may be estimated as around 100 ug/day of whicn only a
minor fraction is intake by inhalation.
5.1.2 Water, soil, plants, ambient air and cigarettes
Beryllium occupies the 35th place in the terrestrial abund-
ance list of elements and its overall concentration in the
lithosphere is estimated at 5 mg/kg.
Ordinary agricultural soils and natural waters contain beryllium
in the ug/kg or ug/1 range. In birch, aspen and willow, beryllium
content may rise as high as 3 mg/kg (Nikonova, 1967).
Early reports on "neighborhood cases" of pulmonary berylliosis
at a frequency of 1-3% in the general population living within
about a mile of the plant (Eisenbud et al., 1949) led -co inves-
tigations disclosing that beryllium was emitted in the stack
gases resulting in ambient concentrations of about 100 ng/ir.^
around the plant. Average beryllium content of general urban
air was reported by Sterner and Eisenbud (1951) as follows:
Boston 0.3, New York 0.5, Brookhaven 0.7, Cleveland 1.3, and
Pittsburgh 3.0 ng Be/m . Much of this probably originated
from the burning of bituminous coal, which contains 0.1-3.G
mg/kg of beryllium.
89
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In three brands of West German cigarettes, beryllium levels
were 0.47, 0.68 and 0.74/ug/cigarette, with 4.5, 1.6 and 10.0%
of the beryllium content, respectively, escaping into the
smoke during smoking (Petzow and Zorn, 1964).
5.2 Working environment
Beryllium production in quantity commenced in the 1930's,
and because of the early ignorance regarding its toxicity,
no environmental controls were practiced until the late
1940"s. Few measurements exist regarding the pre-1950
in-plant levels of beryllium to which workers were exposed,
but they are retrospectively estimated as very high. Breslin
and Harris (1959) reviewed early reports and concluded that
inhalable beryllium in ore treatment rooms, around baking
furnaces, in the neighborhood of lathes, or at the sites of
fluorescent phosphor blending, milling, and salvaging, must
have been around 1 mg/in .
In 1949, the U.S. Atomic Energy Commission, a major consumer
of beryllium products, adopted the first occupational exposure
standard at 2 ug Be/m which in 1955 was adopted as the ACGIH
threshold limit value. This resulted in substantial and widespread
improvement of conditions, with average air concentrations
in well-monitored plants dropping to below 2 and sometimes
to as low as 0.1 ug Be/m (Mitchell and Hyatt, 1957). In less
well- monitored plants, breathing zone concentrations sometimes
were appreciably higher. Locker room and shoe-change room
facilities, as well as lunch rooms, frequently showed general
air concentrations as high as regular production areas.
6. Metabolism
6.1 Absorption
6.1.1 Skin
Since most beryllium salts do not remain soluble at physio-
logical pH, there is ordinarily no ready systemic diffusion
following local contact. Ionic beryllium applied to the skin
becomes largely bound to epidermal constituents, mainly alkaline
phosphatase and nucleic acids (Belman, 1969). Resorption of
90
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7
trace levels of BeCl^ through rat tail, with subsequent systemic
distribution, was reported by Petzow and Zorn (1974).
6.1.2 Inhalation
Following intratracheal injection, BeSO. in trace amounts
was either retained in the lungs of rats for long periods
or mobilized after 16 days; Be citrate (a soluble, non-ion-
izing complex) was completely mobilized after 4 days (VanCleave
7
and Kay lor, 1955) . BeCl2 in the amount, of 10 iiCi showed a
pulmonary half-time of 20 days; 18% of the dose accumulated
in the bones in 147 days (Kuznetsov et al., 1974).
During inhalation exposure to BeSO., beryllium concentrations
in the lungs of rats built up to an equilibrium in about 36
weeks and remained at a plateau for the balance of the exposure
(Reeves et al., 1967). The inhalation concentrations determined
the plateaus according to the following correlations: at
1.75 ug/m , about 2 mg/kg; at 17.5 ug/jrv , about 6 mg/kg; at 35
j 3
/ig/m , about 9 mg/kg; at 175 wg/m , about 18 mg/kg.
Clearance of inhaled beryllium from the lungs of rats was
multiphasic, each phase corresponding to a logarithmic
function. Pulmonary beryllium content was approximately
halved during the first 2 weeks post exposure; thereafter
the clearance rate diminished rapidly and a residuum of the
inhaled beryllium in the amount of 0.2-0.7 mg/kg, perhaps in
incapsulated form, remained in the lungs for years.
6.1.3 Ingestion
Reeves (1965) measured absorption of ingested beryllium
sulfate from the gastrointestinal tract of rats. At levels
of 0.6-6.6 ug Be/day in the drinking water, about 80% of
the intake passed the gastrointestinal tract unabsorbed.
The remainder was probably absorbed from the stomach,
the pH of which (about 3.0-3.6 in the rat) allowed the
beryllium sulfate to remain in ionized condition. Upon
entering the alkaline milieu of the intestine, the beryllium
became precipitated as the phosphate and was excreted ir. Jcr.^.
feces.
91
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6.2 Transport, distribution, excretion, and biological
half-time
The transport of beryllium in body fluids has been studied by
Feldman et al. (1953), Reeves and Vorwald (1961), and Vacher
and Stoner (1968a). The consensus of these studies is that the
bulk of circulating beryllium is in the form of a colloidal
phosphate, probably adsorbed on plasma a-globulin. Minor por-
tions are carried as citrate or hydroxide. A complex with
serum proteins is formed only at acidic pH and has, as transport
form, no in vivo significance.
Vacher and Stoner (1968b) measured the removal rate after
intravenous injection of BeSO, (radioactively tagged with
7 7
Bed ) or of carrier-free Bed from rat blood. The bio-
^ ^
logical half-time for the carrier-free form was about 3
hours; the clearance curves indicated biphasic removal,
the second phase showing inverse relation of the rate to
the dose. At higher concentrations, the beryllium ion formed
phosphate aggregates, which were removed by the reticuloen-
dothelial system (Vacher et al., 1974).
Circulating beryllium was carried to all tissues, and analyses
following administration normally yielded measurable levels in
most organs. On a short-term basis (2.5 hours after intravenous
injection) organ distribution was dose-dependent, favoring the
skeleton for smaller doses ( <50 ug Be/kg) and the liver for
larger doses (up to 500 ug Be/kg). Hepatic beryllium appeared
to be colloidal, and perhaps protein-bound. Beryllium became
gradually mobilized from the liver of rats in the course of
about 100 days and transferred to the skeleton; it apparently
followed magnesium and became structurally incorporated into
bone (Van Cleave and Kaylor, 1955). Part of the absorbed
beryllium, variously estimated as 20-60%, was excreted in
the urine. Plasma beryllium did not pass the glomerulus and
the mechanism of excretion was tubular, with some damage
inflicted upon the tubular epithelium in the course of
secretion.
According to studies conducted on cows with radioactive
beryllium, less than 20 mg/1 of injected activity was reco-
92
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vered in the milk. The biological half-time in milk was 19
hours (Mullen et al., 1972).
7. Levels in tissues and biological fluids
7.1 Normal levels
In view of the increasing ubiquitousness of beryllium, it may
be expected that biological specimens will in most cases con-
tain detectable levels. In human pulmonary tissue, amounts
less than 20 /ug/kg (dry weight basis) are not regarded as
indicative of occupational exposure. Blood and urine levels
of unexposed persons (i.e. less than about 1/ug/l) were
undetectable by the classic methods and determinations with
the newer methods are yet to be made.
7.2 Biological indicators of exposure
Pulmonary levels of beryllium in occupationally exposed
workers may be as high as 1-100 mg/kg dry tissue. Often,
various segments of the same lung may exhibit widely differing
levels. Beryllium in blood and urine is also variable,
the levels in exposed persons being 0.02-3.0 ug Be/1 (Lieben
et al., 1966).
8. Effects and dose-response relationships
8-1 Locaj. effects and dose-response relationships
8.1.1 Skin contact
8.1.1.1 Humans
Beryllium dermatitis was described by Van Ordstrand et al.
(1945) as edematous papulovesicular lesions which appeared par-
ticularly on the exposed surfaces of the body of workers
handling soluble beryllium salts. However, if insoluble
beryllium compounds became imbedded in the skin, e.g. after
injury with a fluorescent tube, necrotizing granulamatous
ulcerations followed which did not heal readily. Curtis (1951)
recognized that the dermatitis was the allergic-eczematous
type and developed a patch test. In 1955, Sneddon reported
that a patient with a patch test positive to beryllium dev-
eloped a sarcoid-like granuloma at the test site. Nishirnura
(1966) examined 111 cases of contact dermatitis, 11 cases of
93
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skin ulceration and 40 cases of conjunctivitis in a beryllium
refinery and concluded that delayed allergy was responsible
for acute beryllium disease. Epstein (1967) classified the
skin reaction to beryllium as granulomatous hypersensitivity,
and observed lymphocyte blast transformation (Hanifin et
al., 1970) and macrophage migration inhibition (Henderson
et al., 1972) in preparations originating from beryllium-
sensitive subjects.
8.1.1.2 Animals
Dutra (1951) produced experimental beryllium granulomas in the
skin of pigs which resembled the human lesion. Cutaneous
sensitization of guinea pigs with soluble beryllium compounds
was accomplished by Alekseeva (1965).
8.1.2 Inhalation
8.1.2.1 Humans
Acute pulmonary beryllium disease was first seen in beryllium
extraction plants in Germany, Italy, the Soviet Union, and in
the American state of Ohio. The cases resulted from inhalation
of aerosols of soluble beryllium compounds, typically the
fluoride, in relatively high concentrations. All segments of
the respiratory tract were sometimes involved, with rhinitis,
pharyngitis, tracheobronchitis, and pneumonitis. The acidity
of beryllium salt solutions was the probable etiological factor
and there appeared to be a definite dose-response relation both
with respect to rapidity of onset and severity and duration
of the inflammation (Van Ordstrand et al., 1943). The thres-
hold of an injurious concentration (in mg Be/m ) is about
30 for the high-fired oxide, 1-3 for the low-fired oxide,
and 0.1-0.5 for the sulfate (Hall et al., 1950, Stekinger
et al., 1950). Although there were some fatalities resulting
from the acute syndrome, recovery after several weeks or
months was the rule. No non-occupational cases have been
observed.
8.1.2.2 Animals
Acute chemical pneumonitis following inhalation of beryllium
sulfate was produced in a great variety of animals by Stokinger
94
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et al (1950). The fluoride ion had a synergistic effect on
beryllium toxicityj alternate exposure to BeSO and HF,
or exposure to BeF produced about twice as severe effects
at any given beryllium concentration as those attributable
to BeSO. alone.
Acute pneumonitis was also produced with insoluble beryllium
compounds in 1950 by Hall et al., using different grades of
beryllium oxide. High-fired BeO did not produce injury in most
animals at concentrations of up to 30 mg Be/m . Low-fired
BeO at about 1/10 of the former concentration caused mortality
in rats and marked pulmonary damage in dogs in 10-40 days.
8.2 Chronic effects and dose-response relationships
8.2.1 Pulmonary granulomatosis ("berylliosis")
8.2.1.1 Humans
Hardy and Tabershaw (1946) described a chronic pulmonary con-
dition among fluorescent lamp workers in Massachusetts. The
character of this syndrome was quite different from that
of the acute cases, with shortness of breath being the leading
symptom. Pulmonary X-rays showed miliary mottling, and histo-
pathological examination of lung tissue showed interstitial
granulomatosis. The granulomas were composed of monocytes,
surrounded by a zone of lymphocytes and plasma cells (Vorwald,
1948; Dudley, 1959).
Insoluble beryllium compounds, particularly the low-fired
oxide, appeared to be most often involved in the causation
of this condition. A dose-response relation between extent
of exposure and severity of disease was emphatically absent,
with workers from the cleanest plants and "neighborhood cases"
sometimes showing the worst clinical forms (De Nardi et al.
1949; Sterner and Eisenbud, 1951; Hardy and Tepper, 1959).
The onset of berylliosis may be insidious, with only slight
cough and fatigue which can occur as early as 1 year or as
late as 25 years after exposure. Progressive pulmonary insuf-
ficiency, anorexia, weight loss, weakness, chest pai.-., a.-._
95
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constant hacking cough characterize the advanced disease.
Cyanosis and clubbing of fingers may be seen in about 1/3
of cases, and cor pulmonale is another frequent sequel. In
past years, the mortality rate was nearly 30%, but after
institution of corticosteroid treatment it has improved somewhat.
8.2.1.2 Animals
The granulomatous pulmonary lesions characteristic of the
chronic disease in humans have been reproduced in animal
models with only partial success. Policard (1950) reported
nodular granulomata in the lungs of guinea pigs exposed to
beryllium oxide, but the lesions regressed after the 40th
day of exposure. Various lesions resembling in some measure
the human type of chronic berylliosis, but also involving
edema or emphysema, were produced in rats by intratracheal
injection of beryllium oxide by Lloyd-Davies and Harding
(1950) .
8.2.2 Other chronic effects
8.2.2.1 Chronic effects on the skeleton
Guyatt et al. (1933) discovered beryllium rickets in poultry
and other livestock fed beryllium salts at 0.5% dietary level.
The condition was apparently caused by intestinal precipita-
tion of beryllium phosphate and resultant decrease of plasma
phosphorus levels. However, Sobel et al. (1935) found that
the cartilage of rats fed a beryllium-containing diet would
calcify only very imperfectly in vitro in solutions containing
adequate concentrations of phosphate, the effect being attrib-
utable to inhibition of alkaline phosphatase.
Cloudman et al. (1949) demonstrated osteosclerosis in the
long bones, pelvis, and skull of rats and mice injected with
beryllium sulfate or zinc beryllium silicate. Marrow was
replaced by spongy bone, causing disturbances of hematopoiesis
with macrocytic anemia and decrease in the rate of hemoglobin
biosynthesis (Stokinger et al., 1953).
Gardner and Heslington (1946) discovered osteosarcoma in
rabbits after intravenous injection of zinc beryllium sili-
96
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cate. Similar results were obtained subsequently by others
with a variety of beryllium compounds, including the oxide
and phosphate. Occurrence of the tumors required 8-13 months
after injection; their histological type was chondroblastic,
osteoblastic, or fibroblastic.
8.2.2.2 Chronic effects on visceral organs and blood
Focal necrosis of the liver with progressive destruction of
parenchymal cells was observed in rats following intravenous
beryllium administration (Aldridge et al., 1950). Beryllium
accumulated in the lysosomes and nuclei, and it was observed
that dietary protein depletion protected the livers against
the toxic effects of intravenous beryllium sulfate. Apparently,
the site of attack of BeSO. on the cell became inaccessible
after protein depletion (McLean and Witschi, 1966).
Mietkiewski and Malendowicz (1966) observed, after intraperi-
toneal injection of Bed- into rats, enhanced excretion of
steroid hormones from the adrenal cortex. Clary et al. (1972)
considered adrenal imbalance a triggering factor in the
development of chronic berylliosis.
Macrocytic anemia in dogs, rabbits, and rats was produced
with beryllium fluoride. Both the newly formed intra-
erythrocytic protoporphyrin and globin were significantly
decreased (Stokinger et al., 1953).
8.3 Carcinogenic effects
8.3.1 Humans
In 1952, a "Beryllium Case Registry" was established at the
Massachusetts General Hospital, which accumulated the records
of all reported cases of occupational and environmental
beryllium exposure (Hardy et al., 1967). Mancuso (1970) has
recently examined this material and other epidemiological
sources, a total of more than 800 cases. It appears from this
study that the prevalence of lung cancer among beryi_^um-
exposed persons, in comparison to a control cohort, was not
elevated. However, the prevalence of lung cancer did show
positive correlation with the prevalence of preexistenc
97
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pulmonary disorders, including berylliosis. On the other hand,
incidence of pulmonary cancer among beryllium workers was
inversely related to length of employment in the plant.
The presently available evidence is incomplete and allows
contradictory interpretations regarding the carcinogenicity
of beryllium in man. The Occupational Safety and Health auth-
orities of the U.S.A., as well as Germany and Sweden, view
beryllium as a potential human carcinogen, based essentially
on the experimental animal evidence. Individual human case
reports notwithstanding (Niemoller, 1963), there is as yet
no convincing epidemiological evidence to support that view.
8.3.2 Animals
Inhalation exposure of rabbits to beryllium oxide at a con-
centration of 6 mg Be/m (5 hrs/day, 5 days/week, for 48
weeks) produced osteosarcoma of the pubic bone with extension
into the contiguous musculature and metatases to the lung
(Dutra et al., 1951). Inhalation exposure of rats to beryllium
sulfate at a concentration of 33 ug Be/m (7 hrs/day, 5.5
days/ week, for 60 weeks) or intratracheal injections of
BeO at a total dose of 338 ug Be (in saline) produced pulmonary
adenocarcinomas with metastases to the tracheobronchial lymph
nodes and pleura (Vorwald et al., 1955). Schepers et al. (1957)
and Reeves et al. (1967) studied these tumors further and
established that incidence of pulmonary adenocarcinoma in rats
after inhalation exposure to beryllium sulfate at levels of
20-200 ug Be/m was 100% after 13 months. Carcinogenic activity
in the rat was confirmed for other beryllium compounds including
the fluoride, phosphate, silicate, and for dust of beryl ore
(Wagner et al., 1969). The tumors were of various histological
types including acinar, papillary, mucigenous, and epidermoid.
Pulmonary carcinomas were also produced in rhesus monkeys by
Schepers (1964) and Vorwald (1968).
8.4 Mechanisms of toxic action
8.4.1 Effect on enzymes
The beryllium ion is the strongest known inhibitor of alkaline
phosphatase and this inhibition is non-competitive. Belman (1969)
98
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showed that beryllium chemically combined with cutaneous alkaline
phosphatase, and Reiner (1971) showed beryllium binding of
Escr.enchia coli alkaline phosphatase. However, it is
noteworthy that serum alkaline phosphatase activity in
rats remained unaffected by inhalation exposure to
beryllium sulfate (Reeves et al., 1967).
Beryllium also inhibits other phosphatases, notably
phosphatidic acid, adenosine triphosphatase and
3-glycerophosphatase. These enzymes are Mg - or K -
activated, and the inhibition was in some cases competit-
ive (Thomas and Aldridge, 1966).
Other enzymes which various concentrations of beryllium
have been able to inhibit are phosphoglucomutase (Cochran
et al. 1951), phosphoglyceromutase (Thomas and Aldridge,
1966), hexokinase and deoxythymidine kinase (Mainigi and
Bresnick, 1969), lactate dehydrogenase of rabbit or sheep
muscle or of rat lung homogenates (Schormuller and Stan,
1965; Reeves, 1967), malic, succinic, and ct-ketoglutaric
dehydrogenases in the livers and lungs of rats (Mukhina,
1967), nonspecific esterases in rat liver cells (Mietkiewski
and 'Maiendowicz, 1967), amylase in pancreatic tissue, saliva,
serum, and urine (McGeachin et al, 1962), enolase (Malmstrom,
1955), hepatic acetanilide hydroxylase, aminopyrine demethylase,
tryptophan pyrrolase, and aryl hydrocarbon hydroxylase (Witschi
and Marchand, 1971).
8.4.2 Effect on protein and nucleic acid metabolism
The binding of beryllium to various proteins as a step in
the elicitation of toxic action was first suggested by Aldridge
et ai. (1950), studied by Belman (1969), and recently reviewed
by Reiner (1971). Although beryllium proteinates are not a
substantial transport form in body fluids, they do form in situ
in minute quantities and they may be antigenic (Krivanek and
Reeves, 1972. Chevremont and Firket showed in 1951 that
beryllium sulfate inhibited cell division in the metaphase,
with marked decrease in the intensity of the Feulgen reaction
for DNA. The effect was specific to DNA, with RNA biosynthesis
99
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remaining unaffected. Modes of interaction of the beryllium ion
with DNA of various species were studied by Truhaut et al.
(1968) who noted preferential accumulation of radioberyllium
in the nuclei of regenerating rat livers, and increase of
the sedimentation constant of DNA after contact with BeSO..
However, Witschi (1970) showed that, while beryllium did
inhibit the replication of DNA in regenerating rat livers,
it did not become attached to DNA. Increased misincorporation
of polydeoxyadenosylthymidine by micrococcal DNA polymerase
during polymerisation was noted by Luke et al. (1975).
The effect was associated with a strong inhibition of the
3'-5"exonuclease activity of the enzyme. The sum of present
evidence indicates that beryllium is a specific inhibitor,
or perhaps modifier, of events leading to DNA replication.
8.4.3 Effects on immune factors
The epidemiology of berylliosis cases was suggested as in-
dicating the involvement of an immunological factor (Sterner
and Eisenbud, 1951). Curtis (1951) concurrently developed
a patch test. The patch test itself appeared to be sensitizing
and was believed to be responsible for both dermal and pulmona-
ry exacerbations of beryllium disease. It was consequently
not used much as a diagnostic tool (Curtis, 1959). However,
the phenomenon did indicate that beryllium was antigenic.
Search for humoral antibodies was made (Pugliese et al., 1968;
Resnick et al., 1970) but it now seems well established that
beryllium hypersensitivity is essentially cell-mediated
(Alekseeva, 1965) . Passive transfer of hypersensitivity was
accomplished in guinea pigs with lymphoid cells while the
transfer of serum was ineffective. Chiappino et al. (1969)
could inhibit all cutaneous reactions to beryllium in guinea
pigs by injection of an antilymphocyte serum from rabbits.
Inhalation exposure to beryllium sulfate could also suppress
cutaneous reactivity (Reeves et al., 1972).
Mode of administration and choice of beryllium compound also
influenced the nature of the immunological reaction. Vacher
(1972) found only those forms and routes which were capable
of producing a complex with skin constituents as immunogenic;
100
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freely diffusible forms were "tolerogenic", including a very
low dose of oeryliium (4.78 ng/kg) intraperitoneaily, or
a r.igr. toxic dose (400 ug/kg) intravenously. Knvanek and
Reeves (1972) showed chat the beryllium ion acts as a
hapten i.n provoking the immune logical reaction. Complexes
where the beryllium ion was unavailable (aurintricarboxylate,
citrate) could not elicit sensitivity, whereas beryllium
serum albuminate could elicit stronger sensitivity than the
beryllium ion alone.
Methods for measuring hypersensitivity other than those rel-
ated to skin response were developed recently. Among these,
lymphocyte blast transformation (Hanifin et al., 1970) and
macrophage migration inhibition (Henderson et al., 1972)
appear promising. They were applied both to human clinical
material (Deodhar et al., 1973) and to experimental guinea
pigs (Marx and Burrell, 1973) .
9. Diagnosis and treatment
9.1 Diagnosis
History taking is probably the most important diagnostic
measure in the recognition of beryllium disease. All patients
must have had at one time substantial exposure to beryllium,
and it is now believed that the early "neighborhood cases"
were all traceable to direct contact with a contaminated
person or object rather than general air pollution (Radford
and Tepper, 1967).
Beryllium in urine, blood, or pulmonary specimens helps to
establish exposure but the concentrations have no relation
to the severity of disease. In fact, in unaffected workers
the levels may be as high as or higher than in patients
with the acute or chronic disease (Lieben et al., 1966).
It must also be remembered that some beryllium originating
from general air pollution is invariably present in tr,e
lungs of most persons, especially city dwellers. The
threshold of significant concentration is usually regarded
as about 20 ug/kg dry weight.
/
101
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The first finding in berylliosis is often an abnormal X-ray
picture. Unfortunately, the observable densities are not typical
for this disease, and their appearance in any case can be
delayed for a year or more. Pulmonary function abnormalities
may or may not parallel the development of X-ray changes .
The basic lesion, when fully developed, is a decrease of diffusing
capacity across the interstitial membranes, an "alveolocapillary
block".
Patch testing (Curtis 1951j 1959) is not recommended as
a diagnostic measure. It can give false positives as well
as false negatives; it can be itself sensitizing, and was
reported to cause flareups in dormant pulmonary lesions.Other
tests based on hypersensitivity such as lymphocyte blast trans-
formation or macrophage migration inhibition (Deodhar et al.,
1973) may become useful adjuncts of diagnosis, but extensive
experience is as yet lacking.
The most important problem of differential diagnosis is the
distinction of beryllium disease from the sarcoidosis of Boeck
and Schaumann, another chronic granulomatous inflammation
of the lungs. The specific serologieal test for sarcoidosis,
the Kveim test, is negative in berylliosis and other common
complications of sarcoidosis including lymphadenopathy, ocular
granuloma, uveo-parotid fever, peripheral neuropathy, hepato-
splenomegaly, or leukopenia are rare or nonexistent in berylliosis
Other pneumoconioses, mycotic diseases of the lung, or miliary
tuberculosis have sometimes been confused with berylliosis.
The ultimate diagnostic proof is histopathological examination
of pulmonary tissue which may be obtained by needle biopsy.
Its results must be interpreted in consort with other test
results discussed above.
9.2 Treatment
Corticosteroids, perhaps because of their immunosuppressive
effect, are useful in arresting the inflammatory disease
process (De Nardi, 1951). Chelating agents for removal of
deposited tissue beryllium have been explored. Among these,
aurintricarboxylic acid ("aluminon") proved effective in pro-
102
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tecting mice and rats if given parenterally 1-8 hrs after
intravenous injection of an otherwise lethal dose of beryllium
sulfate. The chelate tended to accumulate in the kidneys and
spleen (Schubert et al., 1952).
In the Soviet Union, aminoalkylpolyphosphinic acids were tried
in animal experiments (Arkhipova et al., 1968). However, for
the alleviation of chronic poisoning, chelating agents have
proved thus far ineffective, and clinical trials were disappointing
(Dequindt et al., 1973).
For beryllium implanted in the skin, the method of treatment
is surgical.
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109
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BISMUTH
Bruce A. Fowler and V.B. Vouk
1. Abstract
Bismuth compounds are considered as poorly to moderately
absorbed following inhalation or ingestion but there are no
quantitative data. Absorbed bismuth is distributed throughout
the soft tissues and bone, the highest concentrations being
found in the kidney and liver. Bismuth passes through the
placenta. Absorbed bismuth is excreted primarily via the
urine. The biological half-time for the whole body retention
is about 5 days but intranuclear inclusions containing
bismuth seem to remain for years in the kidney of patients
treated with bismuth compounds.
Bismuth is not essential either for man or animals.
High level exposure causes renal failure associated with de-
generation and necrosis of epithelium of the renal proximal
tubules, fatty changes and necrosis of the liver, reversible
dysfunction of the nervous system, skin eruptions and pigmentation
of the gums and intestine.
There are no reports on occupational exposures. For the
general population the total intake from food is about 5-
20 /ug, with much smaller amounts contributed by air and
water. An important source of exposure for specific segments
of the population"in the past was the therapeutic use of
bismuth compounds. The cosmetic use still continues to be
fairly widespread.
Short reviews on the toxicology of bismuth have been published
by Browning (1969) , Filepova (1971) and Avena (1974) .
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2. Physical and chemical properties
Bismuth, Bi, atomic weight 208.98; atomic number 83;
density 9.7 (20°C); melting point 271.3°C; boiling point
1560+5°C; white crystalline metal with pinkish stain. Bismuth
belongs to the Vb group of the periodic system together with
arsenic and antimony. Its conductance in the solid state is
only 0.48 of the liquid conductance, and it has the lowest
thermal conductivity of all metals. Bismuth forms compounds
in oxidation states +3 and +5. Of technological and toxicological
interest are bismuth oxide, bismuth sulfide, bismuth oxychloride
and salts of inorganic oxoacids (carbonate, nitrate, sulfate)
and of organic acids (salicylate, triglycollate). Many of
these salts have a basic form, such as basic nitrate or
sub-nitrate. Bismuth forms trialkyls which are unstable in
air but stable and insoluble in water (e.g. trimethyl bismuth).
3. Methods and problems of analysis
Atomic absorption spectrophotometry is an adequate method
for the determination of bismuth in biological and environmental
samples. Its limit of detection at 223.1 nm (air-hydrogen
flame) is about 0.4 mg/1, and amounts as low as 1.5 ,ug can
be determined in 1 g of tissue with a relative standard
deviation of 5%. Biological samples should be wet-ashed with
nitric, sulfuric and perchloric acids (Kinser, 1966; Hall
and Farber, 1972; Delves et al., 1973). Spectrophotometry
with dithizone has a detection limit of about 0.01 mg/1 but
lead interferes and has to be separated from bismuth (Pinta,
1970). Spark source mass spectrometry (SSMS) has been used
recently for the determination of bismuth in human tissues;
it has a limit of detection of 0.002 mg/kg wet weight (Hamilton
et al., 1972/1973). There is not enough information to
evaluate the accuracy of these methods.
4. Production and uses
4 .1 Production
Bismuth occurs in native form and in minerals such as bismite
(bismuth oxide) and bismuthite (bismuth sulfide) which is
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usually associated with sulfide ores of lead and copper and
with tin dioxide. The production of metallic bismuth is
linked to lead and copper refining. The current world production
is about 4000-5000 tons, the main producers being Japan,
Bolivia, Peru and Mexico. Pyrometallurgical separation of
calcium-magnesium-bismuth drosses from which associated
metals such as copper, lead and zinc are removed by suitable
fluxes is a widely used technological process for the production
of bismuth (Paone, 1970; Panel on Bismuth, 1970).
4.2 Uses
About 64.5% of bismuth is consumed in the United States as
low melting alloys and metallurgical additives including
electronic and thermoelectric applications. The remainder is
used for catalysts, pearlescent pigments in cosmetics,
Pharmaceuticals and industrial chemicals (Panel on Bismuth,
1970) .
A variety of bismuth, compounds have been used as dusting
powders, astringents, antiseptics, antacids and radioopague
agents in X-ray diagnosis (now replaced by barium sulfate).
Another obsolete use is in the treatment of syphilis where
bismuth compounds have been replaced by penicillin. Bismuth
compounds that have been most widely used in therapy include
bismuth potassium tartrate, basic carbonate, gallate, nitrate,
salicylate and bismuth magma (suspension of hydroxide and
basic carbonate suspension) (Panel on Bismuth, 1970) .
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food
Using pooled samples of food representative of the main
regions of the United Kingdom, Hamilton and Minski (1972/1973)
estimated the daily intake of bismuth as less than 5 ,ug
(SSMS). The concentrations in individual dietary samples
were not reported. According to Woolrich (1973) the daily
112
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intake from food and water is about 20 ,ug but again data on
concentrations of bismuth in specific food items were not
given. This estimate agrees with the model value for daily
balance of elements in the reference man (ICRP, 1975).
5.1.2 Ambient air, water, soil and rocks
The concentrations of bismuth in urban air range from 1 to
66 ng/m , and in rural air from 0.1 to 0.6 ng/m (Division
of Atmospheric Surveillance, 1972). The concentration of
bismuth in respirable fly ash (ADD<5 ,um) was found to be
about 4-5 g/kg (Davison et al., 1974). The daily intake of
bismuth via inhalation is estimated as <0 . 01-0 . 76,ug (Wool
1973; ICRP, 1975).
Concentrations of bismuth in drinking water have not been
reported. Sea water contains
mental Studies Board, 1972) .
reported. Sea water contains about 0.2 ,ug Bi/1 (Environ-
Bismuth levels in soil are about 1 mg/kg, and in rocks from
0.1 mg/kg (coal) to 3 mg/kg (sandstones) (Bowen, 1966).
5.1.3 Pharmaceuticals and cosmetics
Pharmaceuticals and cosmetics are still a source of exposure
to bismuth compounds for specific groups of the general
population.
5.2 Working environment
Exposure to bismuth and some of its compounds may occur in
the production of metallic bismuth and in the manufacture of
Pharmaceuticals, cosmetics and industrial chemicals but no
reports are available on such exposure.
6. Metabolism
6.1 Absorption
Bismuth compounds are considered to be slightly to moderately
absorbed through the respiratory and gastrointestinal tracts,
depending on their solubility, but there are no quantitative
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data. Absorption through the skin is of interest in relation
to the use of bismuth compounds in oil-based cosmetics but
again there is no quantitative information (Sollman et al.,
1938; Sollman and Seifter, 1939).
6.2 Distribution
Four days after i.m. injection of BiOCl or BiO(OH) to rats,
14.4% of the dose was found in the kidney, 6.6% in the
liver, 1.5% in bone, 0.6% in muscle and less than 0.1% in
blood. Seventeen days after administration only 0.6% remained
in the kidney (Durbin, 1960) . Two hours after i.v. injection
of bismuth citrate and sodium bismuth thioglycollate to dogs
and rabbits, about 3-5% of the dose was found in the kidney,
6-10% in the liver and 0.4% in the lungs. Within 24 hours
the relative concentration in the kidney increased to 7-10%,
and in the liver it decreased to 1-4%. Within one week, the
concentration in the kidney and liver was reduced to 2.5%.
After 4-5 weeks the liver concentration was again higher
(1%) compared to the kidney (0.45%) (Sollman and Seifter,
1942) .
The autopsy distribution of bismuth in 22 patients who
received therapeutic i.m. injections (mainly bismuth salycilate)
was as follows (median values, mg/kg, wet weight): kidney
33.3; liver 6.8; spleen 1.6; colon 1.2; lung 0.9; brain 0.6
and blood 0.5 (Sollman et al., 1938).
6.3 Excretion
Ingested bismuth is largely eliminated unabsorbed in feces.
Model values for the daily balance of bismuth in reference
man are - dietary intake 20 ,ug; fecal elimination 18 ,ug;
urinary excretion 1.6,ug (ICRP, 1975).
Absorbed bismuth is mainly excreted in urine. The rate of
excretion of bismuth following i.m. injection into rabbits
of 13 different compounds was studied by Kolmer et al.
(1939) . Water soluble compounds were excreted more rapidly
than those suspended or dissolved in oil. Excretion in four
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days varied from 82.1% of the dose for aqueous solution of
bismuth thioglycollate to 1.9% for oil suspension of bismuth
oleate but the excretion continued for at least 36 days.
Durbin (1960) compared the excretion of elements of group V
in rats following i.m. injection of soluble compounds in
oxidation state +3. The metabolism of radiobismuth closely
2+
resembled the metabolism of U0~ suggesting that Bi(III)
was in an oxygenated or "basic" form. The retention in the
kidney was short and by the 17th day after injection 95% of
the dose had been excreted.
The permeability of the placenta to bismuth was demonstrated
by Leonard and Love (1928) following i.m. injection of
potassium bismuth tartrate and sodium potassium tartro
bismuthate into pregnant rabbits and cats.
6.4 Biological half-times
ICRP (1960) adopted the following model values for the
biological half-times of bismuth in man: whole body retention
5 days; kidney 6 days; liver 15 days; spleen 10 days and
bone 13.3 days.
7. Normal values in tissues and biological fluids
The concentrations of bismuth in healthy human tissue in the
United Kingdom were recently reported by Hamilton et al.
(1972/ 1973), using SSMS. The highest mean concentration
(400 ,ug/kg wet weight) was found in the kidney, followed by
the bone (<200 ,ug/kg) . The brain, lung and lymph nodes
contained bismuth in concentrations from 10-40 /ug/kg. Concentrations
in the range from 2-8 .ug/kg were found in the testis, blood,
muscle, liver and basal ganglia. 95% of bismuth concentrations
in normal lung and lymph node tissue (158 samples) were
below 40 ,ug/kg, dry weight (SSMS; Brown and Taylor, 1975).
8. Effects and dose-response relationships
Bismuth is not an essential element, either for man or for
animals.
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8.1 Local effects and dose-response relationships
8.1.1 Animals
Application of trimethyl and triethyl bismuth to the skin of
rats and rabbits has been reported to produce intense inflammation
and edema. Local necrosis at injection sites was also observed.
Acute local effects of inhalation of trimethyl bismuth by
rats, cats and dogs include pulmonary edema. Eye irritation
is another local effect observed in inhalation exposures to
alkylbismuth (Sollman and Seifter, 1939).
8.1.2 Humans
Application of trimethyl bismuth to intact human skin produced
no marked effects but intense irritation was noted if the
skin had been scratched. Irritations of the upper respiratory
airways and of the eye were also observed (Sollman and
Seifter, 1939) .
8.2 Systemic effects and dose-response relationships
The main systemic effects of bismuth compounds both in man
and in animals are exerted on the liver and kidney.
8.2.1 Animals
8.2.1.1 Liver
Cloudy swelling with nuclear degeneration and occasional
small foci of necrosis in the liver were observed in rabbits
after lethal injections of sodium and potassium tartro
bismuthate (i.v. 10-30 mg/kgj i.m. 150-350 mg/kg) and bismuth
trioxide (i.m. 450 and 500 mg/kg) (Lucke and Klander, 1923).
After six months, peroral treatment of rats and rabbits with
potassium bismuthate (2.5, 0.25, 0.025 and 0.05 mg/kg) and
bismuth sulfate (5.0, 0.5, 0.05 and 0.025 mg/kg) produced dilatation
of intertrabecular capillaries, vascular stasis, and marked
dilatation and congestion of the vessels. The hepatic tissue
contained large irregularly shaped foci of reticuloendothelial
cells. The severity of these changes was closely related.
The activity of succinic dehydrogenase in the liver and of
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cholinesterase in the serum and liver was reduced even at
doses of 0.025 and 0.05 mg/kg. Hepatic excretory function
was abnormal in rabbits (bromsulfthalein retention). There
were no effects when animals were given 0.005/ug/kg potassium
bismuthate and 0.025 mg/kg bismuth sulfate (Seljankina et
al., 1970).
8.2.1.2 Kidney
Kidney damage was produced in rats by single i.m. injections
(0.03 to 1.5 g/kg) of 13 different bismuth compounds. Histological
examination of 104 rats showed that 36 of 37 animals that
died before 21 days had nephritis of varying degree of
severity as had 11 of 67 surviving rats. The site of major
effects was the proximal convoluted tubules. The least toxic
was bismuth thioglycollate, doses of 0.04-0.080 g/kg producing
severe nephritis (Kolmer et al., 1939). Following subcutaneous
injections (5 g of bismuth subnitrate each day for 3 days),
degenerativef changes and intranuclear and intracytoplasmic
inclusions appeared in renal proximal tubules of rabbits
(Beaver and Burr, 1963a). These inclusion bodies are pathognomonic
for bismuth exposure (Fowler and Goyer, 1975). Hemorrhages
in the cortical and cerebral layer of the kidney and lympho-
histiocystic infiltrations were found in rats after 6 months
of peroral treatment with potassium bismuthate and bismuth
sulfate (0.025-5.0 mg/kg) (Seljankina et al., 1970).
8.2.1.3 Nervous system
Immediately following inhalation exposure to trimethyl
bismuth (10-20 min., concentration not stated) cats and dogs
showed ataxia, restlessness and convulsive seizures. Between
attacks the animals were depressed. Within about 24 hours
they developed signs of severe encephalopathy (Sollman and
Seifter, 1939). Disturbances in conditioned reflexes occurred
in rats and rabbits treated with potassium bismuthate (ingestio:;,
2.5, 0.25 and 0.025 mg/kg) and bismuth sulfate (ingestion,
5.0 mg/kg) (Seljankina et al., 1970).
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8.2.1.4 Other systemic effects
Blood pressure of dogs receiving hypodermic or intramuscular
injections of trimethyl bismuth (4 doses, 350 mg/kg body
weight) sank progressively to shock level without significant
change of heart rate, arythmia or block. The animals were
anesthetized with barbiturates (Sollman and Seifter, 1939) .
Intravenous injection of elemental bismuth (0.50 mg/kg)
caused slight decrease in blood pressure and in amplitude
and heart rate. Higher doses (1.8 mg/kg) resulted in heart
block, and all fundamental functions of the heart were
affected, including excitability, conductivity and contractility
(Mason, 1927).
8.2.2 Humans
Although bismuth compounds had been extensively used for the
treatment of syphilis and for other therapeutic uses, Beerman
(1932) compiled only 22 fatalities as resulting from such
therapy. Delayed deaths were mainly attributable to the
involvement of the gastrointestinal tract, the liver or the
kidney or a combination of two or all three of these systems.
Deaths of 11 children occurred within 2-5 days following the
use of suppositories containing bismuth salt of heptadien-
carboxylic acid, and were preceded by vomiting, drowsiness,
pain in the abdomen, convulsions and coma (Weinstein, 1947).
There are no reports on the occupational exposure effects of
bismuth (Filipova, 1971). No effects were observed in 13
normal human volunteers receiving about 450 mg Bi daily (as
"bistrimate" - C24H2gO25N.Bi"Na_) from a few days to over a
year (Lehman and Fassett, 1947).
8.2.2.1 Liver
An instance of jaundice with liver damage was reported in a
6-year child who received 4-5 mg/kg body weight of bismuth
thioglycollate in a single injection. On the basis of this
and a number of fatal cases reported by other authors Karelitz
and Freeman (1951) concluded that soluble bismuth compounds
are definitely hepatotoxic to man, producing fatty degeneration
of the liver. This confirms the analysis of Beerman (1932)
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and Wolman (1940). Jaundice indicative of hepatitis occurred
in 10.3% of 1032 persons treated for syphilis with bismuth
compounds between 1932 and 1942 (Kulchar and Reynolds,
1942).
8.2.2.2 Kidney
Acute renal failure can occur following oral or parenteral
administration of bismuth compounds such as bismuth sodium
triglycollamate or thioglycollate, particularly in children
(Boyette, 1946; Urizar and Vernier, 1966) . The tubular epithelium
is mainly affected with little change in the glomeruli. In
30 cases of bismuth nephropathy reviewed by Urizar and
Vernier, the interval between medication and onset of symptoms
and signs ranged from 6-7 weeks (mainly bismuth sodium
thioglycollate, i.m. doses 5-200 mg; oral, 1.5-19 g). Functional
alterations in acute bismuth nephropathy include severe
depression of glomerular filtration rate, renal plasma flow,
and proximal tubular reabsorption, as indicated by glucosuria,
phosphaturia and aminoaciduria (Czerwinski and Ginn, 1964).
Bismuth inclusions were found in the renal tubular epithelium
of 12 of the 14 patients treated parenterally with bismuth
compounds (Beaver and Burr, 1963b).
8.2.2.3 Neurological effects
A neurological syndrome possibly associated with bismuth
subgallate ingestion and characterized by confusion, tremulousness,
clumsiness, myoclonic jerks and gait disturbance was observed
in four patients (Burns et al., 1974). Robertson (1974) also
described similar neuropsychiatric symptoms and signs in 4
geriatric patients administered large doses of the same
compound orally for several months.
8.2.2.4 Skin and mucosa
Pityriasis rosea-like eruptions and other skin manifestations
such as the "erythema of the ninth day" syndrome have been
occasionally described as a result of therapy with bismuth
compounds (Goldman and Clarke, 1939; Dobes and Alden, 1949).
Ulcerative stomatitis has been observed following bismuth
119
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therapy (Peters, 1941; Silverman, 1944). Bismuth pigmentation
has been found in the colon, vagina and the skin (Heyman,
1944) .
8.2.2.5 Other effects
Colitis, gastrointestinal bleeding, purpura, agranulocytosis
and aplastic anemia have also been reported as resulting
from administration of bismuth compounds (Avena, 1974) .
8.3 Carcinogenicity, teratogenicity and mutagenicity
There is no evidence of Carcinogenicity or mutagenicity of
bismuth compounds, although bismuth penetrates the placenta
(Leonard and Love, 1928). No teratogenicity has been reported.
9. Treatment of bismuth poisoning
According to Avena (1974), dimercaptol (BAL) brings good results
if given early. Other measures include atropine and meperidine
to relieve gastrointestinal discomfort. Caution is required
in fluid administration during anuric and oliguric phases of
nephrosis, but loss of fluid and electrolytes should be
covered in the subsequent diuric phase (Karelitz and Freedman,
1951).
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REFERENCES
Avena, J.M. (1974). "Poisoning." 3rd edition, pp 81-82.
Charles C. Thomas, Springfield, Illinois.
Beaver, D.L. and Burr, R.E. (1963a). Amer. J. Pathol. 42,
609-617.
Beaver, D.L. and Burr, R.E. (1963b). Arch. Pathol. 76, 89-
94.
Beerman, H. (1932) . Arch. Dermatol. Syph. 26, 798-801.
Bowen, J.M. (1966). "Trace Elements in Biochemistry." pp 16-
17. Academic Press, London and New York.
Boyette, D.P. (1946). J. Pediatr. 28, 193-197.
Brown, R. and Taylor, H.E. (1975). "Trace Elements Analysis
of Normal Lung Tissue and Hilar Lymph Nodes by Spark Source
Mass Spectrometry." National Institute for Occupational
Safety and Health, U.S. Department of Health, Education and
Welfare, Cincinnati.
Browning, E. (1969). "Toxicity of Industrial Metals." 2nd
edition, pp 87-89. Butterworths, London.
Burns, R., Thomas, D.W. and Barren, V.J. (1974). Brit. Med.
J. 1, 220-223.
Czerwinski, A.W. and Ginn, R.E. (1964). Amer. J. Med. 37,
969-975.
Davison, R.L., Natusch, D.E.S., Wallace, J.R. and Evans,
C.A., Jr (1974). Environ. Sci. Technol. 8^ 1107-1112.
Delves, H.T., Clayton, B.E. and Bicknell, J. (1973). Brit.
J. Prev. Soc. Med. 27, 100-107.
Division of Atmospheric Surveillance (1972) . "Air Quality
Data from the National Air Surveillance Networks and Contributing
State and Local Networks." pp 100-103. Office of Air Programs,
Environmental Protection Agency, Research Triangle Park,
North Carolina.
Dobes, W.L. and Alden, H.S. (1949). South. Med. J. 42, 572-
579.
Durbin, D.W. (1960). Health Phys. 2, 225-238.
Environmental Studies Board (1972). "Water Quality Criteria."
A Report of the Committee on Water Quality Criteria, p 244.
National Academy of Sciences, National Academy of Engineering,
Washington, D.C.
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Filipova, J. (1971). In: "Encyclopaedia of Occupational
Health and Safety." Vol. I, pp 186-187. International Labour
Office, Geneva.
Fowler, B.A. and Goyer, R.A. (1975). J. Histochem. Cytochem.
23_, 722-726.
Goldman, L. and Clarke, G.E. (1939). Amer. J. Syph. Gonorrh.
Ven. Dis. 23, 224-227.
Hall, R.J. and Farber, T. (1972). J. Assoc. Off. Anal. Chem.
_55_, 639-642.
Hamilton, E.J. and Minski, M.J. (1972/1973). Sci. Total
Environ. I, 375-394.
Hamilton, E.J., Minski, M.J. and Cleary, J.J. (1972/1973).
Sci. Total Environ. 1, 341-374.
Heyman, A. (1944). Amer. J. Syph. Gonorrh. Ven. Dis. 28,
721-732.
ICRP (1960). "Recommendations of the International Commission
on Radiological Protection. ICRP Publication 2. Report of
Committee II on Permissible Dose for Internal Radiation."
pp 218-219. Pergamon Press, Oxford.
ICRP (1975). "Report of the Task Group on Reference Man." p
365. International Commission of Radiological Protection,
No. 23. Pergamon Press, Oxford.
Karelitz, S. and Freedman, A. (1951) . Pediatrics £3, 772-777.
Kinser, R.E. (1966). Amer. Ind. Hyg. Assoc. J. 2^7, 260-265.
Kolner, J.A., Brown, H. and Rule, A.M. (1939). Amer. J.
Syph. Gonorrh. Ven. Dis. 23, 7-40.
Kulcher, G.V. and Reynolds, W.J. (1942). J. Amer. Med.
Assoc. 120, 343-346.
Lehman, R.A. and Fassett, D.W. (1947). Amer. J. Syph. Gonorrh.
Ven. Dis. 31, 640-656.
Leonard, C.S. and Love, R.S. (1928). J. Pharmacol. Exp. Ther. 34,
347-353.
Lucke, B. and Klander, J.V. (1923). J. Pharmacol. Exp. Ther. 21,
313-321.
Mason, G.A. (1927) . J. Pharmacol. Exp. Ther. 30, 39-72.
Panel on Bismuth (1970). "Trends in the Usage of Bismuth."
Committee on Technical Aspects of Critical and Strategic
Materials, National Materials Advisory Board, National
Academy of Sciences, National Academy of Engineering, Washington,
D.C.
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Paone, J. (1970). In: "Mineral Facts and Problems." U.S.
Bureau of Mines Bull. 650, 503-513. Department of Interior,
U.S. Government Printing Office, Washington, D.C.
Peters, E.E. (1942). Amer. J. Syph. Gonorrh. Ven. Dis. 26,
84-95.
Pinta, M. (1970). "Detection and Determination of Trace
Elements." pp 199-200, 315-319, 478-480. Hamphrey Science
Publishers, Ann Arbor, London.
Robertson, J.F. (1974). Med. J. Austral. 1, 887-888.
Seljankina, K.P., Lencenko, V.G., Petina, A.A., Petrova,
N.N. and El'nicnik, L.N. (1970). Gig. Sanit. 35, 161-164.
Silverman, S.S. (1944). Mil. Surgeon 9J5 / 486-489.
Sollman, T., Cole, H.N., Henderson, K. (1938). Amer. J.
Syph. Gonorrh. Ven. Dis. 22, 555-583.
Sollman, T. and Seifter, J. (1939). J. Pharmacol. Exp. Ther. 67,
17-49.
Sollman, T. and Seifter, J. (1942). J. Pharmacol. Exp. Ther. 74,
134-154.
Urizar, R. and Vernier, R.L. (1939). J. Amer. Med. Assoc.
198, 187-189.
Weinstein, J. (1947). J. Amer. Med. Assoc. 133, 962-963.
Wolman, I.J. (1940). Amer. J. Syph. Gonorrh. Ven. Dis. 24,
330-336.
Woolrich, P.F. (1973). Amer. Ind. Hyg. Assoc. J. 34, 217-
226.
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CADMIUM
Lars Friberg, Gunnar Nordberg and Magnus Piscator
1. Abstract
About 5 % of ingested cadmium is absorbed by human beings, but
calcium deficiency may increase this amount. The portion of
inhaled cadmiu:. absorbed is dependent on particle size and
solubility. Absorbed cadmium is mainly stored in kidneys and
liver. The excretion is slow, less than 0.01% of the total body
burden per day, which corresponds to a biological half-time of
more than 20 years in human beings. In liver and kidneys cadmium
is mainly bound to the low molecular weight protein - metallo-
thionein - which also might be the transport protein for cadmium
and ultimately responsible for the prominent accumulation of
cadmium in the renal cortex. The placental barrier is effective
against cadmium and the newborn is practically free from this
metal. There is a considerable accumulation with age, the mean
kidney concentrations at age 50 being from 15-50 mg/kg wet weight
in European countries, and USA, whereas considerably higher "norm-
al" values have been found in Japan.
Ingestion of highly contaminated food or drink gives acute
gastrointestinal effects. Excessive exposure to cadmium via
inhalation may cause acute or chronic lung disease and chronic
renal disease. The latter can also appear after long-term
exposure via food. The renal damage is primarily a reabsorption
defect in the proximal tubules, and the first sign of chronic
cadmium intoxication is the appearance in urine of low molecular
weight proteins - tubular proteinuria. Aminoaciduria, glucosuria
and phosphaturia may occur later. Disturbances in mineral metab-
olism may cause mineral depletion in bone and osteomalacia has
been found both in industrially exposed workers and in women
exposed to excessive amounts of cadmium in rice - the latter
disease being called the Itai-itai disease. Anemia and disturbed
liver function may also result from excessive cadmium exposure.
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Exposure to cadmium causes changes in the distribution and
metabolism of zinc and some of the toxic effects of cadmium
are tnougnt to be due to the interference of cadmium with
zinc enzymes
3
Exposure to cadmium concentrations in air around 50-100 ug/m
for a few years has given rise to emphysema and renal tubular
disorders. In the general population the main exposure to cad-
mium is via food and long-term exposures with daily intakes
of 300-480 /ug have been estimated to cause renal tubular dys-
function. This estimate was based on cadmium concentration in
rice. When data on fecal excretion of cadmium were used instead,
a daily intake of around 200 ug was found. This is in accord
with estimations based on a metabolic model for cadmium and
a critical concentration in sensitive individuals of about 200
mg cadmium/kg wet weight in the renal cortex. WHO (1977) has
recently stated that the critical level may be between 100 and
300 mg/kg with 200 mg/kg being the most likely estimate.
In order to detect renal tubular dysfunction at an early stage,
electrophoretic examination of urine proteins or determination
of certain low molecular weight proteins must be used. Once
fully established, the renal dysfunction does not regress, even
if exposure ceases. The progress is, however, very slow. There
is no specific therapy for chronic cadmium poisoning, but treatment
can be instituted against the metabolic disturbances.
The extensive literature on toxicological and environmental
aspects of cadmium has recently been reviewed in detail by Friberg
et al. (1974, 1975) and Fulkerson et al. (1973) and the following
review is to a large extent based on those previous reviews.
2. Physical and chemical properties
Cadmium, Cd, atomic weight 112.4; atomic number 48; density 8.6;
melting point 320 .9 C; boiling point 765 C; crystalline form
hexagonal, silver-white malleable metal; oxidation state 2.
Some compounds which can be mentioned are cadmium acetate,
cadmium sulfide, cadmium sulfoselenide, cadmium stearate, cad-
125
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mi urn oxide, cadmium carbonate, cadmium sulfate and cadmium
chloride. Of the many inorganic cadmium compounds, several
are quite soluble in water, e.g. the acetate, chloride and
sulfate. Cadmium oxide is insoluble in water, whereas cadmium
sulfide is almost insoluble. Cadmium is easily complexed
with some organic compounds, e.g. thiocarbamates, this prop-
erty furnishing the basis for several analytical methods.
There are some synthetic organometallic compounds, but these
have not been found in the general environment, since they
are rapidly decomposed
3. Methods and problems of analysis
Dithizone methods have long been used extensively for the analysis
of cadmium and amounts of about 100 ng may be determined accurately
(Smith et al., 1955). Emission spectroscopy has earlier displayed
varying sensitivity and accuracy for cadmium. Modern equipment
seems to ensure accurate analysis of about 50 ng (Imbus et al.,
1963).
Neutron activation analysis is regarded as an accurate method, but
has not been widely used for cadmium (Westermark and Sjostrand,
1960; Linnman et al., 1973). In vivo determination of cadmium
in liver by neutron activation has been described by Harvey
et al. (1975). In cadmium exposed workers it was possible
to demonstrate elevated liver levels of cadmium. A further dev-
elopment of this method has brought about portable equipment for
field use (Thomas et al., 1976).
The usefulness of newly developed electrochemical methods,
such as anodic stripping voltammetry, for determination of
cadmium in biological material is difficult to evaluate
at present.
Atomic absorption spectrophotometry is the most common method
for the determination of cadmium to date. By flameless AAS
methods, about 5 ug/kg can be accurately determined. However,
interference of salts (e.g. Na-salts), may cause inaccuracies
if appropriate precautions are not taken (Pulido et al.
1966; KjellstrSm et al. 1974).
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In the past and even into the present, a substantial amount
of published data has been based on inadequate methods.
Errors have been seen with regard to both emission spectroscopy
and atomic absorption spectrophotometry (Fulkerson et al.,
1973; Friberg et al., 1974).
4. Production and uses
4.1 Production
Cadmium displays chemical similarity to zinc and occurs together
with zinc, the cadmium: zinc ratio in minerals and soils being
1:100-1:1000. Cadmium is obtained as a by-product in the refining
of zinc and other metals, particularly copper and lead. There is
no specific cadmium ore worth mining for its content of cadmium
only. The world production of the metal in 1970 was 16,000 tons.
It had increased yearly with 14 % during the preceding five years.
Only a very minor part of this world production is recycled, and
cadmium has been named "the dissipated element" (Fulkerson et al.,
1973).
Although cadmium has been recognized for only a relatively short
period of time, environmental pollution has taken place for several
thousand years, ever since man started to produce metals from ores
which happened to contain cadmium.
4.2 Uses
Cadmium is used in a number of industrial processes. Because of
its ability to protect iron items from rusting, it is used for
coating such items by electroplating. Cadmium-plated parts for
automobiles and the like are more resistant to rust than zinc-
coated (galvanized) objects. Cadmium sulfide and cadmium sulfo-
selenide are used as color pigments in plastics and in various
types of paint. Cadmium stearate is used as a stabilizer in plastics
Because of its ability to stiffen copper and increase its mechanical
resistance at increased temperatures, it is used in copper-cadmium
alloys, which are used for automobile radiators and the like.
Cadmium may serve as an electrode component in so-called NIFE
alkaline accumulators (Fulkerson et al., 1973). Cadmium is also
used in silver solders. During a recent year in the U.S.A. 60 %
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of the cadmium produced or imported was used for plating, 11 %
in color pigments, 19 % as stabilizers in plastics, 3 % in ac-
cumulators and 7 % for other purposes (U.S. Environmental Pro-
tection Agency, 1975). In U.K. and West Germany about one third
of annually produced or imported cadmium was used for plating
and one third as pigments and stabilizers (Teworte, 1973).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
An extremely wide range of cadmium concentrations in foodstuffs
has been reported from various countries. Different results
from different .investigators analyzing the same types of food
in the same area can be explained in some cases by the inadequate
analytical methods.
When data from reliable analyses performed in several countries
are considered (Schroeder and Balassa, 1961; Essing et al., 1969;
Rautu and Sporn, 1970; Ministry of Agriculture, Fisheries
and Food (UK), 1973; Beckman et al., 1975; Mahaffey et al.,
1975; Kjellstrdm et al., 1975; Jonsson, 1976), the following
concentrations (mean values mg/kg wet weight) emerge:
Beef meat 0.03 - 0.06
Beef kidney 0.2 - 1.6
Fish meat (other than crab) 0.01 - 0.2
Wheat grains 0.01 - 0.15
Rice (USA & Hungary) 0.03 - 0.04
Rice (Japan, non-contaminated
areas) 0.05 - 0.07
White bread 0.02 - 0.16
Milk <0.001
Potatoes 0.001 - 0.09
These values have been obtained in areas generally believed
to be non-contaminated by cadmium. In some contaminated areas
of Japan average concentrations of about 1 mg Cd/kg have been
found in rice and considerable increases in certain marine
products have been found as well.
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Estimations of the daily intake of cadmium based on data on
cadmium concentrations in single foods and on total diet
studies have been made in several countries. In "uncontaminated"
areas the average daily intake ranges from 25 to 60 lag/day
for a 70 kg person (Friberg et al., 1974). An extensive study
from U.K. recently estimated the intake at between 10 and 30
Aig for a 70 kg person (Ministry of Agriculture, Fisheries and
Food, 1973). Recent estimates from Sweden indicate that the
daily intake there is 10-20 >ug (Wester,1974; Elinder et al.,
1976). In U.S.A. yearly estimates 1968-1974 for 15-20 year
old males (the period of highest calorie intake) have varied
between 26 and 61 ug, on an average 39 ug (Mahaffey et al.,
1975) .
Measurement of cadmium in the feces will give an approximate
estimate of the daily intake since 90-95 % of ingested cadmium
will remain unabsorbed. Studies performed on this material
agree with the range estimated above for daily intake of cadmium
(Friberg et al., 1974, 1975j Wester, 1974).
5.1.2 Water and soil
In natural water cadmium is found mainly in bottom sediments and
suspended particles, whereas the concentration in the water phase
is low. Cadmium concentrations in non-polluted natural waters
usually are lower than 1 /ug/1. Contamination of drinking water
may occur as a result of cadmium impurities in the zinc in
galvanized pipes, and the presence of cadmium-containing solders
in fittings, water heaters, water coolers and taps.
Concentrations up to 16 mg/kg have been reported in soft drinks
which had been in contact with cadmium-containing parts in
vending machines. Regular drinking water usually does not have
concentrations of cadmium exceeding 5 ug/1. Seawater contains
between 0.04-0.3 ug/1.
Both waterborne and airborne cadmium can cause an increased
concentration of cadmium in soil. In non-polluted areas the
cadmium concentrations in soil will usually be less than I
mg/kg. In certain areas of Japan where cadmium pollution h
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been suspected, levels of between 1 and 69 mg/kg have been
found in the top soil of ricefields. The cadmium connected
with the epidemic of Itai-itai disease (see below) came from
ricefield soil contaminated by cadmium-polluted irrigating
water. The use of cadmium-containing sewage sludge and super-
phosphate as fertilizers in agriculture may also contaminate
the soil. Sewage sludge may contain 100 mg cadmium/kg dry weight
(Berrow and Webber, 1972) . Information concerning the factors
determining the uptake of cadmium in plants is scarce, but
it has been shown that pH and concentrations of other minerals
will be of importance (Linnman et al., 1973). Both rice and
wheat can take up considerable guantities of cadmium from soil.
5.1.3 Ambient air
Cadmium in ambient air occurs in particulate form. Its exact
chemical form has seldom been reported but it is probable that
cadmium oxide is an important part.
Annual averages during 1969 in larger cities of the USA ranged
from 0.006 ug/m - 0.036 ug/m (National Air Sampling Network,
USA). In European countries, urban values of 0.002 - 0.05
have been reported. In Tokyo mean values over several months
varied from 0.01 - 0.053 ug/m . In nonurban areas lower values
were found, 0.001 - 0.003 ug/m . Higher values, weekly means of
0.2 - 0.6 ug/m , have been recorded around certain cadmium-
emitting industries (Friberg et al., 1974). Cadmium in air can
also be measured indirectly by analyzing the cadmium content in
mosses or leaves (Ruhling and Tyler, 1973) .
5.1.4 Tobacco
Smoking of tobacco may be an important route of exposure for
the general population. The smoking of one cigarette, generally
containing 1-2 ug of cadmium, causes the inhalation of about
0.1-0.2 ug of the metal. A smoker of 2 packs per day may accu-
mulate an additional body burden of about 15 mg cadmium over
a 20 year period (Lewis et al., 1972).
5.2 Working environment
Data on cadmium exposure within industries are scarce. Acute
inhalation exposures are known to occur in e.g. welders of
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cadmium-containing materials. . Systematic studies in the
breathing zones of workers in industries where prolonged ex-
posures take place are not known. Sporadic measurements in
some industries producing alkaline batteries in the 1940's and
I950's indicate that exposure to cadmium oxide dust, particle
size not known, reached a couple of mg/m of air (Friberg, 1950).
Later studies in the same type of industry indicate that con-
centrations have been generally lower, in the range of 50-200
ug/m (Friberg et al., 1974). In the manufacturing of cadmium
alloys the exposure is mainly to cadmium fume which consists
of cadmium and cadmium oxide particles, generally of smaller
aerodynamic diameter than cadmium oxide dust. Concentrations
of cadmium in the air of such industries have ranged from 4-
270 /ug/m .
The magnitude of exposure to cadmium in the plating industry
has not been reported but it is conceivable that both inhalatory
and transdermal exposure could occur. The production and use
of cadmium pigments may give rise to inhalation of high con-
centrations of cadmium oxide, carbonate, sulfide and sulfoselenide
in air.
6. Metabolism
Data on absorption, retention, distribution and excretion of
cadmium are fundamental for the evaluation of the risks to
human health connected with exposure to cadmium. Though an
abundance of such data is available, several gaps in the knowl-
edge at hand continue to hamper an exact evaluation.
6.1 Absorption
6.1.1 Inhalation
Cadmium exposure via inhalation is in the form of an aerosol.
General laws governing deposition of particulate matter in the
lung indicate that, depending on particle size, between 10-50%
of the inhaled particles will be deposited in the alveolar part
of the lung. For the finely dispersed cadmium aerosols, as is
the case due to exposure via cigarette smoking, it can be cal-
culated, based on cadmium concentration in cigarette smoke and
autopsy data from people smoking different quantities of cig-
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arettes, that absorption is between 25 and 50% (Lewis et al.,
1912-, Friberg et al., 1974; Blinder et al., 1976). There are
no industrial data which lend themselves to an exact calculation
of absorption of inhaled cadmium. Animal data, both from single
and chronic exposure studies, indicate a high absorption of
cadmium via the respiratory route, between 10 and 40% of the
cadmium inhaled. Particles of larger size and particles with
very low solubility will probably be in the lower part of this
range, while particles with high solubility and smaller diameter
will be in the upper part (Friberg et al., 1974).
6.1.2 Ingestion
Absorption of cadmium through food is most important for the non-
industrially exposed. In several reports in which the fate of a
single oral dose of radioactive cadmium has been followed in
rats, mice and monkeys, an absorption of between 0.5-3% has
been found (Friberg et al., 1974). The absorption in humans
is higher. Five volunteers given a single dose of radioactive
cadmium by mouth showed an average absorption of 6% (Rahola
et al., 1972) with a range between 4.7-7.0 %. Animal experiments
have shown that a low intake of calcium, iron and protein may
increase the absorption considerably. It is likely that the
situation for the human being is similar, which may be of importance
above all in certain highly exposed areas in Japan.
6.2 Transport and distribution
After absorption from the lungs or the gut, cadmium is trans-
ported via the blood to other parts of the body, and stored
mainly in liver and kidneys. Upon chronic exposure in animal
experiments, about 75 % of cadmium injected or absorbed from
the gut is found in these two organs. In normal humans, after
long-term low level exposure, about 50 % of the retained cadmium
is found in the liver and kidneys together and about 1/3 of
the body burden is in the kidneys alone. When exposure is excessive,
as can be seen industrially and in several contaminated areas
in Japan, concentrations of cadmium in liver and kidney are
very high as can be seen in Figures 1 and 2. When kidney damage
has occurred, cadmium excretion increases considerably, which
explains the fact that in the most severely poisoned workers
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and in Itai-itai patients kidney levels, in contrast to liver
levels, are low, often not higher than in normal human beings
(Friberg et ai., 1974).
A considerable accumulation of cadmium also takes place in pan-
creas and the salivary glands. In bone tissue, muscles and central
nervous system, only small guantities of cadmium are normally
found. The placental barrier is effective against penetration
of cadmium into the fetus. In the kidney, the highest concentration
of cadmium is in the cortex (Friberg et al., 1974).
In the blood of cadmium-exposed experimental animals, cadmium
is mainly found in the red cells, where it is bound to a protein
of low molecular weight, probably metallothionein. In organs
such as kidney, liver, pancreas and testicles, cadmium is also
bound to a great extent to metallothionein (Nordberg, 1972;
Nordberg and Nordberg, 1973). This protein has a molecular
weight of about 6,000-7,000. It can bind up to 11% of cadmium
and zinc, because it has a large number of sulfhydryl (SH)
groups. This protein has been isolated in large guantities
from the liver of cadmium exposed animals, and similar proteins
have also been found in the mucosa of the duodenum of such
animals. It is possible that the transport from the gut takes
place as a cadmium-metallothionein complex. The low molecular
weight of metallothionein enables the protein to be filtered
through the glomerular membrane and thereafter reabsorbed from
the tubular fluid into the cells of the renal tubules. This
mechanism may explain the selective accumulation of cadmium
in the kidney cortex (Friberg et al., 1974). It has recently
been shown that injected metallothionein is rapidly excreted
and accumulates in the kidney (Nordberg and Nordberg, 1975).
6.3 Excretion
As is obvious from what has been mentioned above only a small
part of the absorbed cadmium will be excreted. This excretion
takes place via feces and urine, and comprises probably only
0.005-0.01 % of the total body burden of cadmium in human beings.
The excretion via urine increases with age on a group basis
and is proportional to the body burden of cadmium. This has
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been possible to show in animal studies (Nordberg, 1972) and
is supported by findings in studies on human beings (Tsuchiya
et al., 1972). The individual variation is large as can be
seen from Figure 3.
When renal damage has occurred, the cadmium excretion by urine
increases dramatically, as shown in studies on rabbits and
mice (Friberg, 1952-, Nordberg, 1972; Friberg et al. , 1974).
6.4 Biological half-time
Once absorbed, cadmium is very efficiently retained in the
body, and very small guantities are excreted. The biological
half-time in the mouse and in the rat is 200-400 days regardless
of the exposure route. In squirrel monkeys it is probably around
2 years (Nordberg,1972). The biological half-time in the human
kidney is very long, probably between 20-40 years. In long-
term low level exposure, such as arises from natural levels
of cadmium in the environment, accumulation in the kidney
thus will take place during the whole life-span. This is in
accord with observations on the cadmium content in organs from
human beings (Figures 1 and 2).
6.5 Mathematical model for cadmium accumulation
in renal cortex
Of the total body burden in a normal human being, about 1/3
will be in the kidneys, with the concentration in the kidney
cortex being 1.5 times that in the whole kidney. By using
equations for accumulation, the concentration in the kidney
cortex can be calculated. Kidney weight and caloric intake
vary with age, which influences the shape of the curves when
the kidney cortex concentration in various age groups is to
be calculated. Taking these matters into consideration, theoreti-
cal accumulation curves can be calculated with empirically
obtained values. If theoretical accumulation curves (Friberg
et al., 1974) are compared with empirical values (Figure 4),
it is obvious that the excretion constant is somewhere between
0.00005 - 0.0001, corresponding to a biological half-time of
19-38 years.
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7. Levels in tissues and biological fluids, normally and
as indices of exposure and concentrations in critical
organs
Newborn babies are almost free of cadmium, the total body bur-
den being only about 1 jug (Henke et al., 1970). A man of 50
years of age in USA, Sweden and East Germany will have a total
body burden of cadmium of between 15-30 mg. This corresponds
to concentrations in the liver of about 2-3 mg/kg wet weight
and in the kidney cortex,25-50 mg/kg (corresponding to about
15-20 mg/kg calculated on a whole kidney).
Normal values in Japan are higher, e.g. data from Tokyo indicate
average kidney cortex concentrations at age 50 of above 100 mg/kg
(Friberg et al., 1974; Tsuchiya et al., 1972).
The variation of "normal" levels in liver and kidney cortex
according to age and area is shown in Figures 1 and 2. There
will also be differences between smokers and nonsmokers.
In blood "normal" levels in nonsmokers are generally below
1 /ug/1, whereas considerably higher values, up to 7.6,ug/l,
have been found in smokers (Ulander and Axelsson, 1972) . There
are great discrepancies among published data on "normal" blood
levels but it has been concluded that most data speak in favor
of the low levels presented above (Friberg et al./ 1974, 1975).
In urine "normal" levels will also vary with age, area, and
smoking habits, generally being <1 ug/g creatinine, but 1-
2 ug/g creatinine has been reported in some areas in Japan
(Friberg et al., 1974, 1975).
7.1 Concentrations in biological material as indices of exposure
Available evidence from animal experiments and human data have
been compiled (Friberg et al., 1974), revealing that during
exposure blood values probably do not reflect kidney accumula-
tion of cadmium, but may reflect the most recent exposure.
Whereas it may thus be difficult to use blood values for an
evaluation of renal cadmium concentrations, blood values might
be possible to use for evaluations of exposure. Experience is
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not yet sufficient to state a numerical relationship between
blood concentration and exposure.
It has been shown (Nordberg, 1972) in animal experiments that
during the early phase of exposure, before renal tubular impair-
ment has occurred, a correlation exists on a group basis between
the body burden and urinary concentration of cadmium. Tsuchiya
et al. (1972[ in studies on normal Japanese not excessively
exposed to cadmium, found that on group basis the urinary con-
centrations of cadmium followed the accumulation of cadmium in
the kidneys as seen in autopsy cases. A large individual scatter
was evident, however (Figure 3).
7.2 Concentrations in biological materials as indices of
concentrations in critical organ
Conclusive evidence on the relation of blood values of cadmium
to the concentration in the kidneys has not been presented.
The biological half-time in the blood seems to be shorter than
in the kidney. This means that high blood values may be found
before critical levels are reached in the kidneys while low
blood values do not exclude the possibility that a considerable
cadmium accumulation has taken place in the body.
Based on animal as well as human data it seems that cadmium in
urins theoretically could be used as an index of the body burden
and the concentrations in the kidneys. In long-term, low level
exposure, a urinary cadmium excretion of about 10 mg/kg creatininc
indicates that in the renal cortex the cadmium concentration is
near the critical concentration (Piscator, 1972). At high expo-
sures the excretion of cadmium may be quite high, reflecting more
recent exposure. Further, as has been referred to earlier, when
tubular dysfunction occurs an increase of urinary excretion of
cadmium will occur. When excretion of cadmium in urine is excessive
suspicions will always exist that tubular dysfunction has already
arisen.
8. Effects and dose-response relationships
Cadmium may give rise to both acute and chronic types of poi-
soning. The following review will describe symptoms and signs
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in human beings suffering from such poisoning, but will also
deal with animal data that may have a bearing on the interpretation
of these effects both clinically and from the standpoint of
establishing adequate dose-response relationships for setting
of standards.
8.1 Acute poisoning
8.1.1 Inhalation
The symptoms may not appear until 24 hours after exposure has
terminated, which may cause difficulties in obtaining the proper
diagnosis (Friberg et al., 1974). The predominant symptoms and
signs are shortness of breath, general weakness, fever and in
severe cases respiratory insufficiency with shock and death.
The cadmium induced acute pulmonary disorder is a chemical
pneumonitis or sometimes a pulmonary edema.
This type of effect may most frequently result from the inhala-
tion of fumes generated by welding upon cadmium-containing materials
or by smelting or soldering such materials, both under conditions
of poor ventilation. Approximately 5 mg/m inhaled over a time
period of 8 hours may be lethal and approximately 1 mg/m inhaled
over the same time period gives rise to clinically evident symptoms
in sensitive individuals (Friberg et al., 1974).
8.1.2 Ingestion
The symptoms and signs are nausea, vomiting, abdominal cramps,
and headache. In more severe cases diarrhea and shock may develop.
The onset of symptoms is usually a matter of minutes upon inges-
tion of the cadmium-containing food item.
This type of poisoning may arise as a result of contamination
of food or drink with cadmium from solders in water pipes, taps,
cooling or heating devices or from dissolution of cadmium from
pottery, usually when storing acid juices and the like in these
items. Cadmium-plated cooking utensils, long since prohibited
in most countries, at one time frequently caused acute cadmium
poisoning. The concentration of cadmium in water that gives
rise to vomiting is about 15 mg/1. For protein containing-foods
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somewhat larger concentrations are probably required to induce
vomiting.
8.1.3 Injection
Injection of single doses of soluble cadmium salts (1-3 mg/kg
body weight) gives rise to dramatic effects on the testicles
of several species of experimental animals. Effects on non-
ovulating ovaries of females as well as on sensory ganglia have
also been reported. Within hours after injection, these organs
undergo complete destruction, without evident damage to other
organs (Parizek, 1956; Gabbiani, 1966; Friberg et al., 1974).
A vast literature on various aspects of these effects has been
published, but it is of limited value for an evaluation of human
health effects from environmental cadmium exposure.
8.2 Chronic poisoning
8.2.1 General aspects
8.2.1.1 Long-term inhalation in industry
Fully developed industrial cadmium intoxication after chronic
exposure via inhalation consists of a syndrome including lung
emphysema and kidney disease with proteinuria (Friberg, 1950).
The relative severity of the renal versus the lung damage is
dependent on the intensity of the exposure (and presumably also
on variations in individual susceptibility) so that with more
intense exposure relatively more lung damage is seen whereas
with low exposures for very long time periods, a more or less
isolated renal affection may develop.
In addition, anemia, liver disturbance and changes in bone min-
eral metabolism may be seen.
The concentrations that may give rise to effects will be dealt
with more in detail in the section on dose-response relationships
(section 9).
8.2.1.2 Long-term ingestion
Long-term ingestion of cadmium has taken place in Japan. It
has given rise to a renal tubular disease of the same type as
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in industrial long-term exposure and as well as a severe bone
disease known as Itai-itai disease. The patients may also have
gastrointestinal changes with resorption defects, anemia and
liver disturbance. For more details on the Itai-itai disease,
see sections 8.2.2 and 8.2.6.
8.2.2 Kidney damage
The most typical feature of chronic cadmium intoxication is
the kidney damage. Cadmium affects reabsorption functions
of the proximal tubules and the first sign is usually an
increase in the excretion of low molecular weight proteins -
tubular proteinuria (Figure 5). Normally, these proteins occur
in plasma, are filtered through the glomeruli, and are reabsorbed
almost completely. One of these proteins is p2-microglobulin.
The cadmium poisoned kidney reabsorbs these proteins to a lesser
extent which results in an increase in protein excretion. Later
effects may be aminoaciduria, glucosuria and phosphaturia (Piscator,
1966). Disturbances in the renal handling of phosphorus and
calcium may cause resorption of minerals from bone. Signs of
these disturbances have been kidney stones in Swedish workers
(Friberg, 1950; Axelsson, 1963), and osteomalacia in French
workers (Nicaud et al., 1942).
Tubular dysfunction of the same type as seen in cadmium workers
has been a common finding in cadmium-contaminated areas in Japan,
especially in Fuchu, Toyama Prefecture, where the so-called
Itai-itai disease was first seen. This disease is an osteomalacia,
which mainly has been found in women above 45 years of age and
with many pregnancies. Low calcium intakes and losses of calcium
during pregnancy and lactation periods contribute to this extreme
manifestation of chronic cadmium poisoning.
Once tubular proteinuria is manifest, it persists even if exposure
ceases, as has been shown by long-term observations on cadmium
workers (Piscator, 1966). It is not known whether or not the
very first changes in reabsorption are reversible.
8.2.3 Anemia
Slight decreases in hemoglobin levels have been a common
finding in cadmium exposed workers. This is a reversible effect
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and bears no relationship to the renal damage. Cadmium probably
has no direct effect on hematopoiesis, but the deficient iron
absorption from food engenders decreased availability of iron
to the bone marrow. Decreased haptoglobin levels have also been
observed in cadmium workers and in animal experiments indicating
that the anemia may be partly of hemolytic origin. An increased
destruction of erythrocytes has been shown in animal experiments
(Friberg et al., 1974).
8.2.4 Hypertension
Some animal experiments show that hypertension can be induced
by cadmium (Schroeder, 1964). This is not always the case, as
indicated by later authors. Both differences in susceptibility
among strains and in intake of sodium have been implicated as
important factors (Friberg et al., 1974).
Autopsy studies pointing towards a higher concentration of
cadmium in people dying of cardiovascular diseases have been
reported (Schroeder, 1967). The effect of smoking was not
taken into account. There are no reports of hypertension in
industrially exposed workers, but the question has not been
carefully evaluated. Whether cadmium actually affects the
blood pressure in human beings cannot be said at present.
8.2.5 Liver disturbances
The liver is one of the major storage organs for cadmium and
may be adversely affected by this metal. In exposed workers
changes in liver function generally are slight compared to
the changes in renal function. Data from animal experiments
(Friberg, 1950; Sporn et al., 1970; Stowe et al., 1972)
indicate that morphologically evident damage as well as
changes in the activity of certain enzymes in the liver may
occur at long-term parenteral or oral exposures. Such changes
may occur without showing up on classical clinical diagnostic
tests for liver damage.
8.2.6 Effects on bone
As mentioned in 8.2.2, the renal damage disturbs the metabolism
of bone minerals. Some experimental data suggest that cadmium
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may also affect calcium metabolism before renal damage has
occurred. In calcium-deficient animals the retention of cadmium
was higher than in animals on a normal calcium intake and
cadmium accelerated the osteoporotic process caused by calcium-
deficiency alone (Larsson and Piscator, 1971; Piscator and
Larsson, 1972). High oral exposure has also caused osteomalacia
in animals at renal cortex concentrations of cadmium of only
about 50 mg/kg wet weight (Kawai et al., 1976).
The Itai-itai disease is an osteomalacia caused by the combination
of primary calcium deficiency and severe tubular dysfunction
from cadmium exposure. The symptoms are dominated by pains in
the be.crc and legs. Pressure on bones, especially the long bones
in the legs and the ribs, prc.duces further pain. When the disease
progresses, even mild trauma may give rise to fractures of
various parts of the skeleton. Skeletal deformation takes place
with a marked decrease in body height (Tsuchiya, 1969 j Friberg
et al., 1974).
8.3 Carcinogenic effects
In human beings interest has mainly been focused on cancer
of the prostate, since Potts reported in 1965 that 8 deaths
had occurred among 74 men with at least 10 years of exposure
to cadmium oxide dust and that 3 of them were from cancer of
the prostate. Kipling and Waterhouse (1967) found that 4 deaths
from cancer of the prostate had occurred in 248 workers from
the same factory (including those described by Potts, 1965)
with more than 1 year of exposure. The expected number was
0.58. Lener et al. (1976) reported that 4 of 292 smelter
workers with at least 2 years of exposure to cadmium oxide
dust and fumes had died from cancer of the prostate, whereas
the expected number was 1.15. When the time elapsed since
the onset of exposure was taken into account, a significantly
increased risk of cancer of the prostate was shown, 4 observed
as compared to 0.89 expected, 20 years after the onset of
exposure. The numbers in these two studies are low and the
data are not yet conclusive.
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Cadmium sulfate given subcutaneously to rats and mice repeatedly
over a two-year period did not lead to any signs of malignant
tumors in the prostate (Levy et al. , 1973).
With regard to other forms of cancer Leman et al. (1976) reported
a significant excess of respiratory cancer, 12 deaths versus
5.11 expected in the above mentioned group of smelter workers.
Data on smoking were not given, however.
Among the 58 Swedish battery workers reported on by Friberg
(1950) 17 had died in 1972, 3 of them in cancer of the urinary
bladder, lung and large bowel respectively (Friberg et al.,
1974). There was no control group, and no conclusions can be
drawn.
The association between occupational cadmium exposure and
cancer has been evaluated by IARC (1976). It was stated,
"Available studies indicate that occupational exposure to
cadmium in some form (possibly the oxide) increases the
risk of prostate cancer in man. In addition, one of these
studies suggests an increased risk of respiratory tract cancer."
Intensified studies on groups of humans exposed occupationally
or through food are fully motivated by the data at hand.
8.4 Genetic effects
Data on genetic effects are scarce. One study on Itai-itai
patients did show some chromosome aberrations (Shiraishi et al.,
1972) while another one did not show any such effects (Bui et
al., 1975). In exposed workers, Bui et al. (1975) did not find
any chromosome anomalies, whereas Deknudt and Leonard (1975)
found a significant increase in anomalies. In mice examined
3 months after a single interperitoneal injection of 1.75 mg
Cd/kg, no chromosome abnormalities were found (Gilliavod and
Leonard, 1975).
Doyle et al. (1974) exposed lambs to cadmium via feed (60 ug
Cd/kg) for 191 days. They found a significant increase in ex-
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treme hypodiploidy, but did not look for chromosome aberra-
tions. Available data thus do not show any consistent pattern
but clearly indicate a need for further research.
8.5 Teratogenic effects
In animal experiments teratogenic effects have been shown
after single injections of high doses (3 mg Cd/kg or more)
to pregnant golden hamsters or rats. Effects include cleft
lips and palates and limb defects (Perm and Carpenter, 1968;
Friberg et al., 1975}. Schroeder and Mitchener (1971) found
teratogenic effects after long-term exposure to 10 mg cadmium/1
in double deionized water. The mice were followed for three
generations and congenital abnormalities, including sharp
angulation of the distal third of the tail, were observed
in several litters. Such effects may be caused by zinc deficiency
due to the retention of zinc in the mothers (Friberg et al.,
1974) .
No reports on teratogenic effects in cadmium-exposed humans
have come to the fore. In a study on cadmium-exposed women in
the U.S.S.R., malformations were not seen in the newborns but
birth weights were lower than in newborns of controls and a
few cases of rachitis were seen (Cvetkova, 1970).
8.6 Interaction between cadmium and other metals;
biochemical observations
Animal experiments have shown that some effects of cadmium may
be prevented by the simultaneous administration of other metals.
For example, cadmium-induced acute testicular necrosis can be
prevented by administration of zinc, cobalt or selenium.
Hypertension elicited by cadmium in rats', may be reversed by
administration of zinc chelates. Cd-Zn interactions are thought
to be of special importance in cadmium toxicity. A biochemical
explanation is offered by the replacement of zinc by cadmium
in zinc-dependent enzymes. Cadmium causes a redistribution of
zinc, more zinc being stored in liver and kidneys and less _.'
some other organs, which also may affect some essential functions,
This behavior of cadmium is believed to play a role for other
manifestations of cadmium toxicity in addition to those mentioned
above (Friberg et al., 1974, 1975).
143
-------
A biochemical phenomenon that has been studied in relation to
cadmium-induced organ damage is the binding of cadmium and zinc
to metallothionein. The role of this low molecular weight protein
in transport and distribution has already been alluded to. In
addition it seems that the binding of cadmium to this protein is
inversely related to the occurrence of acute effects of cadmium,
e.g. testicular necrosis (Nordberg, 1972).
Metallothionein thus seems to play a dual role in cadmium
toxicity. On the one hand it acts as a detoxification agent
against the acute effects of cadmium and as a "normal"
storage protein for cadmium but on the other hand it may be
involved in the elicitation of the critical chronic effects
of cadmium on the kidney (Nordberg et al., 1975).
In normal human beings the increase in cadmium in the renal
cortex with age is accompanied by an equimolar increase in
zinc. This is thought to be due to the metallothionein stored
in the kidney, which contains equimolar amounts of the two
metals (Piscator and Lind, 1972) .
9. Dose-response relationships
9.1 Based on critical concentration in the kidney
and a metabolic model
Information about morphological changes, proteinuria and cadmium
levels in kidneys of human beings is available from about 30
autopsies and biopsies from persons exposed to cadmium. It is
not possible to establish 3. detailed dose-response curve with
this limited amount of data at hand. In persons with no renal
changes or only slight changes in tubular function cadmium levels
in kidney cortex with one exception varied between 150 and
450 mg/kg wet weight (Friberg et al., 1974).
Animal data provide much evidence that tubular dysfunction
and/or morphological kidney changes occur at kidney cortex
concentrations of 200-400 mg/kg wet weight (Bonnell et al.,
1960; Axelsson et al., 1968; Stowe et al., 1972; Nomiyama
et al., 1976; Kawai et al., 1974). Some data speak in favor
144
-------
of an effect at even lower concentrations (Piscator and
Larsson, 1972; Kawai et al., 1976).
Friberg et al. (1974) when evaluating human and animal data,
concluded that the critical level in the kidney cortex of
the more sensitive part of the population should be about
200 mg/kg. A WHO group has concluded that the critical level
may be between 100 and 300 mg/kg, with 200 mg/kg as the most
likely estimate (WHO, 1977).
Using a metabolic model and assuming a critical concentration
of 200 mg/kg wet weight in kidney cortex, calculations of
exposure situations giving rise to this concentration can
be worked out and have been presented by Friberg et al. (1974).
Data for industrial exposure and exposure via food are given
in Tables 1 and 2 respectively. Different assumptions concerning
the biological half-time have been used. If the biological
half-time is set at 19 years and the pulmonary absorption
at 25 %, it can be calculated that a cadmium concentration
3
in inhaled air of 13 ug/m under industrial exposure conditions
(ventilation 10 m per day during an 8-hour workday, 225
workdays per year) would give rise to the critical renal
cortex values after 25 years of exposure. With a biological
half-time of 38 years the corresponding value would be 11
3
ug/m . The necessary daily cadmium intake via food for an
adult, caloric intake - 2,500 calories - to reach the critical
concentration at age 50 would be 350 ,ug/day or 250 ug per
day under the assumption of a biological half-time of 19
years and 38 years/respectively.
9.2 Based on direct observations of dose and effect
Data from industrial exposure (Bonnell, 1955; Bonnell et
al., 1959; Harada, 1973; Harada, 1974; Friberg et al., 1974;
Lauwerys et al., 1974; Kjellstrom et al., 1977) may favor
the assumption that 50 ug/m gives rise to up to 50 % prevalence
of cadmium induced tubular proteinuria after prolonged exposure.
These data are very uncertain.
Increasing prevalence of proteinuria and glucosuria in relation
to dose has been reported from Japan. Dose in Japan is often
145
-------
estimated from the cadmium concentration in rice. From the data
by Fukushima et al. (1973), it can be estimated that an increase
in this concentration from about the one found in non-polluted
areas: 0.05 mg Cd/kg (wet weight) to 0.5 mg Cd/kg would increase
the prevalence of concurrent proteinuria and glucosuria among
people over 50 years of age from about 5 % to about 20 %. This
estimation is supported by results obtained by Kjellstrom et al.
(1977).
Comparisons between polluted and control areas show statistically
significant differences in prevalence of proteinuria in at least
four different areas, but the epidemiological methodology is
often not designed for dose-response studies. It has been
concluded, however (Friberg et al., 1974, 1975), that somewhere
between 0.4 and 0.6 mg Cd/kg in rice the exposure would be
so high as to induce tubular proteinuria in a significant
part of a population. These figures correspond to a daily
intake of about 0.24-0.36 mg. Similar estimates have been
made by a WHO expert group which concluded that cadmium con-
centrations in rice of 0.5-0.8 mg/kg caused an increase in
the prevalence of tubular proteinuria, corresponding to a
daily intake of 0.30-0.48 mg. An estimate based on the fecal
excretion of cadmium showed that about 0.20 mg per day could
cause the increase in the prevalence of proteinuria (WHO,
1977) .
The figures thus are in fairly good agreement with the figures
reached when using the metabolic model for cadmium and starting
from a critical kidney cortex concentration of 200 mg/kg wet weight.
10. Diagnosis, prognosis and treatment of cadmium poisoning
10.1 Acute poisoning
10.1.1 Inhalation
10.1.1.1 Diagnosis
Acute cadmium intoxication should be suspected when respiratory
symptoms occur suddenly in welders. The welder himself may
not be aware of having worked with cadmium-containing material.
The diagnosis in such cases rests upon identification of cad-
146
-------
mium related exposure. Amounts of cadmium involved are relatively
small. It is not certain that blood values will be clearly
above normal limits, but confirmation by cadmium analyses
of blood should be attempted. Such analyses should preferably
be done as soon as possible after exposure and repeated at
intervals.
10.1.1.2 Treatment and prognosis
Results from animal experiments (MacFarland, 1960) indicate
that treatment with adequate doses of BAL as soon as possible
after exposure may be beneficial in acute cadmium poisoning.
Such treatment should be given under careful observations of
signs of renal complications (including tests for proteinuria,
indicating renal tubular damage) since BAL is likely to trans-
locate cadmium from pulmonary to renal tissues. In workers
with previous long-term exposure to cadmium, BAL should not
be given since renal damage is likely to be precipitated thereby.
In addition it is evident that general symptomatic treatment
of respiratory insufficiency should be included.
Prognosis after regression of the acute symptoms is usually
good but an incapacitating pulmonary disease may remain for
years.
10.1.2 Ingestion
This type of acute cadmium poisoning should be suspected when-
ever the symptoms mentioned in section 8.1.1 arise. What is
indicative is the generally very short interval between ingestion
of contaminated food or drink and vomiting. Treatment is sympto-
matic and prognosis usually good when the acute symptoms have
subsided. Complications are not known, but no follow-up studies
have been reported.
10.2 Chronic poisoning
10.2.1 Diagnosis
10.2.1.1 General aspects
The diagnosis of chronic cadmium poisoning rests on identifica-
tion of long-term cadmium exposure and symptoms (see section
147
-------
8). Appropriate spirometric and other investigations should
be performed to identify signs of emphysema. Blood chemistry
and even bone biopsy may be necessary together with appropriate
X-ray investigations for diagnosis of cadmium-related osteo-
malacia.
10.2.1.2 Tubular proteinuria
Since there are no accurate means of predicting renal burdens
of cadmium/ it is of utmost importance to use reliable methods
to detect early changes in protein excretion, since cessation
of exposure at that stage may prevent more extensive damage.
Qualitative tests, using trichloracetic acid or sulfosalicyiic
acid, are useful for detecting a fully developed proteinuria.
Test tapes are not sensitive enough. Quantitative determination
of urinary protein is not always sufficient, since the excretion
of some low molecular weight proteins might be increased con-
siderably while the total protein is still within the normal
range (Piscator, 1972). Electrophoretic separation of concen-
trated urinary proteins makes it possible to detect small
changes in the distribution of proteins, but also has its
limitations. Accurate quantitative determination of small in-
creases in the urine of certain low molecular weight proteins,
e.g. $2-:microglobulin, is possible and has recently been intro-
duced in the routine control of cadmium workers. This method
also has its limitations in that the excretions may vary with
the pH of the urine. The general status of the renal handling
of proteins is not revealed by this method. A combination
of determination of total protein, 32~microglobulin and electro-
phoretic separation is probably the best way to obtain an
accurate estimate of renal status (Piscator, 1972 ). In more
advanced cases, diagnosis is easily obtained by electrophoretic
methods, as shown in Figure 5.
10.2.1.2 Cadmium determinations in blood and urine
As discussed in section 7, there are not any good means of es-
timating renal cadmium accumulation based on urine or blood
concentrations of cadmium. However, such determinations may
be helpful in diagnosis. In long-term low level exposure a
148
-------
urinary cadmium concentration above 10 ug/1 or 10 mg/kg
creatinine generally signals impending or actual renal tubular
impairment. A blood value above 10/ug/1 tells us that cadmium
exposure of a significant degree has taken place. It is not
always possible to gauge the risk for renal damage on the basis
of the blood values.
10.2.2 Treatment
Some chelating agents like EDTA can cause a redistribution of
cadmium in the body so as to increase renal accumulation of
cadmium. The use of chelating agents therefore should be warned
against, since they might cause the renal dysfunction to undergo
further impairment (Friberg, 1956; Friberg et al., 1974).
In cases of manifest tubular damage with disturbances in min-
eral metabolism, treatment should be directed against the metabol-
ic disturbance, e.g. therapy with phosphates could be tried. In
cases of Itai-itai disease, large doses of vitamin D have been
administered/ bringing about a slow healing of fractures and
relief from pain. Of importance in these cases is that the
patient has an adequate supply of calcium and phosphate in
his diet for restoring lost mineral content of bones. Of general
importance both from preventive and therapeutic aspects is
an adequate intake of zinc and protein.
10.2.3 Prognosis
The prognosis in patients with a slight or moderate isolated
renal tubular disorder without emphysema and without complications
such as osteomalacia generally is favorable with regard to
survival. However, only a few follow-up studies of people with
cadmium intoxication have been reported. Mortality figures
for workers with fully developed cadmium intoxication in the
1940"s in an alkaline accumulator industry show that emphysema
and kidney damage are not at all harmless from the standpoint
of survival time (Friberg et al., 1974). These workers had
a significant overmortality in relation to expected mortality
among Swedish men (Figure 6). The exposure in the 1940's was
3
excessive, however, probably now and then several mg/m . Workers
examined in the early study and some other workers not so heav-
149
-------
ily exposed were examined in a follow-up study about 10 years
after the original examination. It was then shown that persons
in whom proteinuria had been established in the first examina-
tion still had this damage, despite their having been removed
from cadmium exposure.
150
-------
Table 1. Cadmium concentration in industrial air ( ,ug/m )
necessary for exposed workers to reach the critical
concentration (200 mg Cd/kg wet weight) in renal
cortex under different absorption, excretion and
exposure time alternatives. Ventilation = 10 m
during an 8-hour workday, 224 workdays per year
(From Friberg et al., 1974).
Excretion per day, percent of body
burden (corresponding biological
Pulmonary Exposure half-time in
absorption time in ~ ,. _02
percent years , . (9S}
10
25 25
50
21.
8.
4.
3
5
3
22.
9.
5.
1
3
1
years in
0.005
(38)
23
10
6
.3
.6
.5
parenthesis)
0.01 0.02
(19) (9.5)
25
13
9
.4
.0
.3
30
18
16
.0
.6
.0
50
10
25
50
10.7 11.1 11.7 12.7 15.0
4.3 4.7 5.3 6.5 9.3
2.2 2.6 3.3 4.7 8.0
151
-------
Table 2. Necessary daily cadmium intake from food for an adult
(daily calorie intake = 2,500 cal) to reach critical
concentration (200 mg/kg wet weight) in renal cortex
at age 50 along with the necessary cadmium concentra-
tion in a basic foodstuff to reach these cadmium in-
takes* (From Friberg et al., 1974).
Excretion per day, percent of body
burden (corresponding biological
half-time in years in parenthesis)
0 0.002 0.005 0.01 0.02
(~) (95) (38) (19) (9.5)
Cadmium intake 164 196 248 352 616
Cadmium concentration
in basic foodstuff
mg/kg wet weight 0.27 0.33 0.41 0.59 1.03
* Assumptions:
a) 1/2 of the daily cadmium intake from this foodstuff
b) 300 g of this foodstuff ingested daily
c) 5% absorption of ingested cadmium
152
-------
Cadmium in renal cortex
mg/kg wet weight
•':*
I East Germany, women
II U.S.A., both sexes
III East Germany, men
IV Sweden, men
V U.S.A., men
VI U.S.A.
VII Kobe, Japan
VIII Kanazawa, Japan
IX Tokyo, Japan
Figure 1.
Cadmium concentrations in renal cortex from normal
human beings in different age groups. Linear
scale (From Friberg et al., 1974).
153
-------
Cadmium in liver
mg/kg wet weight
Figure 2.
Cadmium concentrations in liver from normal human
beings in different age groups (mean values),
exposed workers (single values), and Itai-itai
patients (single values) (From Friberg et al.,
1974) .
154
-------
Figure 3.
Average cadmium concentration in urine within
different age groups in Tokyo (From Tsuchiya
et al., 1972).
155
-------
M9 Cd/g
wet weight in
kidney cortex
100 -
75-
50-
25-
0.005%
0.01%
0.02%
0.05*
10
20 30 40 50
60
70 80age
Figure 4 .
Calculated cadmium concentrations in kidney
cortex by age for different body burden excretion
alternatives. Adjusted for variation in calorie
intake and kidney weight by age, except dotted
line (From Friberg et al., 1974).
156
-------
B
Alb.
Figure 5 .
Scanned electrophoretic patterns for urinary
proteins - A and B. Cadmium workers; C. normal
man; D. person with chronic nethritis. The
prominent 3-fraction in A and B is mainly com-
posed of 3 --microglobulin and some other 3-
proteins, whereas transferrin constitutes only
a minor part of the 3-fraction (From Piscator,
1966) .
157
-------
Figure 6.
Observed and expected mortality of 19 Swedish
cadmium workers with very high exposure to cad-
mium at different times after the first clinical
investigation in 1947 (From Friberg et al.,
1974) .
158
-------
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163
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CHROMIUM
Sverre Langird and Tor Norseth
1. Abstract
In nature most chromium is found in the trivalent state as chromite
ore. Bichromate (Cr ) is produced from chromite ore and the
further uses of dichromates and monochromates in the chemical
industry are important from an occupational health standpoint.
Chromium in the hexavalent state is more easily absorbed both via
lungs and gastrointestinal tract than in the trivalent state.
Chromium is found in all organs of the newborn and of adults,
the highest concentration in the latter usually being found in
lung tissue. An accumulation of chromium with age takes place
in the lung as a result of deposition from inhaled air. In all
other organs the concentration of chromium decreases with age.
Chromium is predominantly excreted in the urine. An exponential
character of the excretion with three different half-times of
0.5, 5.9 and 83.4 days has been described in rats.
Chromium is an essential metal in man and in animals and plays
an important role in insulin metabolism as the glucose tolerance
factor. The daily requirement of chromium in human nutrition
has not been established. In man the daily diet is the main
source for chromium intake. Small quantities are found in municipal
drinking water and in ambient air.
Both acute and chronic adverse effects of chromium are mainly
caused by hexavalent compounds which are very toxic to man. There
is little conclusive evidence on toxic effects caused by divalent
and trivalent chromium compounds. Depending on concentration and
exposure time, hexavalent compounds may cause skin ulcerations,
irritative dermatitis, allergic skin reactions and allergic asthmatic
reactions. Hexavalent chromium may also cause ulcerations in the
mucous membranes and perforation of the nasal septum.
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Inhalation of hexavalent chromium compounds may cause bronchial
carcinomas, lung fibrosis and pneumoconiosis. The ability of
hexavalent chromium compounds to induce bronchiogenic cancer
in humans is well established. However, animal experiments
with chromates have not been able to identify the specific
hexavalent compound or compounds of most pronounced activity.
Hexavalent chromium compounds have been found to induce
adenocarcinomas, but not bronchiogenic carcinomas in the lung
of experimental animals. Local sarcomas in muscles and local
carcinomas of the skin have also been demonstrated. Hexavalent
chromium compounds also seem to be mutagenic.
The largest human exposures in the general population are
via food. No adverse effects have been reported from such
exposures.
The medical and biological effects of chromium have recently
been reviewed (Chromium, 1974j Effects of Chromium in the
Canadian Environment, 1976). The occupational exposure to
chromic acid has been specifically reviewed (NIOSH, 1973),
as have the exposure to hexavalent chromium (NIOSH, 1975)
and the carcinogenic effect (IARC, 1973).
2. Physical and chemical properties
Chromium, Cr, atomic weight 52; atomic number 24; density
7.2; melting point 1857+20°C; boiling point 2672°C; crystalline
form steel gray, cubic, very hard; oxidation state chiefly
2,3,6.
Besides the naturally occurring ferrous chromite, chromium
compounds taken up in this chapter include lead or barium
chromate, and sodium or potassium chromate or dichromate,
chromium acetate, chromium citrate, chromic chloride, chromic
acid mist, zinc chromate, calcium chromate and strontium
chromate.
The relatively unstable divalent (chromous) ion is rapidly
oxidized to the trivalent (chromic) form. Hexavalent chromium
compounds (chromates) are oxidizing agents. Reduction of the
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hexavalent form to the trivalent may be of importance for
the toxicity of chromium compounds.
Chromium in biological materials is probably always trivalent.
For example, the so-called glucose tolerance factor, which has
not been fully identified, is a trivalent chromium complex with
niacin (Mertz, 1975). Other chromium complexes which biochemically
meet some of r.ho requirements of the glucose tolerance factor
have been synthesized. No organic chromium complexes of toxicolo-
gical importance have been described.
3. Methods and problems of analysis
Several methods are available for the analytical determination
of chromium in biological material in the range of interest
(lO-lOOO/ug/l), but it is not possible today to generalize
as to the best method. Methods for the analytical determination
of chromium have been evaluated by Beyermann (1962a, 1962b) and
a review of the literature on chromium analysis has been given
in Chromium (1974).
The traditional colorimetric method employing the violet complex
of 1,5 diphenylcarbazide is still a valuable method for analyzing
chromium in urine. The detection limit is 3.5 ng but the method
is subject to interference by other ions (Beyermann, 1962a, 1962b).
Flame photometry, X-ray emission spectrography and polarography are
less sensitive than the diphenylcarbazide method. Polarographic
methods with a detection limit as low as 1 ng have been described,
but these are also subject to interference by other ions (Beyermann,
1962a, 1962b). Neutron activation does not at present seem to
offer special advantages for chromium analysis in biological
materials but has been used for the determination of chromium
in urine (Cornelis et al., 1975). A gas liquid chromatographic
method with a detection limit of 0.01 ng for chromium has been
described, but the practical experience (Sievers et al., 1967)
with the method is limited to date. Atomic absorption spectro-
photometry with a flameless technique was reported to have a
detection limit of 0.0125,ug (Grafflage et al., 1974).
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Separate determination of trivalent and hexavalent chromium is
possible by analyzing the sample before and after oxidizing the
trivalent to the hexavalent form. Only the hexavalent form is
determined both by the colorimetric 1,5 diphenylcarbazide method
and by atomic absorption methods if organic extraction is used
to concentrate the sample (Mertz, 1969). Variables not controlled
in ordinary extraction and mineralization procedures are introduced
when chromium is bound to organic compounds as in the glucose
tolerance factor. Methodological problems have caused some
disagreement as to the valence state of chromium in biological
materials, but most probably only the trivalent form is present
(Mertz, 1969).
4. Production and uses
4.1 Production
The only important chromium ore is chromite, FeOCr-O.,, which is
never found in pure form. FeO may be replaced with some MgO, and
the mineral also contains silica in varying amounts, as well as
small quantities of other compounds. The highest grade of ore
contains about 55% chromic oxide. Both trivalent and hexavalent
chromium are found in nature, but the trivalent is the more common
form.
The world production of chromite in 1971 was about 7 million tons,
the USSR (about 2 million tons) and the Republic of South Africa
(about 1.8 million tons) being the main producers (Morning, 1971).
Ferrochromium is produced by direct reduction of the ore. Chromium
metal is produced either electrolytically after chemical treat-
ment of high carbon ferrochromium, or by reduction of chromium
compounds.
Sodium chromate and dichromate are produced by roasting chromite
ore with soda ash, or with soda ash and lime, followed by chemical
treatment for removing impurities. Most other chromium compounds
are produced from sodium chromate or dichromate.
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4.2 Uses
The principal industrial consumers of chromium are the metallurgical,
refractory and chemical industries. The US 1971 figures for
consumption by these industries were 66%, 18% and 16%, respect-
ively, of the total consumption (Morning, 1971).
An important consumer of chromium for many years has been the
tanning industry. Other uses are in pigment production and
application, the graphics industry and industries using chromium
alloys or plated materials. Ferrochromium and chromium metal
are the most important classes of chromium used in the alloy
industry.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food, total daily intake
The daily intake of chromium from food has been estimated to
be in the range of 0.03 to 0.1 mg (Schlettwein-Gsell and
Mommsen-Straub, 1973). Since other sources contribute only
minor amounts in relation to these values they represent also
an estimate of the total daily intake of chromium for the
general population. Food items vary considerably in concen-
tration of chromium. Among large sources are meat, vegetables
and unrefined sugar, while fish, vegetable oil and fruits
contain smaller amounts. Values are reported from non-detect-
able to about 0.5 rag/kg wet //eight for various food items.
The glucose tolerance factor is predominantly found in yeast,
liver and meats. Of all forms of chromium, this has the
highest biological availability to man.
5.1.2 Water, soil, ambient air and cigarettes
The chromium concentration in rivers and lakes is usually
between 1 and 10 ,ug/l, that in seawater being considerably
less, from < 0.1 to about 0.5 ,ug/l (Chromium, 1974). Muni-
cipal drinking water has been reported to contain higher
amounts of chromium than river water.
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Soil content ranges from trace to 250 mg/kg with occasionally
higher values. The average chromium concentration in the earth's
crust is 125 mg/kg. Chromium in phosphates used as fertilizers
raay be an important source of chromium in soil, in water, and
in some foods.
Urban air concentrations of chromium have been reported from
less than 10 ng/m up to about 50 ng/m . Annual mean values
for rural stations seldom reached 10 ng/m (Chromium, 1974).
Cigarettes have been reported to contain 390 /ug/kg of chromium
(Schroeder et al., 1962), but no estimates of the inhaled amount
from smoking have been published.
5.2 Working environment
Potentially hazardous exposures are incurred in the production
of dichromate, in the use of chromates in the chemical industry,
in the stainless steel industry, in the production and use of
alloys, in refractory work, and in the chromium plating industry.
In the last mentioned industry, the health hazard is related to
the chromium-containing mist. Chromium exposure in welders may
constitute a health hazard, both because chromium is an important
constituent in stainless and acid stable steel, and because
chromate is extensively used in anticorrosive paints (Ruf,
1970; Gylseth et al., 1977).
Chromium levels in industry have been reported to only a limited
degree. Mancuso (1951) reported exposure levels up to 1 mg/m of
chromium in a chromate plant. Most values were in the range of
0.26 to 0.51 mg/m . A five-day, eight-hour mean value of 1.35
rug/m of chromates in air was reported for a sack-filling opera-
tion in an old chromate plant by Langard and Norseth (1975);
in another, modern plant levels were below 0.1 mg/m . Most
chromium values recorded by personal sampling during 8 hours
in a ferrochromium plant were in the range of 0.02 to 0.05 mg/m ,
but occasional values were up to 0.4 mg/m (Gylseth and 0ien,
1975). In a recent review a chromium exposure up to about 5
mg/m in the chromium plating industry was mentioned, but most
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exposure levels reported were in the range of 0.1 to
0.2 mg/m3 (NIOSH, 1973).
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
There are very few reports on absorption of chromium compounds
after inhalar.ion. The high concentrations of chromium found
in lung tissue of humans exposed to chromium indicate that at
least part of the chromium is deposited in the pulmonary
tissue in an insoluble form. From the fact that hexavalent
chromium compounds are more soluble it may be assumed that
these compounds are more easily absorbed than the trivalent
ones.
Laskin and Isloa (1972) studied the retention of chromium in
the lungs in animals for 48 hours following 6 hours of
inhalation. Neither dose levels, chromium compound, nor
animal species were given. Urinary excretion of chromium
increased for the first 6 hours, then gradually decreased.
Fecal excretion of chromium also increased. Exposure to
welding smoke from stainless steel containing from 18 to 26%
chromium resulted in high after-shift urinary excretion of
chromium indicating rapid absorption (Gylseth et al., 1977).
A correlation between exposure to chromium and the urinary
excretion of chromium was demonstrated.
6.1.2 Ingestion
Animal experiments indicate that trivalent chromium is
poorly absorbed from the gastrointestinal tract, values less
than 1% of an oral dose having been reported (Mertz, 1969).
Chromates are absorbed at 3-6% in rats (Mertz et al., 1965),
and about 2% in man (Donaldson and Barreras, 1966). There is
evidence that not only the valence state of chromium in the
diet but also the functional state of the intestines has
bearing on absorption since the balance between trivalent
and hexavalent chromium may be altered (Donaldson and Barreras,
1966). Increased absorption of hexavalent chromium has been
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observed in achylic patients, probably due to an absence of
reduction induced by sodium chloride. These absorption
values, which are based on urinary excretion after oral
administration, may be underestimated as the gastrointesti-
nal tract also takes part in chromium excretion (Hopkins,
1965) .
Based on a normal urinary excretion of 2 - 10 ,ug/l of chromium
and a aaily intake of 30 - 100/ug, an absorption of 10% or more
cf cnromium naturally occurring in food must be assumed. These
values probably reflect the higher absorption of the chromium
as the glucose tolerance factor.
6.2 Distribution
The distribution of chromium in the rat is dependent on the
chromium compound in question (Kraintz and Talmage, 1952;
\isek et al., 1953; Hopkins, 1965). All chemical forms except
chroiuates clear rapidly from the blood. Trivalent chromium
acetate or citrate are also rapidly excreted, whereas the
tissue concentrations after corresponding doses of chromic
chloride or chromates are higher at the same time intervals.
Organs which specifically retained chromium in experiments with
aose levels of 60 - 250 ,ug/animal were the reticuloendothelial
system, the liver, the spleen and the bone marrow (Visek et
al., 1953). Hopkins (1965) reported retention of chromium in
the bone marrow, the spleen, the testes and in the epidydimis
after injection of chromium to the rat, but the dose levels
were 10 and 1 ,ug/kg rat weight. The organ retention of chromium
after chromate injection to mice decreases with the age of
the animal (Vittorio et al., 1962).
After administration of chromium as the glucose tolerance
factor, the distribution is different as the highest concen-
tration was found in the liver, followed by the uterus and
the kidney (Mertz and Roginski, 1971; Hertz, 1975).
Chromium is found in the newborn and in the fetus. High natural.
chromium content in the mother's diet increases the chromium
content in the fetus (Mertz, 1975). Transplacental transfer of
chromium as the glucose tolerance factor has been demonstrated
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(Visek et al., 1953; Mertz et al.7 1969), and Diab and Sjzfrenmark
(1972) demonstrated transplacental transfer of chromic chloride
in mice using a radiographic method.
6.3 Excretion and biological half-time
Once absorbed and bound in biological tissue chromium compounds
are found in the trivalent form (Mertz, 1969). All excretion
mechanisms and figures given are therefore related to this
chemical forn.
After parenteral administration to rats chromium is excreted
predominantly in the urine. Hopkins (1965) found less than 2%
of an intravenous dose in the feces 8 hours after the injec-
tion. Visek et al. <1953) found less than 20% after 4 days.
Studies on the mechanism of chromium excretion by the kidneys
indicate glomerular filtration followed by tubular reabsorption
of up to about 60% of the filtered amount (Collins et al., 1961).
The site of the gastrointestinal excretion of chromium is not
known, nor is the importance of biliary excretion (Hopkins, 1965)
The fecal content of chromium may vary considerably and is
mainly a consequence of ingested unabsorbed chromium compounds.
The elimination curve for chromium as measured by whole body
counting has an exponential character. In rats three different
components of the curve have been identified with the half-times
of 0.5, 5.9 and 83.4 days, respectively (Mertz et al., 1965).
In human kinetic studies to evaluate red cell life time, a
rapid excretion component related to non-erythrocyte chromium
has been identified. Chromium used for labelling of erythrocytes
is almost exclusively excreted in the urine. Kinetic studies
of this rapid component have not been reported, and half-time
is only given for chromium representing the red cell compart-
ment (Shin et al., 1972). The kinetics of excretion of chromium
as the glucose tolerance factor is not known.
7. Normal levels in tissues and biological fluids
The highest concentration of chromium in humans is found in
hair, values from 200 to 2000,ug/kg having been reported
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(Mertz, 1969). Schroeder et al. (1962) reported about 700 ug/ky
of chromium in the lung in persons in the New York/Chicago area,
other organs having lower concentrations, liver 270,ug/kg and
kidney 90,ug/kg. There are geographical variations in chromium
concentration as the values from the Denver area were 140 ,ug/kg
for the lung, 30 ,ug/kg for the liver and 40 .ug/kg for the kidney.
A high concentration of chromium in the lung and a lower concen-
tration in other organs were confirmed by Tipton and Cook (1963,
1965) jjotli in the US ana in other parts of the world.
The concentration of chromium in blood has been reported to be
20-30 ,ug/l with an even distribution between red cells and
plasma (Feldman et al., 1967). Upon occupational exposure, the
increase in blood value relates mainly to the red cells (Baetjer
et al., 1959b).
A normal urinary excretion of chromium of up to about 10 ,ug/day
has been assumed (Cornelis et al., 1975; Mertz, 1975).
The chromium concentration in all tissues decreases from birth
to the age of about 10 years. After this time there is a slight
increase in lung concentration, but a continuing fall in all other
organs (Schroeder et al., 1962). This indicates that chromium
in the lungs is a result of deposition from inhaled air, whereas
chromium in food is the main source of chromium in other organs.
8. Effects and dose-response relationships
Chromium is considered essential for the maintenance of normal
glucose tolerance in experimental animals and in man. Chromium
as the glucose tolerance factor may have a role as cofactor for
the initiation of peripheral insulin action. The exact structure
of the glucose tolerance factor is not known. A complex of triva-
lent chromium and niacin has been suggested, but other sy.v-_ ., ; .
chromium compounds also meet some of the criteria for esse.-.^ a
Chromium deficiency has been described in three animal species
and in man, but a quantitative definition of the daily
requirement of chromium in human nutrition has not been
formulated (Mertz, 1975).
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8.1 Local effects and dose-response relationships
8.1.1 Animals
Though many reports on local effects in humans have been pres-
ented, few experiments have verified these effects in laboratory
animals.
Samitz and Epstein (1962) induced chromic ulcers in guinea pigs
through application of various hexavalent compounds to the skin.
They also demonstrated that a local skin defect is a prerequisite
for the development of chrome ulcers. Mosinger and Fiorentini
(1954) induced skin ulcers in different animals through applica-
tion of potassium chromate to the skin. Rajka et al. (1955)
produced dermatitis in guinea pigs.
"Bronchiolization" of alveoli (i.e. lining of alveolar walls
by cells resembling bronchial epithelium) has been observed by
different authors exposing animals to chromates (Nettesheim
et al., 1971).
8.1.2 Humans
8.1.2.1 Chromic ulcers
Generally, chromic ulcers are induced by the corrosive action
of hexavalent chromium. In the case of tannery workers, however,
the skin ulcers may be due to chromic compounds (Maloof, 1955).
When chromic acid, dichromate compounds or other hexavalent
chromium compounds are deposited on the broken skin, a deeply
penetrating round hole may develop (Dewirtz, 1929). Favored
sites for ulcer development are the nailroot areas, over the
knuckles and fingerwebs, on the back of the hands, and on the
forearm (Maloof, 1955). Sometimes these ulcers are described
as painful, but most of them are painless. Severe ulcerative
changes penetrating to joints have been described. The ulcer
heals slowly and may persist for months. The ulcer does not
seem to bear any relationship to the development of allergic
sensitization to chromium compounds (Edmundson, 1951).
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6.1.2.2 Acute irritative dermatitis
This disease may be observed in the chromium industry, particular-
iy in workers coming in contact with hexavalent chromium compounds
This dermatitic reaction seems to become less prominent by re-
newed contacts. It must be differentiated from the allergic
eczematous dermatitis.
8.1.2.3 Allergic eczematous dermatitis
This allergic dermatitis was probably seen long before conclus-
ive evidence of chromate sensitivity was given by Engelhardt
and >iayer (1931). Of their workers with dermatitis, 8^% reacted
to the patch test with 0.5% ammonium dichromate. None of their
workers reacted to a trivalent material. Gaul (1953) claimed
that all chromium compounds can cause allergic skin reactions,
but Nater (1962) has given evidence that allergic dermatitis
is related to hexavalent chromium only. Hexavalent chromium
seems to be a strong sensitizer and trivalent chromium a poor
sensitizer and elicitor (Samitz et al., 1969). For the skin
patch test a low concentration (0.5%) of the chromate solution
is chosen, because higher ones may themselves produce acute
dermatitis (Gaul, 1953; Nater, 1962).
Allergic eczematous dermatitis has been described in a variety of
occupations,such as housewives, woodworkers, cement workers and
limestone workers, radio factory workers, painters, polishers,
furriers and others. Long a debated question, the main causal
agent in cement eczema now seems to have been proven to be the
trace of chromate compounds in the cement. Allergic chromium
dermatitis is also widespread in persons without occupational
exposure. Magnusson et al. (1968) reported the patch test,
carried out mostly with an 0.5% solution of potassium dichromate,
to be positive in 3 - 15% of all allergic skin reactions.
These high rates might partly be caused by cross reactions with
other antibodies, but it must be borne in mind that traces of
chromates are ubiquitous. Therefore the hexavalent chromium may
induce allergic reactions unexpectedly.
8.1.2.4 Corrosive reaction in nasal septum
Ulcerations and perforations of the nasal septum in chromate
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workers were described by Delpech and Hillairet (1869) and the
present century has witnessed many reports on this chromium
hazard. The ulcerations and perforations are acquired at work-
places with chromate or dichroiriate dust, or chromic acid mist.
The site of the ulceration is usually about 1.5 - 2 cm from the
anterior and lower margin of the septum, whence it extends
backward and upward (Kleinfeld and Rosso, 1965). The ulceration
seems to be caused by deposition of chromate at this site, where
the mucous membrane is far less vasculated than at other parts
of the septum. As soon as the mucosa is perforated the cartilage
on that side of the septum loses its vascularization and tends
to necrotize. With ulceration on both sides of the septum, local
necrosis of the cartilage will cause perforation of the septum
(Leineberg, 1955).
When exposure to chromates is discontinued before perforation
has developed, the corrosive reaction usually subsides and
the scar becomes crusted with mucus. Since the anterior border
of the septum is never affected, the nose does not become de-
formed. Some workers note a disturbing "whistling" in the nose
and/or an inability to control the liquid flow from the nose.
No reports have been made on spontaneous healing of the estab-
lished perforation.
8.1.2.5 Local effects in the lung
Mancuso and Hueper (1951) described a spotty, moderately severe
but not nodular pneumoconiosib. Sluis-Cremer and du Toit (1968)
have reported fine nodular pnenjnoconiosis, somewhat more radio-
opaque than in simple coalrniner's pneumoconiosis, in a few
chromite workers in South Africa. Therefore, it is possible that
both trivalent and hexavalent chromium compounds might cause
pneumoconiosis.
Princi et al. (1962) reported 4 cases of acute upper respiratory
disease with chest X-rays similar to miliary lung tuberculosis,
the possibility of which was excluded. The true nature of this
toxic effect, which has also been observed by other authors
(Davies, 1974), presently is not clear.
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8.1.2.6 Dose-response relationships
Because development of chromium ulcers seems to be dependent
on a pre-existing local defect in the skin, little can be said
about dose-response relationships. Development of ulcers does
not seem to bear any relationship to atmospheric chromate
concentration, and seems to be dependent on local deposition
of the cnromate compound on the skin.
Easea on the existing literature it is difficult to suggest
any dose-response relationship between local exposure to
hexavalent chromium compounds and development of septal ulcers
and perforations. The present authors have seen septal ulcera--
tion after 2 weeks and perforation after two months of
exposure to approximately 1 mg zinc chromate/m , while we have
not observed any ulcerations or perforations in workers exposed
to 0.02-0.1 mg zinc chromate/m up to 18 months. Kleinfeld and
Rosso (1965) reported perforation in 4 of 9 workers exposed
to chromic acid mist varying from 0.18 to 1.4 mg/m in the
breathing zone. In one of the cases perforation occurred
after one month of exposure.
Sensitization dermatitis appears after variable periods of
exposure to concentrations below those giving rise to primary
irritant action (Klander and Combes, 1955). The dose-response
relationship is therefore difficult to discuss. Pirila (1954)
determined the threshold of hypersensitivity to hexavalent
chromium in 35 persons with sensitivity to chromate compounds.
Using the skin patch test, he found 25 patients with a threshold
at 0.1% dichromate solution, 5 with a higher and 5 with a lower
threshold.
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
As a secondary effect in their chromate studies on mice
Nettesheim et al. (1971) observed increased subepithelial
connective tissue and flattened epithelium in the large bron-
chi. They also observed morphological changes in tracheal ana
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submandibular lymph nodes, atrophy of spleen and liver and
ulcerations in stomach and intestinal mucosa.
Mosinger and Fiorentini (1954) administered potassium chromate
to small animals by various routes, the total doses varying from
2 to 10 mg. The animals were observed from a few days up to a
year. Acute gastritis and enteritis, various parenchymatous
changes in the liver and kidney lesions with destruction of
the epithelial cells of the tubuli were described.
Akatsuka and Fairhall (1934) exposed cats to 80-115 mg/m3
trivalent chromium salts one hour daily for 4 months and fed
another group a diet containing high amounts of chromic salts.
No adverse effects were observed.
8.2.2 Humans
Typical bronchial asthma induced by inhalation of chromate dust
or chromate acid fume has been reported. It seems likely that
the workers are slowly sensitized and that the first symptom
is an irritant cough. All reports mention a time lag of 4 to
8 hours between exposure to hexavalent chromium and the asthmatic
attack. Without treatment the attack will last for 24 to 36
hours. Once the sensitization has taken place, the patient will
react with a new attack upon renewed inhalation of chromates
or upon subcutaneous provocation (Card, 1935; Meyers, 1950).
Broch (1949) reported high incidence of bronchial asthma in
a ferrochromium industry where the workers were exposed to a
mixed dust.
In older literature many descriptions are given of immediate
death following suicidal ingestion of high doses of potassium
dichromate, suggesting a cardiotoxic effect inducing cardiac
arrest. Nephrotoxic effects, described upon ingestion of
smaller doses, possibly represent a tubular necrosis caused
by cardiovascular shock. Liver necrosis has also been described
(Brieger, 1920).
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8.3 Carcinogenic, mutagenxc and teratogenic effects
8.3.1 Animals
Animal experiments have not been very successful in identifying
the compounds which increase the risk of bronchiogenic cancer
so well documented in chromate workers. Hueper (1958) reported
a small number of malignant tumors in rats after intramuscular
and intrapleural administration of roasted chromite ore. Baetjer
et al. (1959a) could not induce bronchiogenic cancers in mice
and rats by daily exposure to 2 mg/m mixed chromate dust in
dust chambers. The animals were exposed four hours per day,
five days per week until they died or were killed. She reported
four cases of lymphosarcomas, but this finding is not confirmed
by any other author. Calcium chromate has been found to induce
injection-site sarcomas in mice (Payne, 1960). After intratrach-
eal administration of calcium chromate and strontium chromate
to rats Hueper and Payne (1962)found three fibrosarcomas at
the end of the second year of observation, the individual
chromate dose being 10-12.5 mg. Nettesheim et al. (1971)
induced adenocarcinomas and adenomas in the bronchial tree
of mice by exposing them to calcium chromate dust at a con-
centration of 13 mg/m in dust chambers for 35 hours per
week during their lifetime. This study is the only one in the
literature demonstrating a carcinogenic effect of a chromate
with inhalation as the route of exposure.
Conclusive evidence for dose-response relationships for the
different carcinogenic chromium compounds in animals can
not be given from the existing literature.
Some reports have been published on mutagenicity of chromates.
In bacterial models Venitt and Levy (1974) have shown that
simple hexavalent chromate salts of sodium, potassium and
calcium work as mutagens. This finding is supported by Nishioka
(1975) using potassium chromates. Transformations of cell
cultures treated with calcium chromate were reported by Fradkin
et al. (1975) .
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Reports on teratogenic effects of chromium have not been
published.
Hexavalent chromium reacts easily with nucleic acids, most
likely bringing about a reduction to trivalent chromium
and complex formation with the nucleic acids. Some nucleic
acids contain high concentrations of chromium and highly
purified RNA fractions contain considerable amounts of
chromium. The function of chromium in RNA is not known, but
it might be of importance for structure stabilizing. Using
BHK fibroblasts Levis and Buttignol (1977) demonstrated
-4
inhibition of DNA synthesis induced by a 10 M concentration
of K?Cr907 and almost complete and irreversible inhibition
of DNA synthesis induced by a 10 M concentration of the same
salt (Levis et al., 1977).
8.3.2 Humans
Newman (1890) reported adenocarcinoma in the inferior turbinate
bone of the nose in a worker who had been involved in chromate
pigment production for 20 years. Lehmann (1932) was the first
to discuss a connection between exposure to chromates and
development of lung cancer. During the 1930's many reports were
published in Germany on this association, and in 1936 the German
health authorities officially recognized lung cancer as a possible
occupational disease associated with chromate dust exposure.
Later many papers have been published in the US (Taylor, 1966),
England (Bidstrup and Case, 1956) and other countries, and in
all approximately 250 "chromate lung cancers" have been re-
ported. Increased incidence of cancer in chromate workers is
reported as late as in 1975 (Langard and Norseth, 1975), the
observed to expected ratio with more than three years of exposure
being 38.
American studies are definitely indicative of highly excessive
lung cancer rates among chromate producers and chrome pigment
makers (Machle and Gregorius, 1948j Mancuso and Hueper, 1951;
Taylor, 1966). Machle and Gregorius observed 193 deaths from
all causes among 1445 workers in factories producing chromates.
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Of the deaths 66 were caused by cancer, 42 of which were lung
cancer.
In a similar plant, Mancuso (1975) reported that 23.7% of
the deaths were caused by lung cancer, lung cancer causing
62.1% of all cancer deaths. Where lung cancer is concerned,
epidemiological studies on occupationally exposed persons
have reported observed/expected ratios from 5 to 40. There
seems to be no doubt that hexavalent chromium plays an import-
ant carcinogenic role in these high figures. Increased incid-
ence of cancer at other sites (Taylor, 1966), particularly
the gastrointestinal tract, has been reported (Enterline,
1974). However, some of these studies do not rule out other
carcinogens as possible additional causes.
In chrornate lung cancers, the highest incidence is at the age
of 50 to 52 years, about 5 years earlier than the highest
incidence of lung cancer in heavy smokers. The time between
the first chromate exposure and the time of diagnoses varies
much from report to report, but a mean seems to be somewhere
between 15 and 17 years (Baetjer, 1950).
Pokrovskaya (1973) reported increased incidence of lung cancer
and cancer at other sites in workers in chromium ferroalloy
production, i.e. in the production of non-hexavalent chromium,
but the workers were also exposed to other carcinogens. Mancuso
(1975) indicated that the carcinogenic effect extends to all
forms of chromium and is directly related to the total amount
of chromium taken into the respiratory system. However, this
study is a cohort study in which the cohorts are not based on
exposure to exclusively trivalent, respectively hexavalent
chromium compounds. There are no studies available today which
conclusively show that chromium compounds other than hexavalent
ones are carcinogenic, although a carcinogenic effect of other
compounds cannot be excluded.
8.4 Biological interactions
In the hexavalent state, chromium is a strong oxidizing agent
and reacts readily with organic materials, leading to a reduc-
181
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tion to the trivalent form. No complexes are known in which
hexavalent chromium can be stabilized against reduction.
All biological interactions of chromates seem to result in
reduction to the trivalent form and coordination to organic
molecules. So far, all the toxic effects of hexavalent chromium
seem to be related to the strong oxidizing action of chromates.
Trivalent chromium may play an important role in the activity
of different enzymatic reactions such as throraboplastic activ-
ity, beta glucuronidase activity and bacterial urease activity.
Indications of interactions of chromium compounds with sub-
stances in cigarette smoke are few. Fisher and Riekert
(1959) mentioned that among 38 chromate producers with lung
cancer only 2 were non'-smokers. Bidstrup and Case (1956) re-
ported that all chromium workers in their study who died from
lung cancer were heavy smokers. They concluded that the increase
of carcinoma of the lung that would be expected if the smoking
habits of their groups differed so much from the general popu-
lation's that all the workers fell into the category of heavy
smokers, would not satisfactorily account for the increase
which they had observed.
9. Preventive measures, diagnosis, jtreatment, and prognosis
Lavage with magnesium carbonate or lead acetate mixed in water
or ingestion of quantities of milk or other emulgations have
been advised in cases of attempted suicide by chromic acid
ingestion.
Acute asthmatic attacks caused by chromates should be treated
like other asthmatic attacks. Persons with an atopic history
should avoid working in the chromate industry. Once an allergic
skin reaction has developed, the person should discontinue his
contact with the chromium-containing agent.
Keeping the chromate concentration in the working atmosphere
below the TLV is the best prevention against the local and
systemic effects of hexavalent chromium. Wearing gloves which
are not too warm is absolutely necessary for workers handling
182
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chromic acid or dichromates. Wounds on the hands and forearms
should be covered. Personal hygiene is very important for
workers exposed even to very low chromate concentrations.
Daily washing of the inside of the nose combined with covering
the nasal septum with zinc or barium ointment should be suf-
ficient to avoid ulcerations and perforation of the septum.
Treatment of chromium ulcers has not been very successful.
Discontinuing the local exposure to hexavalent chromium seems
to allow the ulcer to heal within a few weeks, but persistence
for years has been described. An ointment containing 10% sodium
and calcium EDTA, or a 10% solution of fresh ascorbic acid, seems
to give some protection to the skin.
Some investigators recommend that persons below 35 years of
age not be employed in the chromate industry. As a preventive
measure, X-rays of the lungs yearly or more often have been
advised. Promising results using a three-day "pooled" sputum
cytology test for the early diagnosis of bronchial cancer have
been reported.
183
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COBALT
Carl-Gustav Blinder and Lars Friberg
1. Abstract
Gastrointestinal absorption of cobalt can be estimated to be
about 25%, with wide individual variation; excretion takes
place mainly via the urinary tract. The major part of absorbed
cobalt is excreted within days but a small part, approximately
10%, has a biological half-time of at least a couple of
years.
Cobalt is essential as an integral component of vitamin B-.~.
Addition of cobalt to beer has caused endemic outbreaks of
cardiomyopathy among heavy beer drinkers, resulting in a
number of fatalities. Myocardial degeneration and electro-
cardiographic changes have also been seen in laboratory
animals after repeated intramuscular injections of cobalt.
Industrial exposure has given rise to pneumoconiosis, in
some cases of an invalidating nature. Different pulmonary
defects have also been reported in experimental animals.
In rats cobalt has given rise to sarcoma at the site of
injection and in chicken eggs teratogenic effects have been
seen to result from injection of cobalt.
2. Physical and chemical properties
Cobalt, Co; atomic weight 58.9; atomic number 27; density
8.9; melting point 1495°C; boiling point 2870°C; crystalline
form silver gray metal, cubic; oxidation state 2,3.
Compounds taken up here are cobalt oxide, cobalt tetraoxide,
cobalt chloride, cobalt sulfide and cobalt sulfate.
188
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The pure metal is hard and brittle and has magnetic properties.
3. Methods and problems of analysis
The first methods for analyzing cobalt in biological materials,
which were introduced during the 1940's, were colorimetric.
Detection limits of 0.1 mg Co in 20 1 of blood and 0.05-0.10
rr,g/l in blood have been reported for two respective colorimetric
methods (Stone, 1965; Hubbard et al., 1966).
During the 1960's emission spectrographs, polarographs, X-
ray fluorescence and atomic absorption spectrophotometry
were introduced. Employing AAS, Fishman and Midgett (1967)
gave a detection limit of 0.05 mg/1 in water, and Sachdev et
al. (1967) 0.03 mg/1. Using sequential extraction of cobalt
from samples with low concentrations, Delves et al. (1971)
increased the sensitivity several-fold. A neutron activation
method described by Cornells et al. (1975) could detect
cobalt in urine in concentrations below 0.5/ug/l.
No data on the accuracy of methods for the determination of
cobalt in body tissues and fluids are available.
4. Production and uses
4.1 Production
Cobalt is a relatively rare element composing about 0.001%
of the earth's crust. The most important minerals are arsenites,
i.e. smaltites, cobaltite, sulfides and oxides (Stokinger
and Wagner, 1958; Kaplun, 1963) .
The consumption of cobalt and its compounds has greatly in-
creased in recent years, at a rate of about 5% per year. In
1972 the world production was 203,000 tons (Corrick, 1972).
That same year, the Republic of Zaire produced 56% of the
annual mine output, followed by Zambia with about 5%.
4.2 Us_es
The manufacture of cobalt-blue colored pottery and glass
189
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antedates the Christian era, but it was not until the 20th
century that cobalt was introduced as an alloy. Advantages
of cobalt alloys are high melting point, strength and resistance
to oxidation. In 1971 about three-fourths of the U.S.
consumption of cobalt was in the production of steel and
alloys (Corrick, 1972) . The remaining one-fourth went to
salts and driers.
A marginal part of the refined cobalt is used in fertilizers,
since a low cobalt concentration in soil may cause cobalt
deficiency among sheep and cattle. Cobalt is also used in
human medicine in the treatment of certain iron-resistant
anemias (Coles, 1955; Shuttleworth et al., 1961; Schirrmacher,
1967) .
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Colorimetric and neutron activation analyses of food indicate
that the average daily intake of cobalt is 5-40 ,ug (Harp and
Scouler, 1952; Ripak, 1961; Hubbard et al., 1966; Wester,
1974a). Even though there is good reason to believe that
these values represent an average normal daily intake, some
contradictory data, showing considerably higher values, have
emerged in some studies employing emission spectroscopy and
AAS (Tipton et al., 1966; Schroeder et al., 1967). Certain
seafoods contain higher than average concentrations of
cobalt (Schroeder et al., 1967).
In 15 commercial beers analyzed by Stone (1965) using a
colorimetric method, cobalt usually measured well below 0.1
mg/1 unless the metal had been added in processing, up to
1.1 mg/1 being recorded in such cases.
5.1.2 Water, soil and ambient air
Drinking water has shown low concentrations of cobalt,
190
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usually between 0.1-5,ug/l (Schroeder et al., 1967; Punsar
et al., 1975). In inland waters, about the same concentrations
will be found (Nix and Goodwin, 1970; Paus, 1971). Sea water
has been shown to contain less cobalt than fresh water
(Vinogradova and Prokhorova, 1968; Piper and Goles, 1969).
In U.S. soil, cobalt ranges from 0.1 to 13 mg/kg (Schroeder
et al., 1967) .
In ambient air the concentration of cobalt is usually low.
Tabor and Warren (1958) found detectable amounts of cobalt
(>0.3 ng/m ) in only 90 out of 750 air samples taken from 28
sampling stations in the U.S., using a semiquantitative
spectrographic method. Using neutron activation, Brar et al.
(1970) found cobalt in Chicago air ranging from 0.3 to 23
ng/m .
5.1.3 Cigarettes
Cobalt in cigarettes has been studied by means of neutron
activation by Nadkarni and Ehmann (1970) . The tobacco, on an
average, contained 0.5 mg Co/kg dry weight. When the cigarettes
were smoked in a standard smoking machine, 0.5% was found in
the mainstream.
5.2 Working environment
Cobalt may be released into the air during the production of
cobalt oxide and in the processing of hard metals. From the
USSR, Kaplun (1963) reported occupational air concentrations
reaching 10 and even 100 mg/m in a cobalt oxide plant. The
highest average in a tungsten carbide industry studied by
Fairhall et al. (1949) was 1.7 mg/m .
6. Metabolism
Cyanocobalamin or vitamin B,-, a cobalt-containing tetrapyrrcli*
ring, is essential in mammalian nutrition. The recommended
daily intake of B,2 for an adult is 3,ug, corresponding to
0.12,ug of cobalt (Food and Nutrition Board, 1974). Ruminant
animals in contrast to man and some other monogastric mammals
191
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have intestinal microflora which utilize cobalt in the
formation of vitamin B,2. Deficiency states among ruminants
have been reported from various countries (Young, 1948;
Beeson, 1950. No function for cobalt in human nutrition
other than as an integral part of the vitamin B,~ molecule
has been established (Underwood, 1973) . Concerning the
absorption of B ~, human beings require the interaction of a
glucoprotein, "intrinsic factor", which is formed in the
scomach. In the presence of this factor absorption is about
70%, but without it, less than 2%. The total body vitamin
B,9 content in a normal, i.e. non-deficient, human is about
-L £•*
5 mg (Wintrobe and Lee, 1970) .
6.1 Absorption
In the following, only forms of cobalt other than vitamin
B-,,, will be dealt with. No data on respiratory absorption of
cobalt are available.
6.1.1 Animals
The gastrointestinal absorption ( Co as chloride) in rats
has been estimated to be around 30% (Comar and Davis, 1947;
Carlberger, 1961; Taylor, 1962). Increasing oral doses of
cobalt decreased the relative absorption (Taylor, 1962) .
Iron deficiency increases the absorption of cobalt, and
simultaneous administration of iron and cobalt reduces the
absorption of cobalt (Schade, 1970) .
6.1.2 Humans
Gastrointestinal absorption is reported to vary from 5-45%.
Ripak (1961) studied cobalt balance in three schoolchildren.
The daily intake was calculated to be 41,ug; out of this
figure 92-95% was found in feces and 4-5% in urine. When
radioactive Co as Cod- was given orally to humans, the
average absorption was calculated at 5-44%, these figures
based on the amount of unabsorbed cobalt remaining in the
feces (Valberg et al., 1969; Smith et al., 1972).
192
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Absorption and/or excretion may be influenced by amount of
cobalt given and by nutritional factors. For example, the 48
hour urinary excretion of perorally given labelled cobalt
ranged between 1% and 16% depending on amount of cobalt
given, fasting or non-fasting state of subjects or addition
of albumin to the diet (Paley and Sussman, 1963).
6.2 Distribution
6.2.1 Animals
Cobalt given either parenterally or per os does not show any
prominent accumulation in any specific organ. The highest
concentrations are found in liver, adrenals and thyroid
(Copp and Greenberg, 1941; Comar et al., 1946; Comar and
Davis, 1947).
In dogs exposed to Co oxides (Co.,0. and CoO) the highest
cobalt concentrations were recorded in the lung after 140
days, followed by kidney and liver (Barnes et al., 1976).
6.2.2 Humans
In exposed human beings, liver shows the highest concentration
of cobalt, followed by the kidneys. Employing intravenous
administration of radioactive CoCl~, Smith et al. (1972)
estimated the liver to hold about one-fifth of the total
body burden of cobalt.
6.3 Excretion
6.3.1 Animals
Parenterally administered cobalt is excreted mainly in
urine, about 90% in 48 hours (Copp and Greenberg, 1941;
Comar et al., 1946). Biliary excretion in dogs given CoCl2
intravenously was 5% in 72 hours (Sheline et al., 1946).
6.3.2 Humans
The main part of parenterally given cobalt will be found in
the urine. Kent and McCance (1941) gave daily cobalt injections
193
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of 2.6 mg for 5 days to human volunteers. Two days after the
last injection, 15% of the given dose had been recovered in
urine and 5% in feces. A similar study on human volunteers
was performed by Smith et al. (1972). After 8 days 56% and
11% of the given dose had been excreted in urine and feces
respectively.
6.4 Biological half-time
6.4.1 Animals
In dogs exposed to cobalt oxide aerosols, Co.,0. has been
shown to have a markedly slower elimination from the lung
compared with CoO; remaining lung burdens after 8 days
postexposure were 85% and 10% respectively. After an initial
fast elimination of about 50% of body burden the biological
half-time of Co was estimated at around 60 days and 35
days for Co.,0. and CoO respectively (Barnes et al., 1976).
6.4.2 Humans
Several works concerning the biological half-time of cobalt
have been published (Morsy and El-Assaly, 1970; Newton and
Rondo, 1970; Smith et al., 1972). A fast excretion phase
takes place, followed by a pronounced cobalt retention.
Morsy and Al-Assaly (1970) studied the retention of Co
accidentally swallowed by a worker. The body burden was
estimated by body scanning. Three components of half-times
were calculated, amounting to 0.5, 2.7 and 59 days respectively.
These values correspond to about 5% retention of total
ingested dose after two days and 1% after 30 days. The two
initial rapid elimination components are partly explained by
fecal elimination of unabsorbed cobalt.
The retention of Co given intravenously has been studied
by total body counting for periods up to 1,000 days. Following
a rapid initial clearance within days of about 90% of a
given dose, 10% was eliminated with a biological half-time
of about 2 years (Smith et al., 1972).
194
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The behavior of ° Co in men for up to 11 years after accidental
inhalation was followed by Newton and Rundo (1970). After a
fast clearance of the main part of the absorbed cobalt, the
rest, about 10%, had a biological half-time in the chest as
well as in whole body of 5-15 years.
7. Normal levels in tissues and biological fluids
In autopsy studies, liver has had the highest concentration
of cobalt, individual values ranging from 0.01 to 0.07 mg
Co/kg wet weight (Forbes et al., 1954, a colorimetric method;
Parr and Taylor, 1964, neutron activation; Sumino et al.,
1975, AAS). In serum from normal humans the cobalt concentration
has been found to be about 0.4,ug/l (Wester, 1974b, employing
neutron activation). In urine individual concentrations
ranging from 0.5 to 2.2 ,ug/l have been reported (Wester,
1974b; Cornells et al., 1975).
With regard to vitamin B,p, the total liver content is
estimated at 1.7 mg, which corresponds to a cobalt concentration
in 1.7 kg liver of 0.04 mg/kg wet weight. This indicates
that the cobalt found in human liver to a great extent might
be in the form of vitamin B,~.
8. Effects and dose-response relationships
8.1 Local effects and dose-response relationships
8.1.1 Animals
Inhalation of high concentrations of cobalt causes advanced
edema and multiple hemorrhages (Harding, 1950; Hobel et al.,
1972). Twelve months after a single intratracheal injection
to rats of 50 mg cobalt in the form of metal particles,
Schepers (1955) reported diffuse central fibrocellular
infiltration of the lungs. In contrast, three intratracheal
introductions of 50 mg cobalt oxide produced an acute
response, but within one month the lungs were normal.
195
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Kerfoot et al. (1975) exposed miniature swine to pure cobalt
metal powder at air concentrations of 0.1-1.0 mg Co/m for 6
hours per day, five days a week. After three months a
progressive decrease in ventilatory lung compliance was
detected among exposed animals (35, 23 and 20 cc/cm H~0 for
controls, low cobalt and high cobalt groups respectively).
Electron microscopy demonstrated thickening and collageni-
zation of alveolar septa in lung biopsies.
Divalent inorganic compounds are more toxic than trivalent
ones (Fredrick and Bradley, 1946; Levina and Loit, 1961;
Van Liew and Chen, 1972).
Dickson and Bond (1974) described five cases of fatal cobalt
poisoning in cattle. The average liver concentration of
cobalt was 58 mg Co/kg dry weight (about 15 mg/kg wet weight)
compared with 0.1 mg/kg dry weight among healthy cattle.
A significant reduction of growth in ducklings nourished
with a diet enriched with 0.2% CoCl~ was recorded by Paulov
(1971). Mice drinking cobalt sulfate solution, 47 mg Co/kg,
had a twofold higher mortality in 2 1/2 months when exposed
to encephalomyocarditis virus compared with controls drinking
demineralized water (Gainer, 1972).
8.1.2 Humans
8.1.2.1 Respiratory effects
Occupational exposure to cobalt in air occurs mainly in the
tungsten and cemented carbide industries in which several
cases of pneumoconiosis have been reported. The disease is
reported to have been produced by air concentrations of
cobalt of 0.1-2 mg/m (Miller et al., 1953; Anonymous,
1968; Dorsit et al., 1970; Coates and Watson, 1971). Cobalt
is also considered to be an etiological agent in "hard
metal" pneumoconiosis: i.e., that occurring in hard metal
industries. Hard metal is manufactured by a process of
powder metallurgy from tungsten and carbon with cobalt as a
196
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binder. Titanium and tantalum are sometimes also added (Bech
et al., 1962; Joseph, 1968).
In 1953 Miller et al. described three cases of pneumoconiosis
in a tungsten carbide tool industry where the exposure to
cobalt powder, oxide or salt, had varied between 0.1-0.2 mg
Co/mJ for 2.5-7 years. It was stated that these three men
were the only workers with pneumoconiosis out of about 1,500
men with similar exposure. Coates and Watson (1971) examined
workers exposed to cobalt powder as they were engaged in the
grinding and manufacturing of tungsten carbide. They described
two types of respiratory disease. The first was characterized
by cough, wheezing and shortness of breath and was relieved
by removal from work. This type was suggested to have an
allergic background. The second, manifested by 12 workers,
was a progressive interstitial lung disease. Eight cases
were fatal, and microscopic examination of the lungs showed
interstitial infiltration and fibrosis. Exposure time for
these twelve workers ranged from 1 month to 28 years and
concentrations of cobalt exceeded 0.1 mg/m .
8.1.2.2 Skin effects
The existence of cobalt allergy is well documented; the
dermatitis evoked is of an erythematous papular type (Schwartz
et al., 1945; Marcussen, 1963; Raben et al., 1966; Camarasa,
1967) .
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
8.2.1.1 Effects on blood
Cobalt has an erythropoietic action, increasing blood volume
and total erythrocyte mass considerably in several animal
species (Brewer, 1940; Tribukait, 1963; Liotti et al.,
1971). It has been suggested that an erythropoietic factor
is released from the spleen (Smith et al., 1972).
197
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Intraperitoneal injections of cobalt also result in large
increases of serum lipids, mainly the triglyceride fraction
(Caplan and Block, 1963; Zarafonetis et al., 1965). Fiedler
et al. (1971) demonstrated that cobalt compounds cause hypo-
coagulability .
8.2.1.2 Myocardial effects
Subsequent to the reports of cardiac failure in drinkers of
beer with added cobalt in Quebec (Section 8.2.2.2), a large
number of animal studies have shown that repeated intramuscular
injection of cobalt on the order of 5 mg/kg to rats produces
myocardial degeneration. In an experiment using electron
microscopy, slight changes were seen after only one injection
(Hall and Smith, 1968; Lin and Duffy, 1970). It is claimed
that essential phospholipids in doses of 7 mg/day protect
rats against some myocardial effects (Wojcicki et al.,
1973). Also electrocardiographic changes were reported among
exposed animals (Mohiuddin et al., 1970).
8.2.1.3 Effects on thyroid gland
Animal studies have confirmed the observation made in humans
that cobalt is giotrogenic. Nivikova (1963) noted a decreased
ability of the thyroid to concentrate iodine among rats
given a total of 150 ,ug Co/day as CoCl2 in food.
8.2.1.4 Effects on the pancreas
Single injections of cobalt produce transient hyperglycemia.
Twenty-four hours following an intravenous injection of 200
mg CoCl- to dogs weighing from 15 to 20 kg a complete absence
o,f alpha cells in many of the pancreatic islets was observed
(Lazarus et al., 1953; Hultqvist, 1959).
8.2.1.5 Effects on the kidney
Daily intraperitoneal injections of 30 mg Co/kg (as CoCl-)
to guinea pigs gave rise to protein and sugar in urine after
two days. Anuria developed during the sixth and seventh
days. Histopathological examination showed tubular degeneration
(Beskid, 1963).
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8.2.2 Humans
8.2.2.1 Effects on blood
Cobalt is used in medical treatment of anemias and has an
erythropoietic effect. Polycythemia has also been reported
in heavy drinkers of cobalt-contaminated beer (Morin and
Daniel, 1967; Kesteloot et al., 1968; Alexander, 1972).
8.2.2.2 Myocardial effects
Endemic outbreaks of cardiomyopathy with mortality rates up
to 50% have been described among heavy beer drinkers. Common
findings were heart failure, polycythemia and thyroid lesions.
These outbreaks have been reported in Quebec, Canada, Minneapolis,
USA and Belgium (Morin and Daniel, 1967; Kesteloot et al.,
1968; Alexander, 1972). The syndrome first appeared about
one month after a new brewery process had been introduced
wherein cobalt sulfide was added to beer in order to improve
the stability of the foam. It may be calculated that a
really heavy beer drinker consuming up to 10 liters of
beer/day could get an additional intake of cobalt in the
neighborhood of 10 mg/day. Although this figure is excessively
high compared with nutritional standards, it is not as large
as doses given in the treatment of anemias. It has been
suggested that the syndrome was multicausal, other factors
probably having been malnutrition and excessive alcoholic
consumption.
Morin et al. (1967) studied some of these beer drinking
patients and reported typical signs of heart failure with
shortness of breath, ankle edema and in some cases, cyanosis
and ECG-changes. Upon autopsy Bonenfant et al. (1969) found
striking myocardial fiber degeneration when heart tissue was
examined histologically. In a retrospective study, hearts of
victims were shown to have about 10 times the cobalt concentra-
tions of controls, 0.5 mg/kg wet weight and 0.04 mg/kg wet
weight, respectively (Sullivan et al., 1968).
One case of myocardial toxicity has been associated with
industrial exposure. Barborik and Dusek (1972), upon autopsy
199
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of a 41 year-old cobalt-exposed worker, found a microscopic
picture resembling that seen among cobalt beer drinkers. The
heart, lungs, liver, spleen and kidneys contained about ten
times the cobalt concentration found in two controls (e.g.
heart, 0.37 vs 0.05 and 0.02 mg Co/kg). Exposure time and
exposure levels were not given.
8.2.2.3 Effects on thyroid gland
Goiter is a well-known side effect of cobalt therapy in the
medical treatment of certain anemias. A reduced Iodine
concentration capacity was seen in patients given 20-30 mg
Co/day (Kriss et al., 1955; Roche and Layrisse, 1956;
Schirrmacher, 1967) . Usually these adverse effects are
regarded as reversible. Thyroid changes were also noted
among the Quebec beer drinkers (Roy et al., 1968). Upon
autopsy, 11 out of 14 examined glands showed significant
changes, with reduced size of follicles.
8.3 Carcinogenic and teratogenic effects
Single and repeated subcutaneous injections of cobalt powder
and salts in doses of 10 to 30 mg to rats may cause sarcomata
at the site of injection (Heath, 1956; Gilman and Ruckbauer,
1962). About one year after a single injection of 20 mg CoO
into rat thigh muscles, 50% responded with sarcomas. Mice,
however, given twice as high doses did not develop any
malignant tumors (Gilman, 1962). Herich (1965) found some
chromosome abnormalities in root tips exposed to cobalt.
Slight teratogenic effects have been induced in chicken
eggs by injections of 0.4-0.5 mg of cobalt (Adhikari, 1967;
Kury and Crosby, 1968).
200
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COPPER
Magnus Piscator
1. Abstract
The absorption of ingested copper in food, being about 50 %, is
normally regulated by homeostatic mechanisms. Copper is mainly
stored in liver and muscles. Excretion is mainly via the bile
and only a few percent of the absorbed amount is found in urine„
The metabolism of copper is influenced by molybdenum. The bio-
logical half-time in human beings is about 4 weeks.
Copper is an essential metal.
Accidental ingestion of large amounts of copper salts causes
gastrointestinal disturbances. Inhalation of copper fumes may
cause metal-fume fever. Chronic copper poisoning has not been
described in normal human beings. Systemic effects, especially
hemolysis, liver damage, and renal damage, have been reported
after ingestion of large amounts of copper salts, but recovery
has usually been rapid upon removal from exposure and treatment.
In industry, copper exposure is common, but chronic effects
have not been reported. Lung changes have been reported in vineyard
workers spraying vines with copper sulfate solutions. Since
other compounds may contribute, the role of copper in these
cases has not been fully elucidated. Endogenous copper poisoning
occurs in Wilson's disease, an inborn error of metabolism.
For general reviews on copper see Adelstein and Vallee (1961),
Schroeder et al. (1966), O'Dell (1976) and Underwood (1971).
2. Physical and chemical properties
Copper, Cu, atomic weight 63.5; atomic number 29; density 8.9;
melting point 1083.4°C; boiling point 2.567°C; crystalline
form reddish metal, cubic; oxidation state 1,2. Only two com-
pounds copper sulfate and copper acetate, will be specified
206
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in this chapter. Copper is malleable, ductile and a good con-
ductor of heat and electricity, second only to silver with re-
gard to the latter.
3. Methods and problems of analysis
Reliable methods for determination of copper in biological
material have been available for many decades. The most common
colorimetric method allows sodium diethyl dithiocarbamate to
form a yellow complex with copper, which can be extracted into
an organic solvent, usually amyl alcohol (van Ravesteyn, 1944;
Lyko, 1965). Blood and urine values obtained with this method
agree well with recently published results obtained with more
modern techniques.
Emission spectroscopy (Butt et al., 1964), neutron activation
(Brune et al., 1961; Danielsen and Steinnes, 1970; Cornells
et al., 1975), atomic absorption spectrophotometry (Kubota
et al., 1968; Matousek and Stevens, 1971; Stegavik, 1975; Dorn
et al. , 1975; Korkisch and Sorio, 1975) and electrochemical
methods, e.g. pulse polarography, anodic stripping voltametry
(Whitnack and Sasselli, 1969; Sinko and Dolezal, 1970; Abdullah
and Royle, 1972; Sinko and Gomiscek, 1972; Rojahn, 1972;
Colovos et al., 1973) have all been used for the determination
of copper in biological and environmental samples. Concentra-
tions of 0.01-0.1 mg/kg can easily be determined by such meth-
ods. Atomic absorption spectrophotometry, the most common meth-
od at present, may detect a few ng of copper, especially with
flameless atomization (Matousek and Stevens, 1971), making it
possible to use microliter volumes of blood and plasma.
There are no interlaboratory comparisons of different methods
available, but the good agreement between results obtained in
e.g. blood and urine in different areas in the world during
many decades suggests that copper can be accurately determined
by several methods in most materials.
4. Production and Uses
4.1 Production
The principal copper ores are cuprite, malachite, azurite,
chalcopyrite and bornite. Sulfide ores constitute about 75 %
207
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of the total production. Copper may even occur in nature as
a pure metal, which accounts for about 6 % of used deposits.
Oxides and carbonates may occur in the ores. Copper ores also
contain other metals, such as zinc, cadmium and molybdenum.
Copper is obtained from the ores by smelting, leaching or
electrolysis.
The world production in 1970 was estimated at 6,000,000 tons.
4.2 Uses
The primary use of copper, accounting for approximately half
of the production, is in electrical equipment. Copper is also
a component of many alloys where it may occur together with
other metals, such as silver, cadmium, tin and zinc. Other
important uses for copper are in plumbing and heating. Copper
salts may serve as pesticides.
5. Environmental levels and exposures
5.1 Food and daily intake
The daily intake of copper from food generally varies from about
1 to about 3 mg, corresponding to about 15 to 45 ug/kg b.w. in
adults (Adelstein and Vallee, 1961; Schroeder et al., 1966;
Tipton et al., 1966, 1969; Robinson et al., 1973; Alexander et al.,
1974; Klevay, 1975). Some low protein and low calorie diets may
give less than 1 n\g (Klevay, 1975). The daily requirements have
been estimated to be about 30/ug/kg b.w. for adults, 40 ug/kg b.w.
for older children and 80 /ug/kg b.w. for infants. (WHO, 1973).
Meat, internal organs, fish and green vegetables are good sources
of copper.
Cereals contain less copper and milk is relatively poor in
copper (WHO, 1973). Concentrations in food are generally around
1 mg/kg. Copper-poor items such as milk usually contain less
than 0.1 mg/kg.
5.2 Water, soil and ambient air
In seawater, most reports have indicated concentrations from
1-5/ug/l (Abdullah et al., 1972; Rojahn, 1972; Preston et al.,
208
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1972). In American rivers concentrations ranging from 0.83-
105 /ug/I (median 5.3) have been reported (Durum et al., 1971).
In drinking water very large variations may occur depending
on type of water e.g. hardness and pH and types of pipes and
taps. Concentrations from a few ,ug to more than 1 mg/1 have
been reported (Schroeder et al., 1966; Stegavik, 1975), meaning
that drinking water may sometimes add a considerable amount
of copper to the daily intake obtained via food. Natural copper
concentrations in soil vary from 2-100 mg/kg dry weight (Bowen,
1966). Air levels of copper in the U.S. have been reported to
vary from 10-570 ng/m , the highest values being found in urban
areas (Schroeder, 1970; Kneip et al., 1970). At the South Pole
the average copper concentration in air was 0.036 ng/m (Zoller
et al., 1974).
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
There are no data on absorption rates of copper compounds after
inhalation from animal or human studies.
6.1.2 Ingestion
The gastrointestinal absorption is normally regulated by the
copper status in the body. Studies using radioactive copper
on rats indicated that small doses ( <1 ,ug) were absorbed to
more than 50 %, but that increasing doses were absorbed to a
relatively lesser extent (Owen, 1964). In contrast to most other
metals copper seems to be absorbed to a large extent in the
stomach, as shown in rats (Van Campen and Mitchell, 1965).
Studies using Cu and Cu on seven human subjects showed an
average absorption of 57 % (Strickland et al., 1972b). Re-
sults from a balance study on four women indicated an absorp-
tion between 49 and 65 % (Robinson et al., 1973). Kinky hair
disease (Menkes' steely hair syndrome, Menkes, 1962) is an inborr
error of metabolism in which an abnormally low absorption of
copper, about 12 %, causes low tissue levels of copper (Dckaban
et al., 1975).
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6.2 Distribution
Absorbed copper is stored mainly in liver, heart, brain, kidney
and muscles, where the highest concentrations have been found
both in experiments on animals and in human beings (Adelstein
and Vallee, 1961; Owen, 1965; Schroeder et al. 1966; Sandstead
et al., 1970; Sumino et al., 1975). Copper is transported
primarily with a high molecular weight protein, ceruloplasmin,
which is produced in the liver, and also functions as an
oxidase. In the tissues and blood cells, copper is found
bound to proteins, many being enzymes.
6.3 Excretion
The main excretion route is via the bile as shown in animals
and in human beings (van Ravesteyn, 1944; Owen, 1964; Walshe
1967; Strickland et al., 1972a). In rats a minor part of the
copper in bile is reabsorbed (Owen, 1964; Cikrt, 1973). Whether
or not this is true for humans as well has not been shown.
Some copper may be excreted via sweat (Hohnadel et al., 1973).
Excretion via the urine is low in animals and in man. Less
64
than 1 % of an intravenous injection of a tracer dose of Cu
as the acetate had been excreted via the urine within 72 hours
by normal subjects. In the same time period about 9 % had
been excreted via feces (Tauxe et al., 1966). The urinary
excretion of copper is influenced by the molybdenum intake
of humans. A low molybdenum concentration in the diet causes
a low excretion of copper and a high intake of molybdenum
provokes a considerable increase in excretion of copper
(Kovalskii et al., 1961; Deosthale and Gopalan, 1974) .
Wilson's disease, an inborn error of metabolism, heightens the
urinary excretion of copper considerably. In a comparative
balance study, a subject with Wilson's disease excreted about
90/ug/day whereas a normal control excreted about 20 ug/day
when they had the same dietary intake (Tu et al., 1965). On
the other hand the gastrointestinal excretion is considerably
greater in normal persons than in patients with Wilson's
disease (Tauxe et al., 1966; Strickland et al., 1972a) or
with kinky hair disease (Dekaban et al., 1975). The urinary
210
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excretion of copper increases in some other diseases, especially
in the nephrotic syndrome (Kleinbaum, 1965).
6.4 Biological half-time
From data by Tauxe et al. (1966) who gave an intravenous in-
jection of radioactive copper to normal human beings, it can
be seen that after 72 hours only about 10 % of the given dose
had been excreted in urine and feces together, indicating
a biological half-time of several weeks. External measurements
of liver content of copper showed essentially no changes here
during the 72-hour period. The half-time of injected copper
was found to be about 4 weeks in normal subjects (Strickland,
1972a, 1972b; Dekaban et al., 1975) whereas it was much longer
in subjects with Wilson's disease (Strickland et al., 1972a).
7. Normal levels in tissues and biological fluids
The liver of the newborn has concentrations of copper of about
30 mg/kg wet weight,but during the first year of life its level
decreases to between 5 and 10 mg/kg wet weight. This level is
then relatively constant throughout the life-time (Schroeder
et al., 1966). In the newborn renal levels of copper are about
4 mg/kg wet weight and in the adult around 3 mg/kg wet weight
(Schroeder et al., 1966). Similar results on copper concentrations
in the adult liver and kidney have been reported by Anke and
Schneider (1971), Voors et al. (1975) and Sumino et al. (1975).
The normal concentrations of copper in whole blood, plasma and
erythrocytes have been reported to be around 1 mg/1 (Brune et
al., 1961; Butt et al., 1964; Lyko, 1965; Olehy et al., 1966;
Kubota et al., 1968; Niedermeier and Griggs, 1971; Schenker et
al., 1971; Hahn et al., 1972; Wester, 1973; Heineman, 1974;
Kolaric et al., 1975). The copper content of serum is subject
to variations, especially pronounced in women. A considerable
increase, up to more than two-fold, in copper levels in serum
may take place during pregnancy (Hahn et al., 1972). The inta/ce
of oral contraceptives also increases the level of copper in
serum (Schenker et al., 1971; Heineman, 1974). Behind such
increases in serum copper in women is an increase in serum
211
-------
ceruloplasmin because of the hormonal influence on the syn-
thesis of ceruloplasmin.
Data from children in different age groups indicate that about 2
ug/kg b.w. is excreted daily via the urine up to the age of
12 (Kleinbaum, 1964; Alexander et al., 1974). In adults daily
excretion has been found to be less than 100 ug/day, usually
around 20 ug/day (van Ravesteyn, 1944; Lyko, 1965; Deosthale
and Gopalan, 1973; Robinson et al., 1973; Wester, 1974a, 1974b;
Cornells et al., 1975). In a balance study Robinson et al.
(1973) found that on an intake of about 2 mg of copper/day
the urinary excretion varied between 11-48 ug/day.
8. Effects and dose-response relationships
Copper is an essential element. It is an essential part of sev-
eral enzymes, e.g. tyrosinase, which is necessary for the for-
mation of melanin pigments, cytochrome oxidase, superoxide
dismutase, amine oxidases, and uricase. Copper is essential
for the utilization of iron in the formation of hemoglobin.
In animals molybdenum has been shown to influence the tissue
and blood levels of copper (Huisingh et al., 1973; O'Dell,
1976). Copper deficiency may occur, especially in ruminants,
when the intake of molybdenum is excessive. A decrease in blood
copper and an increase in the urinary excretion of copper have
been reported from an area where people had a high intake of
molybdenum via food (KovalsKii et al., 1961).
In infants gastrointestinal disturbances may cause copper
deficiency.
Excessive intakes of copper have been shown to cause a variety
of toxic effects in several animal experiments. Excessive
exposure to copper has been shown to cause reversible effects
in humans. Such effects have been reported after industrial
exposure to fumes - metal-fume fever - and after ingestion
of large amounts of copper compounds.
212
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8,1 Local effects and dose-response relationships
2.1.1 Animals
Some earlier papers by Brodsky (1934) and Goralewski (1939)
indicate that copper compounds may cause lung changes. Pimentel
and Marques (1969) exposed guinea pigs to Bordeaux mixture
(1-2% solution of copper sulfate neutralized with hydrated
lime). The exposure lasted six months but the dose cannot be
established from the data given. Four of six exposed animals
showed micronodular lesions upon X-ray examination and upon
microscopical examination of the lungs. In some animals, killed
three months after cessation of the exposure, X-ray examina-
tion showed regressions of the lesions but microscopical ex-
amination revealed that changes were still present.
8.1.2 Humans
Industrial exposure to copper dust or fumes may cause some
acute irritation in the upper respiratory tract. Certain in-
vestigators have sought to find out whether exposure to copper
dust or fumes in industry had given rise to chronic lung damage
but their reports have been negative (Gleason, 1968; Hamilton
and Hardy, 1974; Cohen, 1974). From Portugal, Pimentel and
Marques (1969) and Villar (1974) have reported 2 and 15 cases,
respectively, of the so-called vineyard sprayers'lung, a dis-
ease attributed to the inhalation of copper sulfate during spraying
vineyards with the Bordeaux mixture.
Macroscopically, greenish-blue patches were seen on the lung
surfaces. The histological nodular changes resembled those seen
in silicosis, but only copper could be demonstrated. Among the
fifteen patients described by Villar the time since the last
exposure had varied between 1-43 years. Among these fifteen
cases three cases of lung cancer and five cases of tuberculosis
were diagnosed. Seven of these patients were smokers.
Acute gastrointestinal disturbances may result from the acci-
dental ingestion of food or beverages contaminated by copper
released from copper vessels or from hot water geysers (Nicholas,
1968), or from the intentional ingestion of copper salts in
attempted suicide (Chuttani et al., 1965).
213
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Copper sulfate is a powerful emetic and has been used clinically
as such in the treatment of intoxications, especially in chil-
dren. The effective dose in children is 250 mg of copper sulfate,
corresponding to 100 mg of copper (Holtzman and Haslam, 1968).
In adults, the ingestion of about 1 g of copper sulfate, about
400 mg of copper, induces vomiting. Since systemic effects may
be incurred from the absorption of copper, the use of copper
sulfate as an emetic has been decreasing during the last years.
8.2 Systemic effects and dose-response relationships
8.2.1 Laboratory and domestic animals
Daily subcutaneous injections of copper sulfate for 60 days to
rats in a dose of 0.26 mg of copper resulted in large amounts
of copper in the liver, around 1,000 mg/kg wet weight in contrast
to 4.7 mg/kg in control animals. The exposed rats also showed
reductions in hemoglobin content, red cell counts and hemato-
crits. The mean survival time among exposed animals was 67 days.
Histologically, signs of acute toxicity, both hepatic and renal,
were seen (Wiederanders et al., 1968).
Rats and pigs given diets with a high content of copper over
a prolonged period of time did not show any major deleterious
effects (Johnson and Miller, 1961; Kline et al., 1971). On
the contrary rats given 50 mg Cu/kg diet and pigs given up to
250 mg/kg diet gained more weight than usual. Pigs given 500
mg/kg diet did display a reduction in weight gain as well as
anemia. In the pigs given 250 mg/kg, liver concentrations of
copper were about 20 mg/kg wet weight, as compared to about
4 mg/kg in control pigs, but in pigs given 500 mg/kg the liver
concentration of copper was 500 mg/kg wet weight (Kline et al.,
1971) .
Daily oral doses of 20 mg of copper sulfate per kg body weight
to sheep resulted in hemoglysis after nine weeks (Gopinath et
al., 1974). In sheep killed before the hemolytic crisis, whole
blood copper was of the same magnitude as in controls but in
sheep which did undergo hemolysis, the copper concentration
in blood showed a sharp increase. Liver concentrations in
214
-------
controls were around 50 mg/kg wet weight compared to more than
500 mg/kg in both prehemolytic and hemolytic animals. Hemolysis
also caused acute tubular renal damage in the sheep. In an ex-
periment on cows one group was given about 4 mg/kg diet and
another about 10 mg/kg diet. No difference appeared in growth,
reproduction or milk production but liver levels were about
twice as high in animals given the higher copper content (Engel
et al., 1964). In ruminants relatively low copper levels in
the diet, less than 16 mg/kg, may cause toxic effects if the
molybdenum content of the food is low, while a high level of
molybdenum in the diet may cause copper deficiency.
8.2.2 Humans
Industrial exposure to copper dust or fumes has been common,
but health surveys of workers engaged in the processing of cop-
per have not revealed any signs of chronic disease (Cohen, 1974;
Hardy and Hamilton, 1974). Copper fumes and fine dust may cause
so-called metal-fume fever (Friberg and Thrysin, 1947; Gleason,
1968) . Metal-fume fever is an influenza-like syndrome in which
the symptoms disappear after 24 hours (see also the chapter on
zinc). Gleason (1968) reported that metal-fume fever appeared
after exposure to about 0.1 mg/m of fine copper dust. In two
autopsied cases of the so-called "vineyard sprayers'lung" hepatic
granulomas were found and copper deposits could be demonstrated
histochemically (Pimentel and Menezes, 1975). Liver function
tests had indicated liver dysfunction when these patients were
alive, but since they were suffering from very severe pulmonary
disease, it is not clear how well the copper deposits in the
liver were related to the function tests.
After suicidal ingestion of large amounts of copper sulfate,
jaundice and renal damage have been seen at average copper
concentrations in blood of about 8 mg/1, whereas at a copper
level of about 3 mg/1 only gastrointestinal disturbances were
seen.Of 48 patients who were estimated to have ingested from
1 to 100 g of copper sulfate, 9 died (Chuttani et al., 1965).
A child in whom copper sulfate crystals were applied thera: j.
cally to severely burned skin seven times during nine weeks
215
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developed severe anemia. After the last treatment, a hemolytic
crisis with icterus took place (Holtzman et al., 1966). High
levels of copper in serum and urine, 5.4 mg/1 and 2.2 mg/1,
indicated that absorption of copper from the wound dressings
was responsible. A transient elevation of serum glutamic oxalo-
acetic trans^Jninase was observed indicating slight liver damage.
Recovery was rapid after treatment, which included oral admin-
istration of penicillamine. Excessive weight loss and diarrhea
were reported in a child given drinks and food prepared from
water from a copper-contaminated hot water tap over an extended
period of time (Salmon and Wright, 1971). Blood levels of copper
were elevated and liver function tests showed pathological dev-
elopment. After removal of exposure plus treatment, recovery
was rapid. Biopsy of the liver at a later time showed no patho-
logical signs.
Several reports have emerged on the effects of copper released
from dialysis equipment used in the treatment of patients with
renal disease. An uptake of copper in the plasma has occurred,
resulting in hemolytic anemia. In some cases the reactions have
been so severe as to cause death (Ivanovich et al., 1969).
216
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221
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GERMANIUM
V.B. Vouk
1. Abstract
Animal experiments show that germanium compounds, both
inorganic and organic, are rapidly and almost completely
absorbed from the lungs and the gastrointestinal tract. The
distribution among the organs and tissues is fairly uniform
and there is no evidence of preferential uptake or accumulation.
Absorbed germanium is rapidly excreted mainly in urine. Data
on biological half-times are inadequate.
There is no evidence that germanium is essential either for
man or animals.
Germanium tetrachloride is a strong irritant of the respiratory
system, skin and the eye, possibly because of easy hydrolysis
producing HC1. High inhalation exposures produced in mice
necrosis of the tracheal mucosa, bronchitis and interstitial
pneumonia. Systemic toxicity of germanium compounds is
comparatively low. There seems to be no specific target
organs, but the kidney and the liver are usually affected.
Trialkylgermanium compounds are less toxic than the corresponding
lead or tin alkyls. Germanium compounds do not seem to be
carcinogenic. Dimethylgermanium oxide is teratogenic in
chickens, but sodium germanate did not produce malformations
in hamsters.
There is no information on the toxicity of germanium for
man, except some showing that germanium tetrachloride may
produce skin irritation.
Inhalation is the main route of exposure under occupational
conditions; the main source of germanium for the general
population is food.
222
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Short reviews of the toxicology of germanium have been
published by Browning (1969) , Underwood (1971) and Mogilevskaya
(1973) .
2. Physical and chemical properties
Germanium, Ge; atomic weight 72.6; atomic number 32;
density 5.3 (25 C); melting point 937.4 C; boiling point
2830 C; crystalline form grey-white, brittle solid; oxidation
state 2,4. It belongs to the IVb group of the periodic
system together with carbon, silicon, tin and lead. Germanium
has both metallic and non-metallic properties. It is a n- or
p-type semiconductor depending on the impurities present. Of
industrial and toxicological interest are elemental germanium;
germanium dioxide; sodium germanate; germanium tetrahydride
(germane); and germanium tetrachloride. There is a large
number of organogermanium compounds, including alkylgermanes
and hexaalkyldigermanium oxides.
3. Methods and problems of analysis
Atomic absorption spectroscopy, emission spectrography and
spectrophotometry with phenylfluorone are the most widely
used methods for the analyses of germanium in environmental
and biological samples. The limit of detection of AAS is of
the order of 1.5 mg/1 and can be reduced to 0.015 mg/1 by
using a graphite tube atomizer (Amos and Willis, 1966;
Johnson and West, 1973). To reduce losses from volatility of
germanium, biological samples are ashed at low temperature.
Interference of other elements can be eliminated by carbon
tetrachloride extraction. Samples are treated in the same
way for the analysis by spectrophotometry with phenylfluorone,
whose limit of detection is about 0.1-0.5 mg/1 (Luke and
Campbell, 1956) . The achievable precision of the spectro-
photometric method is 5-10% (relative standard deviation)
(Schroeder and Balassa, 1967a). There is not enough information
to evaluate the accuracy of these methods. The limit of
detection of emission spectrography (biological samples) is
about 1 ,ug (Geldmacher v. Mallinckrodt and Pooth, 1969) and
223
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of the spark source mass spectrometry (SSMS) (in human
tissue samples) 0.007 mg/kg wet weight (Hamilton et al.,
1972/1973).
4. Production and uses
4.1 Production
Some silver and zinc ores contain considerable amounts of
germanium but there is no widely occurring germanium ore.
The total estimated world production of germanium is of the
order of 100 tons annually, the largest producers being
South Africa and Zaire; it is primarily linked with zinc
mining. Germanium can also be recovered from waste products
of coal and coke technology. Germanium tetrachloride is an
intermediate in technological processes for the preparation
of germanium dioxide and organogermanium compounds.
4.2 Uses
The high purity elemental germanium is used primarily in
semiconductor devices such as transistors, diodes and rectifiers
(90% of total consumption). Other uses include the manufacture
of specialized optical glasses and infra-red equipment.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food
A spectrophotometric method using phenylfluorone revealed
the presence of germanium in all food items analyzed (Schroeder
and Balassa, 1967a). However, only 5 items had more than 2
mg Ge/kg (raw clams, canned tuna, dried panfish, canned
baked beans and tomato juice) and 15 more than 1 mg Ge/kg.
Selected hospital diets contained on the average 0.88 mg
Ge/kg wet weight. The daily intake of germanium may vary
from 400 to 3500-ug (Schroeder and Balassa, 1967a). Hamilton
and Minski's (1972/1973) estimate of the mean daily intake
in the United Kingdom is 367 + 159 ,ug (spark source mass spectro-
metry).
224
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5.1.2 Water, soil and rocks, ambient air
Durum and Haffty (1961) did not find germanium in 59 water
samples from 15 major rivers in the United States and Canada
(spectrophic method).
Some soils in the United States were found to contain 0.6-
1.3 mg Ge/kg (Schroeder and Balassa, 1967a) which is of the
same order of magnitude as the abundance of germanium in the
earth's crust (1.5 mg/kg) (Fyfe, 1974).
Considerable amounts of germanium are discharged into the
atmosphere by coal combustion. Paone (1970) estimated 2000
tons per year as the amount discharged in stack gases, flue
dust and ashes from coal burning plants in the United Kingdom.
Coal ash may contain 20-280 mg Ge/kg (Coal Research Section,
1972). Concentrations of germanium in urban air have not
been reported.
5.2 Working environment
Exposure to germanium tetrachloride and its hydrolysis
products (Ge02, HC1) may occur in the production of germanium
and its compounds. Dust concentrations ranging from 5 to 70
mg/m (corresponding to germanium concentrations of about 7
mg/m ) have been reported to occur in the production of
germanium monocrystals. In some cases they contained up to
30% of free silica (Gol'dman, 1960; Mogilevskaja, 1973).
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
The rate of clearance of deposited elemental germanium
particles (mean size 1.4 ,urn) from the lungs of rats is
exponential (52% in 24 hours, 18% remaining 7 days after
exposure). Radiochemical examination of the tissues showed
that part of the material enters the circulation and reappears
in the kidney and liver one hour after exposure. The
-------
clearance of germanium dioxide particles (mean size 0.4,um)
was even more rapid (79% within 24 hours) (Dudley, 1953) .
6.1.2 Ingestion
Neutralized germanium dioxide is rapidly absorbed after stomach
intubation to rats (73.4% in 4 hours; 96.4% in 8 hours)
(Rosenfeld, 1954). Equally rapid absorption of tetraethylgermanium
from the gastrointestinal tract of mice was demonstrated by
Caujolle et al. (1963). Schroeder and Balassa (1967a) found
that the concentrations of germanium in human urine were about
the same as the concentrations in the diet, indicating that dietary
germanium is well absorbed.
6.2 Distribution
Absorbed germanium is distributed fairly uniformly between
erythrocytes and plasma (2:3 ratio) and is not bound to
plasma proteins (Rosenfeld, 1954) . There is no preferential
localization of germanium in soft tissues although in exposed
rabbits and dogs (i.v. injection of GeO^) the highest
concentrations were found in the kidney, liver, spleen,
gastrointestinal tract and bone (Dudley and Wallace, 1952) .
Schroeder and Balassa (1967b) and Schroeder et al. (1968)
kept mice and rats for life on normal laboratory diet (0.33
mg Ge/kg) and drinking water containing 5 mg Ge/1 as sodium
germanate. Germanium was widely distributed in the body
and there was no selective retention or storage. Essentially
the same distribution was found in mice following ingestion
of tetraethylgermanium (Caujolle et al., 1963).
6.3 Excretion
Absorbed germanium is preferentially excreted in urine both
in man (Schroeder and Balassa, 1967a) and in animals. In
rats, 64.8% of an i.p. dose of sodium germanate (100 mg/kg) was
excreted in urine and 4.7% in feces within 1 day, the total
excretion in 5 days amounting to 78.8 and 13%, respectively
(Rosenfeld, 1954) . Excretion of germanium by rabbits following
i.v. injection of Ge02 amounted to 72% of the dose in urine,
and 9% in feces within 72 hours. In dogs, 90% of an injected
226
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GeO,, dose was excreted in urine within 72 hours (Dudley and
Wallace, 1952).
6.4 Biological half-time
Using a simple exponential model and Rosenfeld's 1954 data
for rats biological half-times can be roughly estimated as 1
1/2 days for the whole body retention, 2 days for liver and
4.5 days for the kidney. The corresponding values for man as
used by ICRP (1960) are whole body retention 1 day; liver
7.5 days; kidney 12 days. The agreement is not too good,
except for the whole body retention.
7. Normal levels in tissues and biological fluids
There is little information on the "normal" values of germanium
in human tissues and fluids. Hamilton et al. (1972/1973)
published the following preliminary values for some human
tissues in the United Kingdom (mean concentrations, mg/kg
wet weight, spark source mass spectrometry): Lymph node
0.0009; muscle 0.003; liver 0.04; lung 0.09; brain 0.1;
blood 0.2; testes 0.5; and kidney 9.0. The concentrations of
germanium in human lung tissue (SSMS, 247 samples) as reported
by Brown and Taylor (1975) range from 0.08-12 mg/kg dry
weight. Schroeder and Balassa (1967a) found 0.29 mg/1 in
serum, 0.65 mg/1 in erythrocytes and 1.26 mg/1 in urine
(spectrophotometry with phenylfluorone).
8. Effects and dose-response relationships
8.1 Inorganic compounds
8.1.1 Local effects and dose-response relationships
8.1.1.1 Animals
Seven months after an intratracheal administration of 30, 50
and 70 mg of germanium dioxide, rats showed thickening of
alveolar walls and hyperphasia of pulmonary lymphatic
vessels (Mogilevskaja, 1973) . Changes in the respiratory
system following single (1.4-40 g/m , 2 hours) and repeated
227
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(500-700 mg/m , 2 hours/day, 40 days) inhalation exposure of
mice to germanium tetrachloride were dose related and ranged
from irritation of the respiratory system to necrosis of the
tracheal epithelium, catarrhal desquamative bronchitis and
interstitial pneumonia (Kal'sada, 1964). No respiratory
changes were reported as resulting from long-term (3, 4,
5 and 7 mg/m , calculated as HC1, 7 months) inhalation
exposure of rats to germanium tetrachloride (Kurlajandskij
et al., 1968). No local respiratory effects were reported
following inhalation of germanium tetrahydride either in
acute or chronic experiments (Gus'kova, 1974). Neutralized
germanium dioxide (topical application, 2 times/day, two
weeks) induced no irritation of the shaved skin of the rat
(Rosenfeld, 1954). Ulceration and necrosis of the skin were
observed in rabbits following two-hour exposure to germanium
tetrachloride. The effects observed in guinea pigs and rats
were much milder (Kal'sada, 1964; Kurlajandski et al. ,
1968) .
Germanium tetrachloride has a pronounced irritating action
on the conjunctivae of the eye in rats, rabbits and mice
(Kal'sada, 1964; Kurlajandski et al., 1968).
Local effects of germanium chloride are very likely due to a
combined action of the compound and its hydrolysis products
(Ge02, HC1, Ge2Cl6, etc.) (Kurlajandski et al., 1968).
8.1.1.2 Humans
There is no information on local effects of germanium compounds
in the respiratory system. Mild irritation of the skin is
produced by germanium tetrachloride (Kal'sada, 1964).
8.1.2 Systemic effects and dose-response relationships
8.1.2.1 Animals
Inorganic germanium compounds seem to have a comparatively
low systemic toxicity. An exception is germanium tetrahydride.
228
-------
Eight weekly i.p. doses of neutralized germanium dioxide did
not inhibit the growth of rats but the ingestion of the same
compound in food (1000 mg/kg) or drinking water (100 mg/1)
inhibited the growth of young rats and caused a mortality of
50% in four weeks. The survivors seemed to recover after
that although they continued to ingest about the same dose
for another 8 weeks (Rosenfeld and Wallace, 1953).
Lethal doses of germanium dioxide appear to induce a severe
hypothermic shock in rats, and rectal temperatures of 26.7°C
were frequently observed (Rosenfeld and Wallace, 1953).
8.1.2.1.1 Liver
Degenerative changes and necrosis, sometimes associated with
functional impairment (e.g. reduced detoxifying capacity -
hippuric acid test) were observed in acute, subacute and
chronic studies by Kal'sada, 1964 (mice; GeCl. inhalation,
3 3
1.7-40 g/m , single exposures; and 500-700 mg/m , 2 hours/day,
40 days), Kurlajandskij et al., 1968 (rats; GeCl. inhalation,
3
300-700 mg/m , 7 months); and Gus'kova, 1974 (rats and
guinea pigs; GeH. inhalation, 260-1400 mg/m , single exposures).
Increased incidence, compared to controls, of fatty degeneration
of the liver was found in rats following lifetime exposure
to 5 mg Ge/1 as sodium germanate in drinking water (Schroeder
et al., 1968) but there was no effect in a similar experiment
with mice (Schroeder and Balassa, 1967b).
8.1.2.1.2 Kidney
Degenerative changes in the epithelium of the proximal
tubules were noted by Kal'sada (1964), Kurlajandskij et al.
(1968) and Gus'kova (1974) following high level inhalation
exposures to germanium tetrachloride and germanium hydride,
respectively. The same morphological changes accompanied by
proteinuria had higher incidence in rats exposed to sodium
germanate than in the controls (Schroeder et al., 1968). For
exposure condition and animal species used see 8.2.1.1).
229
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8.1.2.1.3 Hematological effects
Early work on biological effects of germanium compounds
indicated an erythropoietic stimulation produced by subcutaneous
injection of germanium dioxide and sodium germanate but this
could not be confirmed by Bailey et al. (1925) (rabbits,
germanium dioxide, repeated i.p. injection, 7 weeks, total
doses 28-280 mg/kg) and Rochow and Sindler, 1950 (rabbits
and hamsters, dimethylgermanium oxide, single and repeated
s.c. doses up to 1 g Ge/kg). Similarly, multiple i.p. doses
of sodium germanate (100 mg/kg) and repeated oral doses of
neutralized GeO2 (0.9-170 mg/kg body weight) had no hema-
tological effects in rats (Rosenfeld and Wallace, 1953).
Some changes in the blood picture, of uncertain biological
significance, such as increased hemoglobin, increased number
of erythrocytes and leukocytes, were observed by Kurlajandskij
et al. (1968) (rats, GeCl inhalation, 300-700 mg/m3, 7
months) and Gus'kova (1974) (rats and guinea pigs, GeH.
3
inhalation, 50-250 mg/m , 4 months).
8.1.2.1.4 Nervous system
Lethal exposures of rats to germanium dioxide (600-1200
mg/kg, single i.p. dose, Rosenfeld and Wallace, 1953), of
mice to germanium tetrachloride (20-40 g/m , Kal'sada, 1974)
and germanium hydride (2 g/m , Gus'kova, 1974) were accompanied
by various neurological signs (excitation, impairment of
locomotor activity, listlessness, hypothermia and convulsions).
Histochemical changes in the brain observed in rats by
Kurlajandskij et al. (1968) following chronic inhalation
exposure to germanium tetrachloride (3-7 mg/m , 7 months)
are difficult to interpret.
8.1.2.2 Humans
There are no data on the systemic toxicity of germanium
compounds in man, and no reports on occupational medicine
experience.
8.2 Organic compounds
The toxicity of several trialkylgermanium compounds was
230
-------
studied by Cremer and Aldridge (1964). Triethylgermanium
acetate was toxic to rats in intravenous doses of 50 mg/kg
body weight, and orally at 250 mg/kg. Tri-n-butylgermanium
was tolerated orally in single doses up to 375 mg/kg.
Trialkylgermanium compounds had less than one-tenth the
toxicity of triethyltin or triethyllead and did not appear
to have a predominant effect on the central nervous system.
Among the tetraalkylgermanium compounds evaluated by Caujolle
et al. (1966) the least toxic were those with saturated
normal symmetric radicals. The ramification and halogenation
of organic radicals increased the biological activity.
Higher hexaalkyldigermanium oxides (butyl, amyl, hexyl) were
less toxic than the ethyl homologue (Bouisson et al., 1964).
8.3 Carcinogenicity, teratogenicity and mutagenicity
Studies of Kanisawa and Schroeder (1967) on mice and of
Schroeder et al. (1968) on rats (lifetime exposure to 5 mg
Ge/1 drinking water as sodium germanate) did not produce any
evidence on the carcinogenicity of germanium compounds.
Dimethylgermanium oxide, an analog of acetone, was shown to
produce a variety of malformations in chick embryos at 72
and 96 hours of incubation, ED-,, being 1.8 and 2.5 mg/embryo,
respectively, as compared to 17.9 and 25.1 for acetone
(Caujolle et al., 1965). Ferm and Carpenter did not find any
teratogenic or fetotoxic effect in hamsters treated with
sodium germanate (40-100 mg/kg, i.v. injection, 8 days
gestation).
There is no information on the mutagenicity of germanium
compounds.
231
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REFERENCES
Amos, M.D. and Willis, J.B. (1966). Spectrochim. Acta 22,
1325-1343.
Bailey, G.H., Davidson, P.B. and Bunting, C.H. (1925). J.
Amer. Med. Assoc. 84, 1722-1724.
Bouisson, H., Caujolle, D., Caujolle, F. and Voison, C.
(1964). C.R.H. Acad. Sci. Ser. D. 259, 3408-3410.
Brown, R. and Taylor, H.E. (1975) . "Trace Element Analysis
of Normal Lung Tissue and Hilar Lymph Nodes by Spark Source
Mass Spectrometry." pp 13-31. U.S. Department of Health,
Education and Welfare, HEW Publication No. (NIOSH) 75-129,
Cincinnati.
Browning, E. (1969). "Toxicity of Industrial Metals." 2nd
edition, pp 158-163. Butterworths, London.
Caujolle, F., Caujolle, D. and Magna, H. (1963). C.R.H.
Acad. Sci. Ser. D. 257, 1563-1565.
Caujolle, F., Caujolle, D., Cros, S., Dao-Huy-Giao, Moulas,
F. and Tollon, Y. (1965). Bull. Trav. Soc. Pharmacol. Lyon
1_, 221-235.
Caujolle, F., Caujolle, D., Dao-Huy-Giao, Foulquier, J.L.
and Maurel, E. (1966) . C.R.H. Acad. Sci. Ser. D. 262, 1302-
1304.
Coal Research Section, College of Earth and Mineral Sciences,
The Pennsylvania State University (1972). "Mineral Matter
and Trace Elements in US Coals." A Report Submitted to the
Officer of Coal Research, United States Department of Interior,
Contract No. 14-01-0001-390.
Cremer, J.E. and Aldridge, W.N. (1964). Brit. J. Ind. Med.
^1, 214-217.
Dudley, H.C. (1953) . AMA Arch. Ind. Hyg. Occup. Med. £5, 528-
530.
Dudley, H.C. and Wallace, E.J. (1952). AMA Arch. Ind. Hyg.
Occup. Med. 6^, 263-270.
Durum, W.H. and Haffty, J. (1961). "Occurrence of Minor
Elements in Water." Geological Survey Circular 445, Washington.
Ferm, V.H. and Carpenter, S.J. (1970). Toxicol. Appl. Pharmacol,
1£, 166-170.
Fyfe, W.S. (1974). "Geochemistry." p 8, Clarendon Press,
Oxford.
Geldmacher v. Mallinckrodt, M. and Pooth, M. (1969). Arch.
Toxicol. 2ji, 5-18.
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Gol'dman, Z.I. (1960). Gig. Tr. Prof. Zabol. No 10, 30-35.
Gus'kova, E.I. (1974). Gig. Tr. Prof. Zabol. No 2, 56-57.
Hamilton, E.I. and Minski, M.J. (1972/1973). Sci. Tot.
Environ. 1, 375-394.
Hamilton, E.I., Minski, M.J. and deary, J.J. (1972/1973).
Sci. Tot. Environ. .1, 341-374.
ICRP (1960). "Recommendations of the International Commission
on Radiological Protection. ICRP Publication 2. Report of
Committee II on Permissible Dose for Internal Radiation
(1959)." p 172. Pergamon Press, Oxford.
Johnson, D.J. and West, T.S. (1973) . Anal. Chim. Acta 67,
79-87.
Kal'sada, I.N. (1964). Gig. Tr. Prof. Zabol. No 4, 57-60.
Kanisawa, M. and Schroeder, H.A. (1967). Cancer Res. 27,
1192-1195.
Kurlajandskij, B.A., Klockova, S.I., Masbic, F.D., Tjuhteneva,
S.N. and Eizengart, R.S. (1968). Gig. Tr. Prof. Zabol. 12,
51-53.
Luke, C.L. and Campbell, M.E. (1956). Anal. Chem. 28, 1273-
1276.
Mogilevskaja, O.Ja. (1973). In: "Problems of Industrial
Hygiene and Occupational Pathology in Work with Rare Metals."
(Z.I. Izrael'son, O.Ja. Mogilevskaja and S.V. Suvorov, eds)
pp 227-239. "Medicina", Moscow.
Paone, J. (1970). US Bur. Mines Bull. No 650, 563-571.
Rochow, E.G. and Sindler, B. (1950). J. Amer. Chem. Soc. 72,
1218-1220.
Rosenfeld, G. (1954). Arch. Biochem. Biophys. 48, 84-94.
Rosenfeld, G. and Wallace, E.J. (1953). AMA Arch. Ind. Hyg.
Occup. Med. 8_, 466-479.
Schroeder, H.A. and Balassa, J.J. (1967a). J. Chron. Dis.
20., 211-224.
Schroeder, H.A. and Balassa, J.J. (1967b). J. Nutr. 92, 245-
253.
Schroeder, H.A., Kanisawa, M., Frost, D.V. and Mitchener, M.
(1968). J. Nutr. 9^, 37-45.
Underwood, E.J. (1971). "Trace Elements in Human Nutrition."
3rd edition, pp 436-437, Academic Press, New York.
233
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INDIUM
Bruce A. Fowler
1. Abstract
Indium compounds are poorly absorbed following ingestion but
moderately taken up after inhalation exposure. Muscle, skin,
and bone constitute the main body storage sites. Ionic indium
is excreted primarily in the urine while fecal elimination is
the predominant route for removal of colloidal indium compounds
from the body. A biphasic pattern of excretion and a whole-body
biological half-time on the order of two weeks have been reported
for both chemical forms.
Ionic indium compounds are concentrated by the kidneys, producing
renal failure, while colloidal indium is taken up by organs of
the reticuloendothelial system, causing damage to the liver and
spleen.
Indium is a non-essential element.
2. Physical and chemical properties
Indium, In, atomic weight 114.8; atomic number 49; density 7.3;
melting point 156.6°C; boiling point 2,080°C; crystalline form
soft silver-white metal, tetragonal; oxidation state 1,2,3. More
than 30 inorganic forms of indium are known. Indium trichloride,
indium.oxide, indium sulfate, indium sulfide, indium sesquioxide,
and colloidal indium hydroxide are the ones to be dealt with
here.
3. Methods and problems of analysis
A spectrochemical method for determining indium in biological
materials has been reported by Kinser et al. (1966). The detection
limit for indium by this method is 0.002 ng indium with a standard
deviation of approximately 10-15 percent. Neutron activation
has been used to analyze for indium in rocks (Key et al., 1970)
234
-------
and seawater (Matthews and Riley, 1970). The detection limit
for indium in seawater is 0.006 ng/1 and the coefficient of vari-
ation is about 5 percent (Matthews and Riley, 1970).
Polarography has been reported to permit indium analysis in
water with a detection limit of 1 /ug/1 and a precision of about
1 percent (Maienthal and Taylor, 1968).
4. Production and uses
4.1 Production
Indium is recovered as a by-product of zinc smelting. Acid leach-
ing of indium from crude zinc liquors with its subsequent pre-
cipitation as a phosphate or acid leaching followed by precipita-
tion on metallic zinc rods are two widely used methods (Stokinger,
1966).
Production figures for indium in the United States are not availa-
ble. In 1970 the United States imported 401,028 troy ounces of
indium (Minerals Yearbook, 1972).
4.2 Uses
The more important uses of indium include its incorporation into
solders, alloys, semiconductors, and automobile bearings as a
hardening agent which improves resistance to corrosion. Indium
oxide is used as a coloring glaze while indium sulfide is used in
electroplating. Radioisotopes of indium in compounds such as
indium trichloride and colloidal indium hydroxide are used in
the treatment of tumors and organ scanning (Stern et al., 1966;
1961; Hart and Adamson, 1971). Indium has been used in the past
to strengthen solders, dental alloys, and as an electroplating
agent.
5. Environmental levels and exposures
5.1 Food
There have been no published reports on indium concentrations in
foodstuffs.
5.2 Water, soil, and ambient air
Indium concentrations in sea water have been found to average loss
235
-------
than 20/ug/1 (Goldberg, 1965). Neutron activation studies
(Matthews and Riley, 1970) have reported the concentration of
indium in Atlantic Ocean water to be about 0.1 ng/1. This element
is also rare in soil as it comprises only about 1 • 10 percent
of the earth^s crust (Sunderman and Townley, 1960).
Indium concentrations in air and rain in England have been re-
ported to be about 0.3 ng/kg and less than 0.59/ug/l, respect-
ively (Peirson et al., 1973).
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
114
The absorption of In sesquioxide particles by rats following
inhalation has been estimated to be between 3-6 percent of the
total dose following a single 1 hou .• treatment and about 18
percent for sequential 1 hour exposures on 4 successive days
(Morrow et al., 1958).
6.1.2 ingestion
The intestinal absorption of indium in rats has been reported
to be about 0.5 percent of the administered dose (Smith et al.,
1960). No data are currently available for humans.
6.2 Distribution
Ionic indium is transported in the blood bound to transferrin
(Hosain et al., 1969; Castronovo and Wagner, 1973) and has been
found to be cleared from the blood of mice given an intravenous
injection within 3 days (Castronovo, 1970; Castronovo and Wagner,
1971) .
Distribution of indium among body viscera is largely determined
by chemical form. Ionic indium is extensively accumulated by the
kidney while colloidal indium oxide is accumulated by the liver,
spleen, and other organs of the reticuloendothelial system.
Three days following a single intravenous injection, about 20
percent of a tracer dose and 30 percent of an LDn ndose of
114
ionic In were found in the kidneys of mice on a per gram
236
-------
114
of tissue basis. In contrast, mice injected with colloidal In
concentrated about 64 percent of the tracer dose and 40 percent
of the LD dose in their livers on a per gram of tissue basis
after three days (Castronovo, 1970; Castronovo and Wagner, 1971).
6.3 Excretion
The primary route of indium excretion from the body is determined
by the chemical form administered. Ionic indium is mainly excreted
in the urine while colloidal indium complexes are primarily ex-
creted via the feces. Mice have been found to excrete 52 percent
of an administered dose of ionic indium in the urine and 53
percent of a dose of colloidal indium in the feces (Castronovo,
1970; Castronovo and Wagner, 1971; Castronovo and Wagner, 1973).
6.4 Biological half-time
The biological half-time for indium is somewhat dependent upon
the chemical form administered and excretion seems to follow
a biphasic pattern. Mice given intravenous injections of
114
indium chloride showed a biological half-time of 1.9 days
for the fast phase component representing about 50 percent of
the body burden and 69 days for the slow phase. Hydrated
114
indium oxide had a biological half-time of 2 days for the
fast phase component representing about 25 percent of the body
burden and 73.8 days for the slow phase following intravenous
injection (Castronovo, 1970; Castronovo and Wagner, 1971;
Castronovo and Wagner, 1973). Stern et al. (1967) found a bio-
logical half-time of 3.5 days for clearance of hydrated indium
oxide from the lungs of mice following intravenous administra-
tion. A whole-body biological half-time of 14-15 days was reported
by these authors.
Smith et al. (1960) reported that about 60 percent of an intra-
tracheal injection of radioactive indium left the lungs of rats
within 16 days. Excretion of indium from the bodies of these
animals was also biphasic. The biological half-time for inhaled
114
indium sesquioxide particles with no apparent correction for
decay has been found to be about 2-4 days in the rat (Morrow et
al., 1958).
237
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7. Normal levels in tissues and biological fluids
There have been no published reports concerning normal tissue
concentrations of indium in humans or other species.
8. Effects and dose-response relationships
Indium is considered non-essential.
8.1 Local effects and dose-response relationships
8.1.1 Animals
There have been no published reports concerning local effects
in animals.
8.1.2 Humans
Raiciulescu et al. (1972) reported that three patients out of
113
a total of 770 injected with colloidal indium for liver
scanning developed severe vascular shock within 20 minutes
after treatment. Shock was found to last from 10 minutes to
1 hour.
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
The primary toxic effects of ionic indium are exerted on the
kidneys while colloidal hydrated indium oxide damages organs
of the reticuloendothelial system. Intravenous injection of
indium chloride has beer reported to cause extensive necrosis
of the renal proximal tubules in both rats (3.6 mg/kg) and mice
(16.5 mg/kg) (Downs et al., 1959; Castronovo, 1970; Castronovo
and Wagner, 1971). Administration of colloidal hydrated indium
oxide by this route produced necrosis cells in the liver and
spleen (Downs et al., 1959; Stern et al., 1967; Castronovo,
1970; Castronovo and Wagner, 1971). Lung damage has also been
reported in mice given subcutaneous injections of In(SO.)_
(Yoshikawa and Hasegawa, 1971). Decreased hemoglobin and neutro-
phil counts have been observed in rats, miye and rabbits in-
jected with ionic indium (Steidle, 1933; McCord et al., 1942;
Downs et al., 1959; Yoshikawa and Hasegawa, 1971).
238
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Administration of ionic indium at a concentration of 5 mg/1
in drinking water has also been reported to cause mild growth
depression in mice (Schroeder and Kitchener, 1971).
Implantation of indium-treated silver discs into rabbits has
been found to produce only foreign body reactions (Harrold et
al., 1943).
8.2.2 Humans
There have been no reported cases of systemic effects in
humans exposed to indium.
8.3 Teratogenic, carcinogenic, and genetic effects
Intravenous administration of ionic indium to pregnant hamsters
has been reported to produce malformations of the fetal digits
at dose levels below 1 mg/kg and embryolethality at higher
dose levels of 2-20 mg/kg (Ferm and Carpenter, 1970). There
are currently no published studies on the carcinogenic or genetic
effects of indium.
8.4 Interactions with ferric dextran, thorotrast, and gelatin
Concomitant administration of ferric dextran to rats and ham-
sters given intravenous doses of ionic indium has been reported
to protect against liver damage and embryopathic effects in
these respective species (Gabbiani et al., 1962; Ferm, 1970).
Administration of thorotrast and gelatin prevented damage to
the reticuloendothelial system by colloidal indium hydroxide
(Evdokimoff and Wagner, 1972).
239
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Morrow, P. E., Gibb, F. R., Cloutier, R. , Casarett, L. J.
and Scott, J. K. (1958). "Fate of Indium Sesquioxide and of
Indium Trichloride Hydrolysate Following Inhalation in
Rats." 33 pp. University of Rochester Atomic Energy Project
Report No. UR508, University of Rochester, Rochester, New
York.
Peirson, D. H. , Cawse, P. A., Salmon, L. and Cambray, R. S.
(1973). Nature 24,1, 252-256.
Raiciulescu, N., Niculescu-Zinca, D. and Stoichita-Papilan, M.
(1972). Rev. Roum. Med. Int. 9_, 55-60.
Rey, P., Wakita, H. and Schmitt, R. A. (1970). Anal. Chim.
Acta 51, 163-178.
Schroeder, H. A. and Kitchener, M. (1971). J. Nutr. 1431-1438.
Smith, G. A., Thomas, R. G., Black, B. and Scott, J. K.
(1960). Health Phys. _4, 101-108.
Steidle, H. (1933). Naunyn-Schmiedeberg's Arch. Exp. Pathol.
Pharmacol. 173, 459-465.
Stern, H. S., Goodwin, D. A., Scheffel, U., Wagner, H. N.
and Kramer, H. A. (1967). Nucleonics 25, 62-68.
Stern, H. S., Goodwin, D.A., Wagner, H.N. and Kramer, H.H. (1966).
Nucleonics 24, 57-59.
Stokinger, H. E. (1966). In: "Industrial Hygiene and Toxicology."
Vol. 2 (F. A. Patty, ed.) . pp 1048-1052. Interscience, New York.
Sunderman, D. N. and Townley, C. W. (1960). "The Radiochemistry
of Indium." p 46, USAEC Division of Technical Information
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Yoshikawa, H. and Hasegawa, T. (1971). Igaku to Seibutsugaku
83, 45-48 (In Japanese).
24]
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LEAD
Kenzaburo Tsuchiya
1. Abstract
The rate of deposition, retention and absorption of inhaled
lead is highly variable, depending on particle size, physico-
chemical form of lead and the efficiency of lung clearance
mechanisms. There is no evidence of accumulation in the
lungs and all lead retained is eventually absorbed or trans-
ferred to the gastrointestinal tract. For practical purposes it
is assumed that, on average, about 30% of inhaled lead is
absorbed.
About 10% of ingested lead is absorbed in the gastrointestinal
tract. This fraction may be higher for infants and children.
Lead body burden consists essentially of two compartments:
bone (containing about 90% of the total content) with a half-
time of about 20 years; the amount of lead in this compartment
increases throughout life; and a smaller compartment with a
half-time of about 20 days (blood, soft tissue and rapidly
exchangeable bone fraction).
Absorbed lead is excreted mainly via urine (about 80%) and
gastrointestinal secretion; small amounts are excreted in milk,
sweat, hair and nails. Placental transfer of lead has been
demonstrated.
There is no evidence that lead is essential for either man or
animals.
The most common form of acute lead poisoning is gastrointestinal.
Acute lead encephalopathy is rare in adults, more frequent in
children. Anemia is a common chronic systemic effect resulting
mainly from the effects of lead on heme synthesis. Inhibition
of (S-aminolevulinic acid dehydrase (ALA-D) and elevation of
protoporphyrin in erythrocytes are the earliest effects followed
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by increase in urinary 6-aminolevulinic acid (ALA) and
coproporphyrin excretion, and fall in hemoglobin level.
These effects are associated with increasing blood lead
levels, inhibition of ALA-D starting at 20-30 ug/100 ml;
increased ALA excretion occurs at blood lead levels of
about 40-50 ug/100 ml. Chronic encephalopathy may result
from prolonged lead absorption but it may also be a residual
effect of acute encephalopathy. Peripheral neuropathy is now
rare, although sub-clinical effects such as reduced nerve
conduction can be detected at lead blood levels of about
50 ug/100 ml. Lead colic may occur at comparatively low
levels of exposure and is usually accompanied by other symptoms
and signs. Renal effects are mostly reversible but long-term
exposure associated with blood lead levels of 70-80 ug/100 ml
may cause irreversible functional and morphological changes.
There is no conclusive evidence that lead can damage liver,
cardiovascular system or reproductive function. Lead compounds
are not considered as carcinogenic to man. Factors that can
modify the effects of lead include age, diet and possibly
cadmium and zinc.
Accidental or occupational exposure to alkyllead compounds
may result in acute encephalopathy which is different from
the effects of inorganic lead compounds on the central nervous
system.
For differential diagnosis of lead it is essential to determine
lead in blood, and ALA and coproporphyrin in urine. CaEDTA is
the most widely and effectively used therapeutic agent. If over-
exposure is detected early, prognosis is good.
Primary route of exposure for the general population is food,
for occupational groups inhalation; important sources of
exposure for children in some countries are lead paint, and
soil and dust. Estimated daily intake via food is for adults
about 200-300 ug; air pollution may contribute up to about 2C _
and drinking water less than 20 ug. Estimated daily absorption
from all sources is up to 30 to 40
ug.
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Comprehensive reviews and symposia on lead toxicology have
been published by NAS (1972), CEC (1972), Associate Committee
on Scientific Criteria for Environmental Quality (1973) ,
Goyer and Rhyne (1973), Interdepartmental Working Group on
Heavy Metals (1974), Task Group on Metal Toxicity (1976) and
WHO (1976).
2. Physical and chemical properties
Lead, Pb, periodic system group IVB; atomic weight 207.19;
atomic number 82; density 11,34; melting point 327.5°C;
boiling point 1740°C; crystalline form silver-bluish white
soft metal, cubic; oxidation states 0, + 2 and + 4.
In most inorganic compounds, lead is in the oxidation state +2.
The salts of lead (II), lead oxides and lead sulfide are
poorly soluble in water, with the exception of lead acetate,
lead chlorate and, to some extent, lead chloride.
Tetramethyllead and tetraethyllead are the most important
organolead compounds because of their widespread use as anti-
knock fuel additives. Both are colorless liquids with
boiling points of 110°C and 200°C, respectively. At these
temperatures, or slightly below, they begin to decompose.
3. Methods and problems of analysis
A major source of errors in the determination of lead in
environmental samples is the secondary contamination during
sampling or analysis, particularly of food and biological
media.
Both high and low volume samplers can be used in air sampling
for lead. The pore size of filters should be less than 0.2 /um
(Lee and Goransen, 1972). For sampling of organolead compounds
both liquid scrubbers with iodine monochloride and solid scrubbers
with activated carbon, cristobalite or iodine crystals are
used (Purdue et al. 1973; Harrison et al., 1974).
For most purposes water samples may be analyzed for lead
without separating suspended material from the liquid phase.
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Soil and dust samples are first dried, then homogenized by
grinding and sieving (Thornton and Webb, 1975)
Pekkarinen (1970) has reviewed the advantages and limitations
of the two main methods for the studies of lead in food: the
duplicate portion technique and the equivalent composite tech-
nique. The first method, used by Kehoe (1961) for the daily
determination of lead intake over long periods, involves the
analysis of duplicates of meals actually consumed, and thus
defines the variability of intake; it is expensive and time
consuming. The equivalent composite technique is based on the
analysis of formulated meals typical for given populations-,
the main problem is the representativeness of such formulations.
Special precautions are needed to avoid secondary contamination
of blood and other tissue and body fluids samples. These
include the use of lead-free silicate glass, glass cleaning
with mineral acids and deionized water, use of polypropylene
syringes and stainless steel needles (NAS, 1972). Even more
stringent precautions should be taken when lead is determined
in micro-samples of blood (Mitchell et al., 1974).
Most analytical methods used for routine determination of
lead require sample pretreatment. Dry as well as wet ashing
is used to destroy organic matter; low temperature ashing can
also be used for small samples of biological material.
The dithizone method based on spectrophotometric determination
of a red complex that lead forms with diphenylthiocarbazone
is still widely used (NAS, 1972), although it is being gradually
displaced by atomic absorption spectrophotometry.
The conventional AAS requires pretreatment of biological
samples by dry or wet ashing. More recently various "flameless"
AAS procedures have been developed in which the sample is
heated and ashed in the receptacle of the AAS instrument
(Cernik, 1974). In addition, the sample size for blood can
be reduced from the milliliter to the microliter range without
increasing the limit of detection which is for the flame AAS
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of the order of 0.01 mg/1 and for the flameless AAS (graphite
atomization) about 1 • 10 mg/1 (Christian and Feldman, 1971;
Slavin et al., 1972). The achievable precision of AAS methods
is of the order of 7-9% (relative standard deviation, lead
in blood; Evenson and Pendergast, 1974).
Electroanalytical methods are also useful, particularly polaro-
graphy and anodic stripping voltametry (ASV). Neutron activation
analysis is not likely to find wide application for lead analysis
in the near future, because of the need of a fast neutron source.
Another non-destructive method with good potential for special-
ized applications is X-ray fluorescence (Kneip and Lauren,
1972; Rasberry, 1973).
Matson et al. (1971) reported good agreement of results obtained
by the dithizone method, AAS and ASV but the experience of the
present author showed that more practice and better trained
analysts are required to obtain reliable results by ASV than
by AAS. Normal levels of lead in blood (10-20 ug/100 ml) can be
easily determined in a 5 ml sample by AA§5;only 0.2 ml is
required for ASV; one drop is sufficient for the flameless AAS
(Delves, 1970).
In spite of comparatively long experience with the analysis
of lead in blood, the concentrations are often not determined
precisely and accurately. In a recent interlaboratory comparison
among 66 European laboratories, the results differed by a
factor up to 10 or more (Berlin et al., 1976).
A very thorough training of the analysts and frequent checks
with standard samples are therefore strongly recommended.
In addition, great care is needed in the ashing of the samples.
4. Production and uses
4.1 Production
The most important lead minerals are galena (lead sulfide),
cerrusite (lead carbonate) and anglesite (lead sulfate). Galena
occurs mostly in deposits which also contain zinc minerals and
small amounts of copper, iron and a variety of trace elements.
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Mixed lead and zinc ores account for about 70% of total primary
lead production.
The most important lead mining countries are the United States,
the USSR, Australia, Canada, Peru, Mexico, China, Yugoslavia
and Bulgaria, accounting for about 70% of the world mine
production in 1975 which amounted to 3.6 million tons as
compared to 2.6 million tons in 1965 (International Lead and
Zinc Study Group, 1976).
Lead is also produced from scrap (secondary lead) which
accounts for about 35% of the total world lead supply (Federal
Institute for Minerals Research and German Institute for
Economic Research, 1972). Total current lead production
(primary and secondary) amounts to about 5 million tons.
Lead production from a sulfide ore (3-8% Pb) includes
concentration (to 55-70% Pb), sintering in which lead is
oxidized, reduction of lead oxide and refining to eliminate
impurities.
4.2 Uses
The largest consumer of lead in 1974 was the storage battery
industry (40%) followed by alkyllead production (12%), cable
sheathing (9.2%),pigments (12%), alloys (10.8%) and various
semimanufacturers (12%). In absolute amounts the world
consumption of lead in 1975 was about 4.1 million tons, more
than 50% of which was used by the automobile industry (mainly
batteries and alkyllead). In 1973 the manufacture of alkyllead
consumed about 380,000 tons of refined lead (International
Lead and Zinc Group, 1976).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food
Lead concentrations in food products range from undetectable
levels to a few mg/kg wet weight (Waldron and Stofen, 1974).
Koriguchi (1974) compared lead concentrations in various food
247
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products in Japan in 1970 with those reported for 1950 (Horiuchi
et al. , 1956). No major differences were found, although two
different analytical methods were used (dithizone and AAS with
wet ashing, respectively). The values reported by Schroeder
et al. (1961) may serve as an example of lead concentrations
in food: coniiments contained about 1 mg/kgj fish and seafood
0.2-2.5 mg/kg; meat and eggs 0.2-0.4 mg/kg; and grains and
vegetables up to 1.4 mg/kg. The concentrations of lead in milk
are of particular concern, milk being the main dietary constituent
for infants. Human breast mij_k contains lead in concentrations
of about 5-12 iig/1 (Lamm and Rosen, 1974; Murthy and Phea, 1971).
Unprocessed cow's milk has a similar concentration. Processing
may considerably influence the lead content. Whole bulk milk
was found to have about 40 wg/1 in contrast to 200 ug/l in milk
that had been processed by evaporation (Mitchell and Aldous,
(1974).
5.1.2 Water
Lazarus et al. (1970) measured lead concentration in rainwater
in 32 US stations; the mean was 34 ug/1 and the maximum value
observed 300 ug/1. The mean concentration of lead in rainwater in
Yokohama, Japan ranged from 8 ug/1 in residential areas to about
30 iig/1 in business areas (Kobayashi, 1972). In the areas of
heavy traffic, lead in rain may exceed 100 iig/1 and reaches
500 ug/1 (Ettinger, 1966).
Since 1962, lead concentrations in water supplies in the USA
have generally not exceeded 50 ug/1, the US Public Health
Service standard (NAS, 1972). This is supported by Durfor
and Becker (1964) who found that lead in water supplies in
about 100 large American cities ranged from traces to about
60 jag/1. However, when lead pipes or tanks are used and
the water is soft, lead concentrations may be so high (up
to 3000 ug/1, Goldberg, 1974) as to cause lead poisoning
(Beattie et al., 1972). Plastic pipes containing lead
stearate may also contaminate drinking water (WHO, 1976) .
Surface water usually contains lead in concentrations below
100 ug/1 (Kopp and Kroner, 1975) and in unpolluted areas
in the range of about 1 ug/1 (Zukovickaja et al., 1966).
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A recent survey of the rivers in the Midi-Pyrenees region,
France, showed mean dissolved lead concentrations of about
7 to 10 ug/1 (Servant, 1973) . Lead concentration in deep
ocean waters is about 0.01-0.02 ug/1 but in surface ocean
water 0.3 ug/1 (Chow and Patterson, 1966).
5.1.3 Soil and plants
The natural concentration of lead in soil is in the range
of 2 to 200 mg/kg (NAS, 1972) with mean values of about 16
mg/kg, but the variation from one location to another is
considerable (Waldron and Stofen, 1974). The concentration
of lead in street dust and surface soil may be sometimes
extremely high and may represent a hazard to children.
For example, the mean lead concentration in street dust
from residential and commercial areas in 77 Mid-western
cities in the USA amounted to about 1600 to 2400 mg/kg
(NAS, 1972) and Kennedy (1960) reported that lead in soil
near a lead mining area in Idaho reached 20,000 mg/kg.
Grass samples may show high lead concentrations near the
roads with heavy traffic, the mean values ranging from about
250 mg/kg at the roadside to about 156 mg/kg at a distance
of 25 m (NAS, 1972). This is mostly due to external contamination,
because the uptake of lead by plants from soil does not seem to
be much influenced by the concentration of lead in soil
(Ter Haar, 1970).
5.1.4 Ambient air
The lead concentrations in ambient air of large cities range
from about 0.02 ug/m to about 10 ug/m (means of 24-hour samples)
(Tepper and Levin, 1975} Tsuchiya et al., 1975; Waldron and
Stofen, 1974). These figures do not necessarily indicate the
exposure throughout the entire year and the sampling sites
were not all at the same distance from the ground. A good picture
of lead concentration in ambient air is obtained from the data
collected in 1971-1972 in some European cities as shown in Table
1- In contrast the lead concentrations in air above the North
Central Pacific Ocean and South Indian Ocean are of the order
of 0.001 ug/m (Chow and Bennet, 1969; Egorov et al., 1970).
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5.1.5 Special exposures
The concentration of lead in illicitly distilled whiskey may
be above 1 mg/1, and cause chronic poisoning (Patterson and
Jernigan, 1969j Whitfield et al., 1972). Wine is another possible
source of lead intake for some people, the average concentrations
ranging from 130-190 yug/1 (Boude'na et al., 1975).
Improper glazing of earthenware vessels results in leaching of
lead, particularly if they contain acidic liquids. Cases of
poisoning from this source were reported, for example, from
Yugoslavia (Beritic'and Stahuljal, 1961) and the United Kingdom
(Whitehead and Prior, 1960) and more recently from the USA
(Klein et al., 1970).
Lead based paints represent an important source of excessive
lead intake in children (Chisholm and Harrison, 1956) .
A recent study revealed that 80% of children examined because
of excessive lead absorption had pica (Sachs, 1974). Guinee
(1973) reported that in children with blood lead concentrations
equal or greater than 60 ^g/100 ml, 75% lived in homes with
at least one lead painted surface, but the high blood lead
levels found in children are not always easily explicable in
this way (Greenfield et al., 1973). High concentrations of lead
in soil in the vicinity of some houses may be another source
of lead intake, related either to the weathering of lead-based
paint or to the accumulation of lead from automobile exhausts
(Ter Haar and Aronow, 1974; WHO, 1976). Children may also be
exposed to lead from colored newsprint (Hankin et al., 1973),
or lead-painted toys„
Lead content in tobacco may vary from about 3 ug (Szadkowski
et al., 1969) to 12 ng per cigarette of which about 2% is
transferred to the mainstream smoke (Petering and Menden, 1976),
resulting in an inhalation of about 1.2 to 4.8 ug lead per 20
cigarettes.
5.2 Working environment
Lead smelting and refining is probably the most hazardous
operation with respect to exposure to lead. Mean concentra-
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tions of lead in air may reach 80-4000 iig/m (WHO, 1976). Tola
(1974) has recently reported on lead exposure in the secondary
lead smelters in Finland; 16 out of 20 workers examined had
lead blood levels exceeding 70 ug/100 ml.
Oxide mixing appears to be the most hazardous operation in
the storage battery production with recorded mean concentrations
of lead in air up to 2000 /ug/m (Tsuchiya and Harashima, 1965).
Although these values may not be representative, they illustrate
the problem. Other occupations with possible lead exposure
include shipbreaking and welding (Rieke, 1969), printing
(Tsuchiya and Harashima, 1965) , alkyllead manufacture
(Linch et al., 1970), plastics production (HM Chief Inspector
of Factories, 1973) and rubber tire industry (Sakurai et al.,
1974). For additional information reference is made to
Hernberg (1973) .
5.3 Estimates of total intake
When averaged over several months the concentration of lead
in urban air would rarely exceed 1 ug/m ; assuming that, on
the average, 20 m of air is inhaled per day, the upper limit
for the inhalation intake would be about 20 ug, but a more
realistic estimate would be about 10-15 ,ug per day.
Lead intake throughdrinking water would generally not exceed
50 iag per day. The mean intake would be closer to 20 ug/day
(Associate Committee on Scientific Criteria for Environmental
Quality, 1973).
As regards the average daily intake in food, estimates from
different countries and by different investigators vary from
about 110 /ig (Coulston et aL, 1972 a, b & c; Boppel, 1975)
to about 520 ug (Lehnert et al., 1969). These differences
reflect different sampling techniques (duplicate portion or
composite sample), different methods of analysis, but also
different eating habits, sex and occupations. There is also
a considerable difference between adults and children, the
estimated intake for a breast-fed infant being about 40 ug
(Alexander et al.,1973). Lead intake in food has apparently
251
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undergone no changes within the last 20 years; Horuguchi's (1974)
comparison of daily intakes in 1950 and 1970 gave approximately
the same value of about 200 ug for adults. Taking into account
all the possible modifying factors, a recent WHO Task Group
concluded that a fair estimate of daily intake of lead via
food would be 200-300 ug (WHO, 1976).
Food is thus the major pathway of lead intake for the general
adult population, contributing more than 80-85% of the total
daily intake. Occupational!/ exposed persons and children have
to be considered separately because the relative contributions
of the various exposure pathways may be quite different.
6, Metabolism
6.1.1 Absorption of inhaled lead
Lead containing particles in the ambient air have an aerodynamic
diameter of the order of 0.1-1.0 urn, and the predicted deposition
in the airways would be about 35% (Task Group on Lung Dynamics,
1966). This is questionable for smaller particles (r<0.1 urn)
which are mainly deposited by diffusion (Lawther et al., 1972).
The actual measurements of deposition in human volunteers gave
results that differed considerably depending on the physical and
chemical properties of inhaled aerosol. A value of 5-16% was
obtained by Muir and Davies (1967), whereas Kehoe (1961) re-
ported a deposition of 36 to 46% for lead (III) oxide particles
with an average diameter of 0.9-2.9 /urn. A high deposition
was also observed by Nozaki (1966) ranging from 42.5-63.2%
for 10 respirations per minute (1350 ml tidal air) and from
21-35% for 30 respirations/min (450 ml tidal air); the lower dep-
osition values apply to the mass median diameter of 0.05
urn, the higher to 1.0 urn.
Overall deposition values alone are not sufficient to assess
the contribution of inhaled lead particles to the body burden.
Regional deposition as well as lung clearance has to be taken
into account. For example Hursch et al. (1969) found that
212
less than 8% of Pb absorbed on natural room aerosols was
deposited in the tracheobronchial tree compared to the total
252
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deposition of 14-45%. Large particles (2.9 yum) are probably
deposited mainly in the nasopharynx and subsequently swallowed
(Kehoe, 1961). High lead concentrations in air may damage
clearance and other lung defense mechanisms as indicated
by studies in vitro and in animals (Beck et al., 1973; Bruch
et al., 1973 and 1976).
The rate of absorption of deposited leads depends on various
factors, and particularly on the physico-chemical form of
lead in particles. There is however no evidence of lead accu-
mulations in the lungs, so that any lead compound once deposited
is eventually absorbed or transferred to the gastrointestinal
tract (Associate Committee on Scientific Criteria for Environ-
mental Quality, 1973).
6.1.2 Absorption of ingested lead
Studies on the absorption of ingested lead indicate that
about 10% is absorbed from the gastrointestinal tract (Kehoe,
1961; . Rabinowitz et al., 1974). For children, the fraction
absorbed may be much higher as pointed out by a recent study
of Alexander et al. (1973) who found an absorption up to
53% in eight children aged from 3 months to 8 years. These
results require verification because of the large scatter
of values and the short period of study (WHO, 1976).
Values between 5 and 10% absorption were also obtained in
animal studies (Horiuchi, 1970; Schlipkotter and Pott, 1973).
Here again, high values (50% or more) were observed for young
animals with tracer doses of lead (Kostial et al., 1971;
Forbes and Reins, 1972).
Animal studies have also shown that certain dietary factors
such as milk, fasting, low calcium and vitamin D, iron deficiency
may promote lead absorption (Kello and Kostial, 1973; Six and
Goyer, 1972; Quarterman et al., 1976).
6.1.3 Estimates of total daily absorption
It is obvious that the total daily absorption of lead differs
very widely for different populations and individuals. It may
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be, nevertheless, useful to have a rough estimate of this figure.
With 10% absorption, the food would contribute 20-30 ug/day.
Assuming an ambient air concentration of 1 ug/rn , 20 m of air
intake per day, 30% deposition and complete absorption in the
respiratory tract, inhalation with no occupational exposure
could contribute up to 6 ug/day, by no means a negligible
quantity. Drinking water would not contribute more than about
2 Tag, assuming 1 liter daily intake and 10% absorption. The
total absorption would be about 28 to 38 ug/day. A Canadian
estimate is 21 ug/day (Associate Committee on Scient? fie Criteria
for Environmental Quality, 1973).
6.2 Transport and distribution
Absorbed lead is transported by blood and initially distributed
in various organs and tissues. It is then gradually re-distributed
to form an exchangeable compartment (blood and soft tissues)
and a storage compartment, essentially bone. In human subjects
with low level exposure about 90% of the total body burden
is found in bone. Barry (1975) found that in the United Kingdom
the lead concentration in bones of men and women over 16 years
of age ranged from 9-34 mg/kg wet weight. The concentration
in liver was about 1 mg/kg and, in the kidney: 0.8 mg/kg in
the cortex and 0.5 mg/kg in the medulla. Studies in the United
States and Japan revealed similar concentrations and distribu-
tion patterns (Gross et al., 1975? Horiuchi et al., 1959). A
comparatively high concentration was found in the aorta with
atheroma (2.5 mg/kg wet weight, Barry, 1975). The same author
reported that the mean lead concentration in the brain cortex
of 50 adult males did not exceed 0.1 mg/kg wet weight with a
range of individual values from 0.02-0.8 mg/kg; in the basal
ganglia the range was 0.04-0.2 mg/kg.
Lead in blood is mainly bound to erythrocytes where its
concentration is about 16 times higher than in the plasma
(Butt et al,, 1964). The manner in which lead combine! with
erythrocytes is not clear, but probably it is associated with
hemoglobin (Barltrop and Smith, 1972).
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Lead has also an affinity for membranes of the cell and
mitochondria (Goyer and Krall, 1968) but not for lysosomes
(Barltrop et al., 1971).
Lead in bone builds up throughout life; this does not apply
to soft tissues where it stabilizes early in adult life;
in some tissues it may even decrease with age (Gross et al.,
1975) .
Placental transfer of lead has been demonstrated by many authors
(TGMA, 1973). There is a fairly good correlation between lead
concentrations in the blood of mothers and newborn children
(Haas et al., 1973; Hower et al., 1975), and the distribution
in fetal tissues is similar to the distribution in the adult
organism (Barltrop, 1969).
The total body lead content of a 70 kg man is of the order of
100-400 mg and increases with age (Associate Committeeon the
Scientific Criteria for Environmental Quality, 1973).
6.3 Elimination
About 90% of ingested lead is eliminated unabsorbed through
feces (Kehoe, 1961; Tepper and Levin, 1972). Absorbed lead is
excreted primarily in urine (about 76%); other excretion
routes are gastrointestinal secretions (about 16%) and hair,
nails and sweat (<8%) (Rabinowitz et al., 1973; Teisinger
and Srbova, 1959). The rate of biliary excretion in man is not
known. The mechanism of urinary excretion appears to be
essentially glomerular filtration (Vostal, 1966).
Lead is also excreted in human milk in concentrations up to 12
ug/1 (Horiuchi, 1970; Murthy and Rhea, 1971).
There is a considerable species variation for lead excretion in
animals. In baboon, the dominant route of excretion is urine
(Eisenbud and Wrenn, 1970) but in rat and sheep, biliary and
transmucosal excretion may be higher than urinary (Castellino
et al., 1966; Blaxter and Cowic, 1946).
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6.4 Biological half-times
Assuming a total body burden of 80 mg of lead at the age of
fifty, an average daily intake of 300/ag throughout life
and 10% absorption from the gastrointestinal tract and applying
an exponential one compartment model, Tsuchiya and Sugita
(1971) obtained an estimate of 5 years for the total body half-
time of lead.
The biological half-time for lead in human bone v -\s estimated
at about 10 years by TGMA (1973). A higher value was obtained
when the recent study of Rabinowitz et al. (1974) 'was used'
as the basis of calculations (Task Group on Metal Toxicity,
1976). This model assumes three compartments: blood lead and
some rapidly exchanging soft tissues with a T , about 19 days;
soft tissues and a rapidly exchangeable bone fraction with
T, /2 about 21 days; and the skeleton with T,/2 about 20 years.
For all practical purposes the two first compartments can be
combined.
7. Concentrations in tissues and body fluids as indicators
of exposure and dose
7.1 Concentrations in biological media as indices of exposure
7.1.1 Lead in blood
Blood lead levels in human subjects with no known high exposure
are fairly constant throughout the world, ranging from between
10 and 35 ug/100 ml on the average (Lehnert et al., 1970; NAS,
1972; Secchi and Alessio, 1974; BoudSne et al., 1975; Tsuchiya
et al., 1975). There do not seem to be any differences by age
(US Department of Health, Education, and Welfare, 1975). Tsuchiya
et al. (1976) showed clear differences in blood levels between
men and women. This is consistent with other recent measurements
of blood lead in women in Sweden (8.5 ug/100 ml, Haeger-Aronsen,
1961) and Finland (7.9 rural, 9.7 ug/100 ml urban, Nordman,
1975). There is a consistent difference between urban and rural
populations, the latter showing lower values (US Department
of Health, Education, and Welfare, 1965; Tepper and Levin,
1972). See Table 2.
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Higher values are found in populations living near highways
with heavy traffic (Waldron, 1975) and in the vicinity of
lead smelters (Nordman et al., 1973; Martin et al., 1975).
European studies indicate lower lead in blood (Pb-B) values
in children than in adults (Haas et al.,1973; Grimes et al.,
1975). This has been recently confirmed by Tsuchiya et al.
(1976) who found Pb-B values in Tokyo children to be on the average
about 8-10 ug/100 ml (Table 3).
In the USA, in some big cities, a large number of children were
found with Pb-B concentration in the range of 40-80 ug/100 ml
(Blanksma et al., 1969; Fine et al., 1972; Pueschel et al., 1972).
Lead levels in blood are under certain conditions a good indi-
cator of exposure, and it is of interest to establish, if possible,
the relationship between Pb-B and intakes by inhalation or
ingestion.
A study by Sakurai et al. (1974) revealed the average concentra-
tion of lead in blood to be about 50 ug/100 ml in workers who
had been exposed to a lead level of about 60 ,ug/m , 40 hours
per week. However, the average lead concentration in air of
3
60 ug/m was not a time-weighted average, but an average of
34 samples obtained from different sites within one large workroom
at random times.
With regard to the relationship between lead levels in ambient
air and blood lead concentration in the general population, the
well-known Three Cities Study (U.S. Department of Health,
Education, and Welfare, 1965) showed higher blood lead levels in
those persons, e.g. policemen and drivers, who spend a good
deal of their working hours outdoors. In another study about
150-200 housewives from 7 large U.S. cities and Los Alamos were
examined for blood lead levels in the period from 1968-1971
(Tepper and Levin, 1975). The annual mean concentrations of lead
3 3
in air were 0.14 ug/m in Los Alamos to 4.55 ug/m in Los Angeles.
The geometric means of blood lead levels varied from 12.5
ug/100 ml to 20.15 ug/100 ml. There was no association between
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the atmospheric concentrations of lead in air and blood lea
levels. However, when Hasselblad and Nelson (1975) analyzed
the same data using a different statistical procedure, they
concluded that the air lead gradient and the urban-suburban
contrast contributed to the blood lead levels significantly
with each explaining approximately 18 percent of the total
area variation of blood lead concentrations. These two (not
independent) comparisons explained more than twice as much
of the total variation in blood lead as did either smoking
or age.
Tsuchiya et al. (1975) studied the association between lead
concentrations in the ambient air of Tokyo and blood lead
levels of approximately 2,300 policemen. The greater Tokyo
area was divided into 10 districts and one remote island
300 kilometers south of Tokyo was also included in the study.
The annual average air concentrations of lead ranged from
0.024 ug/m on the island up to 1.3 /ug/m in one Tokyo district.
The concentrations in the other 9 districts varied from 0.2
ug/m to 1.0/Ug/m . The arithmetic means of blood lead levels
ranged from 15.9 ug/100 ml to 20.6 ug/100 ml, showing a
significant association between atmospheric lead concentrations
and blood lead levels. However, blood lead levels on the island,
where lead concentrations were the lowest, amounted to 17
ug/100 ml, a value higher than those found in two suburbs of
Tokyo. The authors concluded that, in general, blood lead levels
increase with urbanization, but that it was difficult to establish
any direct relationship between lead levels in air and lead
levels in blood and urine.
Griffin et al. J1975) exposed adult male volunteers 23 hours
per day for about 18 weeks to airborne lead at 10.9 and 3.2
ug/m . The particles of alpha lead dioxide were primarily of
submicron size. The mean blood level of the men exposed to
10.9 ug/m reached a plateau of 37 ug/100 ml, after about three
months of exposure. The blood lead level of the men exposed to
3.2 ug/m increased to about 27 ug/100 ml, and also leyeled
off after about three months.
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The contribution of lead in air to Pb-B as inferred by
Goldsmith and Hexter (1967) is about 1.3 ug of lead per 100
ml of blood for each increase of lead in air of 1 iig/m . Azar
et al. (1973) estimated that about 1 ug/100 ml Pb-B corresponded
to about 1 ug/m lead in air (within the range of lead concentra-
tion of 2-9 ug/m ). The data provided by Coulston et al. (1972
a, b & c) and by Rabinowitz et al. (1974) give values of about
2 and 1.2 ug/100 ml per 1 ug/m , respectively. These estimates
apply to air concentrations below about 10 ug/m .
There is some supporting evidence for these estimates in anim-
al studies. Griffin et al. (1975) exposed rats and Rhesus mon-
keys to airborne lead particles (0.05-0.10 urn) 22 hours per
day at a mean concentration of 21.5 ug/m . A year-long exposure
gave rise to an increase of the blood level to 28 ug/100 ml
in rats and 17 ug/100 ml in monkeys. Levels of lead in the
control animals were about 5 ug/100 ml in rats and 4 iig/100
ml in monkeys. Lead concentrations in the organs also showed
elevated levels.
From these and other available studies, it is difficult to
conclude whether there exists a consistent relationship
between lead concentrations in ambient air and blood lead
levels in the general population.
Estimates made on the basis of several studies on the rela-
tionships of Pb-B to the dietary lead intake (Coulston et al.
1972a, b & c; Zurlo and Griffini, 1973; Nordman, 1975) gave a range
from 5.4-18.3 for men and 4.4-13 ug/100 ml per 100 ug oral
lead intake per day for women (WHO, 1976).
7.1.2 Lead in urine
Lead concentrations in urine have been used for the medical
surveillance of workers. Because of fluctuation of specific
gravity of urine, spot samples are not a reliable indicator of
exposure level.
Determinations of lead in urine may be useful for monitoring
lead exposures of groups of workers, along with other indicator
259
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of excessive lead absorption. The lead content of normal urine
varies from nondetectable levels up to 80 ug/1, with an average
of about 30 ug/1 (Elkins, 1959). However, recent studies on
lead levels in urine in persons with no known high exposures
to lead revealed much lower levels. Tsuchiya et al. (1975)
indicated about 12 ug/1 as a mean value obtained from 2,300
policemen in Japan.
Moderate lead absorption will give rise to an increase of
100-150 ug/1 within a few weeks (Elkins, 1959). Values ranging
from 150 to 200 ug/1 may be considered as a borderline, and
an excess of 200 ug/1 is indicative of harmful exposure.
According to the Subcommittee for Occupational Health of the
Permanent Commission and the International Association of
Occupational Health (Subcommittee Reports, 1969), 150 ng/m
lead in air corresponds to 130 ug/1 lead in urine. Tsuchiya
and Harashima (1965) concluded that for a 48-60 hour work week
an average air lead concentration of 100 iig/m would lead to
an average urinary lead level of 150 ,Ug/l.
It should be, however, noted that "normal" rates of lead
excretion in urine may be found even when the exposure is
high (WHO, 1976). Lead in urine following mobilization by
chelating agents is discussed in Section 9.
7.1,3 Lead in teeth and hair
Lead concentrations in teeth and hair have been used as
indicators of long-term exposure, but the information is
inadequate for assessing their usefulness and reliability
(WHO, 1976).
7.2 Concentrations in biological media as indices of
concentration in critical organs
There is no information that could be used for assessing
the concentration of lead in organs considered as critical
(bone marrow, nervous system, kidney) from the concentrations
of lead in blood, urine or other indicator media (Task Group
on Metal Toxicity, 1976 ; WHO, 1976).
260
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8. Effects and dose-response relationships
The following description of the effects and dose-response
relationships is based mainly on human data. Animal data are
used only as supporting evidence, when it is considered
necessary.
Although the biological effects of lead in man are fairly well
defined, the precise exposures or doses that are associated with
the effects are rarely known.
There are few reports on the relationship between environmental
concentrations and effects of lead. An example is Horiuchi and
Ida's study (1955). In order to derive a maximum allowable
concentration of lead in the air of the working environment they
measured lead concentrations in the air of lead smelting plants,
and estimated net exposures for workers in each plant by
conducting a "time study" on each worker. They concluded that
at 50 ug/m lead in the air the values of the erythrocyte count
and coproporphyrin excretion would remain normal, and that
no signs of increased lead absorption would appear.
Some effects of lead are closely related to the measured levels
of lead in blood, others are not. Lead in blood cannot be used
as a reliable indicator of the exposure or dose for individuals,
but it is most useful as an epidemiological indicator for
assessing population exposure (WHO, 1976). The relationship
between blood lead levels and the onset of a number of effects
is shown in Fig. 1. Types of effects of inorganic lead salts
as related to estimates of absorption are summarized in Table
4.
8.1 Local effects
There is no evidence that inhaled lead has local effects on
the respiratory system in man, but the inhalation of lead
(10 ^ug/m for 3-12 months) by rats reduced the number of
macrophages that could be flushed from lungs (Bingham, 1970) .
Damage of alveolar macrophages by lead was demonstrated
in vitro (Beck et al., 1973).
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Aug (1931) considered lead colic as a direct effect of lead
on smooth muscle of the intestine, but this view is not
generally accepted (Hamilton and Hardy, 1974).
8.2 Systemic effects
Lead may cause both acute and chronic effects which usually
result from the accumulation of lead in the body over a certain
period of time. The major effects are related to four organ
systems, i.e. hemopoietic, nervous, gastrointestinal and renal,.
Symptoms, signs and pathology of inorganic lead poisoning have
been described in a number of monographs (Cantarow and Trumper,,
1944; Johnstone and Miller, 1960; Hunter, 1969; Waldron and
Stofen, 1974; WHO, 1976).
8.2.1 Acute effects
The most common form of acute lead poisoning is gastrointestinal.
Acute lead poisoning may result both from short-term massive
exposure and from long-term lead intake. After an initial stage
of anorexia, symptoms of dyspepsia, and constipation, there is
an attack of colic characterized by diffuse paroxysmal abdominal
pain. The skin is usually pale, the pulse slow and the blood
pressure may be increased. These signs and symptoms reflect the
spasmodic contraction of smooth muscle, probably related to vagal
irritation (Hamilton and Hardy, 1974).
Acute lead encephalopathy in adults is rare, but numerous cases
have been observed in children with pica in the United States
(NAS, 1972; Lin-Fu, 1976) and less frequently in Europe and Japan,
Severe forms of encephalopathy develop suddenly with the onset of
seizures and may result in coma and/or cardiorespiratory arrest.
Prodromal manifestations rarely occur, but some children may
have anemia and mild colic prior to the onset of the acute
encephalopathy syndrome which includes vomiting, apathy, drowsi-
ness, stupor, ataxia, hyperactivity and other neurological
signs and symptoms. Lead concentrations in blood associated
with acute encephalopathy may range from about 80-100 to 300
iig/100 ml (NAS, 1972; Chisolm, 1973).
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8.2.2 Chronic effects
8.2.2.1 Hemopoietic system
Anemia is a common sign among occupationally exposed workers,
although it is often so mild or moderate that it may not be
detected unless observation on a group basis is carried out.
Anemia due to lead is micro- or normocytic, but not macrocytic,
being caused by a combined effect of the inhibition of hemoglobin
synthesis and shortened life span of circulating erythrocytes.
The characteristic "pallor" associated with lead anemia is
described less frequently in recent reports. This is probably
due to the fact that past occupational exposures to lead were
higher than they are today.
Increased numbers of basophilic stippled red cells and reticulo-
cytes may also be seen in certain cases of lead anemia, but
this is not pathognomic of plumbism. Nor are they good indicators
for the study of dose-effect or dose-response relationships.
According to numerous studies performed in recent years, many
stages in the pathway of heme synthesis are inhibited by lead,
as summarized in Figure 2.
Delta-aminolevulinic acid dehydrase (ALA-D), which catalyzes the
formation of porphobilinogen from 6-aminolevulinic acid (ALA),
and heme synthetase (heme-S), which incorporates iron into
protoporphyrin IX (PP IX), are the enzymes most easily affected
by lead (Eriksen, 1952; Dresel and Falk, 1956a, 1956b; avian
erythrocytes were used in these studies in vitro). Higher lead
concentrations also block the formation of ALA from glycine
and succinate due to the inhibition of ALA-synthetase (ALA-S);
coproporphyrinogen decarboxylase (CPG decarboxylase), which
converts coproporphyrinogen (CPG) into PP IX, is also inhibited
(Goldberg et al., 1956; Wada et al.f 1972).
Wada et al. (1972) demonstrated a remarkable reduction in the
activities of ALA-D and heme-S, a slight elevation of ALA-S
14
activity, and a parallel reduction of C-glycine incorporation
263
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into heme and globin in erythroid cells of bone marrow of lead-
exposed workers. Increased activity of ALA-S contrasts with
the in vitro observation of Goldberg et al. (1956).
Depression of ALA-D activity in erythrocytes following lead
absorption has been observed in many studies (Lichtman and
Feldman, 1963; Bonsignore et al., 1965; Hernberg and Nikkanen,
1972; Griffin et al., 1975K Partial inhibition of ALA-D is a
useful indicator of lead absorption, but it is no> regarded
as a deleterious effect per se (Zielhuis, 1974) becabre the
enzyme appears to possess a large reserve capacity. In more
advanced states of lead absorption, there may be an increased
excretion of 6-aminolevulinic acid in urine (ALA-U), and of
coproporphyrin in urine (CP-U), an elevation of ALA in serum
and an increase in free erythrocyte protoporphyrin (FEP) due
to an effect of lead on the various stages of heme synthesis.
These inhibiting effects will finally result in a reduction
of heme synthesis and cause anemia.
The inhibition of ALA-D activity is correlated with the concen-
trations of lead in blood. Hernberg et al. (1970) showed a negative
linear regression over a range of 5 to 90 ug/100 g Pb~B, when
ALA-D was plotted on the logarithmic scale (Figure 3). ALA-
D activity is inhibited by about 80% at a blood lead level of
'"O ug/100 ml, and almost totally at the levels of 70-90 ug/100
ml, rimilar results were reported by Millar et al. (1970) and
Weissberg et al. (1971). However, a study by Sakurai et al.
O974) did not show statistically significant negative correlatior
in the control group, whereas Hernberg et al. (1970) found a
correlation coefficient of -0.90 in a control group of 16 medical
students. According to Sakurai et al. (1974), there is a limit
of Pb-B about 20-30 ug/100 ml below which there is no decrease
in ALA-D activity.
Similarly Wada et al. (1976) reported a limiting Pb-B level
of about 15/ug/100 ml, below which ALA-D showed no correlation
with Pb-B levels. Low precision in the determination of ALA-
D levels may be a reason for the results obtained by Sakurai
et al. and Wada. However, as shown in Figure 3, ALA-D activity
264
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of the erythrocytes of workers exposed to very low lead levels
is nevertheless somewhat depressed in comparison with the control
group, although Pb-B levels of both groups were found to be
in the same range of 10-25 ,ug/100 g. The depression of ALA-D
activity among lead workers with normal blood lead levels may
imply that the workers have had higher blood lead levels some
weeks prior to the date of blood sampling. There is a possibil-
ity that a qualitative change in the ALA-D molecule may persist
after the blood lead level returns to normal.
Increased ALA excretion in urine has been observed at blood
lead levels of 40-50 ug/100 g in many studies (Selander and
Cramer, 1970; Hernberg et al., 1970; Haeger-Aronsen, 1971;
Tsuchiya et al., 1972). However, the relationship between ALA
in urine and blood lead levels is not linear. The increase of
ALA in urine becomes very marked when the blood lead level
exceeds 40-60 ug/100 g, as shown in Figure 4.
ALA in urine may also be related to age. Tsuchiya et al. (1975)
found a negative correlation, higher ALA values being found in
urine in younger age groups.
Coproporphyrin excretion in urine starts increasing at approx-
imately 35-40 ug Pb/100 ml blood. According to Tola et al.
(1973), it is almost as sensitive an indicator of lead absorption
as ALA in urine.
PP IX in erythrocytes (free erythrocyte porphyrin, or FEP)
is another sensitive indicator of lead absorption. Zielhuis
(1975) concluded that there is a no-effect level of Pb-B for
the increase of FEP at about 20-25 ug/100 ml in adult females
and children, and at 25-30 ug/100 ml in adult males. This
difference in blood lead levels among men, women, and children
may possibly be explained by the difference in the sensitivity
of FEP to iron deficiency or hemopoietic function.
An increase of the number of reticulocytes as well as basophilic
stippled red cells is noted at blood lead levels of 60-80
265
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ng/100 ml. However, in general, the degree of anemia does not
correlate with blood lead levels. When blood lead level is
about 70-80 /ug/100 ml or more, frank anemia may develop in some
individuals (Task Group on Metal Toxicity, 1976) . However, good
nutritional status may prevent recognizable lead anemia.
Another possible mechanism involved in the development of
anemia is the shortening of the life span of erythrocytes.
Tho exact manner in which the shortening of the life span
occurs has not been elucidated, but it is most likely that
the mechanical fragility and osmotic resistance of erythrocytes
play an important role. A detailed discussion of this mechanism has
been presented by Waldron and Stofen (1974) and Task Group
on Metal Toxicity (1976).
8.2.2.2 Nervous system
Increased lead absorption may give rise to effects on both the
central and peripheral nervous systems. Effects on the central
nervous system which are manifested as encephalopathy are seen
more frequently in childhood lead poisoning from pica or other
causes, possibly because children are more sensitive to the
action of lead than adults (Lin-Fu, 1976). Subclinical effects
on the peripheral nervous system have been reported in occupa-
tionally exposed workers.
It is sometimes difficult to make clear-cut distinctions between
acute and chronic encephalops hy because the so-called chronic
encephalopathy may be either an effect on the brain of a
long-term exposure to lead or a residual effect of an acute
episode of encephalopathy. The severity of encephalopathy
depends on a combination of factors which include intensity
and duration of exposure, and age.
Milder symptoms of the effects on the central nervous system
may include mental deterioration, hyperkinetic or aggressive
behavior, loss of appetite, difficulty in sleeping, abdominal
pain, and vomiting. However, the etiology of such manifestations
is not always clear, because those children who suffer from
cerebral injury due to traumatic, toxic, viral or bacterial
266
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agents often incur persistent pica which may in turn result
in elevated intake of lead (NAS, 1972). Neurological sequelae
of acute lead encephalopathy have been reported by Chisolm
(1973); in severe cases they may include convulsions, cortical
atrophy, hydrocephalus, and idiocy; in milder cases there is
lack of motor coordination and sensory perception (WHO, 1976).
Subclinical neurophysiological effects may be observed among
young children with moderately elevated blood lead levels,
between 40 and 80 ^ig/100 ml (Lin-Fu, 1976). David et al. (1972)
observed higher lead levels and higher post penicillamine urine
lead levels among the children with hyperactivity than in the
control children. However, from this study, it could not be
concluded whether lead exposure was caused by hyperactivity
or whether hyperactivity was caused by lead exposure. Landrigan
et al. (1975) observed neurological dysfunction in 46 symptom-
free children 3-15 years of age with moderately elevated blood
lead concentrations (mean: 48 yug/100 ml) and compared them to
children who showed less than 40 ug/100 ml (mean: 27 vig/100 ml) .
The first group showed lower scores (Wechsler Intelligence Scale)
and poorer results in the fingerwrist tapping test than the
second group, but there were no differences between the groups
in full-scale I.Q., verbal I.Q., behavior or hyperactivity
ratings. This study, however, did not present conclusive
evidence of lead as the causative factor. Lin-Fu (1976) cites
some animal studies which suggest that hyperactivity might
result from moderate lead exposure via mother's milk.
It is not certain whether a Pb-B level in children below 100
ug/100 ml can be associated with an increase in prevalence
of mental retardation (Perlstein and Attala, 1966) or hyper-
activity (David et al., 1972). Recently, Zielhuis (1975)
concluded that there is some evidence that no-effect Pb-B
levels for chronic encephalopathy are somewhat lower in
children (probably at 50-60 ug/100 ml) than in adults (about
80 ug/100 ml). Since chronic effects on the central nervous
system may be a consequence of repeated high exposures, it
is difficult to evaluate dose-effect and dose-response
267
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relationships unless careful follow-up studies, including
exact information on previous lead exposures, are performed.
Reports on peripheral lead ner ;opathy have been rare in recent
years. In the past, wrist drop caused by palsy of the N. radialis
was observed among lead workers with severe exposure. In rare
cases foot drop accompanied wrist drop.
Peripheral neuiopain-.' is characterized by the involvement of
motor neurons but with little sensory involvement. Subclinical
neuropathy may be detected by electrophysiolocical techniques
(Seppalainen and Hernberg, 1972). Nerve-conduction velocity
measurements can be ased for early detection of overexposure,
but not for diagnosis of lead poisoning in individuals
(Seppalainen et al., 1975).
A statistically significant (P<0.02) reduction of the peripheral
nerve conduction was observed in a group of 24 children with
known lead absorption (Pb-B 40 ug/100 ml; more than 600 mg Pb
excreted in urine per 24 h) (Feldman et al., 1973).
Slowdown of nerve conduction in the upper extremities, partic-
ularly in the slower fibers and distal portion, and electro-
myographic abnormalities such as fibrillations and diminished
number of motor units on maximal contraction, were found in
lead workers with a mean lead blood level of 40 ± 9 tig/100 ml
(maximum 65yug/100 ml) and n< signs of lead poisoning (Seppalainen
et al., 1975).
There was no correlation between neurological tests and the
biochemical indices of exposure. According to Hernberg (1976)
the no-observed-effect Pb-B level for such effects is most
likely about 50 ug/100 ml (Fig. 1) but a more precise
evaluation of the degree of exposure is needed to confirm
these findings.
8.2.2.3 Gastrointestinal tract
Lead colic may occur at comparatively low levels of exposure
in industrial workers (40-80 ug/100 ml Pb-B, Beritic, 1971) and
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in children and infants. It is usually accompanied by other
signs of poisoning. There is not enough data to establish
a dose-effect or dose-response relationship (WHO, 1976) .
8.2.2.4 Kidney
Few reports are available on occupational lead poisoning
associated with nephropathy (Clarkson and Kench, 1956; Goyer
et al., 1974). On the other hand, renal tubular dysfunction
has been reported in children (Marsden and Wilson, 1955;
Chisolm and Leahy, 1962). People who consume lead-contaminated
whiskey may also show impairment of the renal tubular transport
mechanism (NAS, 1972).
Renal functional disturbances in children, similar to those
seen in the Fanconi syndrome, are characterized by aminoaciduria,
glucosuria, and hyperphosphaturia with hypophosphatemia (Ferm
and Carpenter, 1967).
Degenerative changes in the proximal tubular lining cells
involve mitochondrial swelling. Eosinophilic dense staining
nuclear inclusion bodies, which indicate a more specific change,
have also been observed. The inclusion bodies seen in lead
poisoning have a characteristic outer fibrillar margin,
recognizable by electron microscopy, which is useful in
distinguishing them from other nonspecific bodies (Task Group
on Metal Toxicity, 1976)
They are excreted during EDTA administration and may contain
lead which is mobilized by EDTA (Goyer et al., 1974). All these
functional and morphological changes are reversible upon
treatment with chelating agents such as EDTA, but only in
cases of relatively short-term lead exposure (Chisolm and
Leahy, 1972). Lead in blood levels associated with such effects
may range from 40-120 ug/100 ml (Pueschel et al., 1972).
Long-term exposure to lead may give rise to the development
of irreversible functional and morphological renal changes.
These consist of intense interstitial fibrosis, tubular atrophy
and dilatation. The involvement of glomeruli may occur at a
2V3
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relatively later stage. A consequence of such chronic renal
damage may be saturnine gout in which uric acid level is
ncreased in urine (Erunerson, 1968). However, it is not well
known whether the pain in the joints often seen in cases of
lead poisoning is directly related to the increase of uric
acid in urine.
It is still controversial whether an exposure to lead in
childhood ib likely to be associated with occurrence of
nephropathv in later life. There is one study from Australia
which sh07s that a long-term exposure to lead early in life
may later result in chronic nephropathy which is identical
to the chronic nephropathy observed in adult cases of lead
poisoning (Emmerson, 1968). On the other hand Tapper (1963)
and Chisolm (1970) in the Unites States performed 10-20 year
follow-up studies on children who had suffered lead poisoning
and found no increase of nephropathy later in life.
A WHO task group concluded that prolonged exposure to lead
associated with Pb-B levels above 70 ug /100 ml may result in chron-
ic irreversible nephropathy (WHO, 1976) .
8.2.2.5 Liver
There have been relatively few recent reports on the liver in
relation to lead poisoning. Quoting a 1934 study of Flury,
Cantarow and Trumper (1944) mentioned that the disturbances in
liver function probably prece uts the actual morphological
changes in the liver cells. Tsuchiya et al. (1955) performed
serum fraction analyses on a.^dd workers in Japan. They noted
an increase of A/G ratio in serum on a group basis, which may
be related to subclinical effects on the liver. A study by
Cooper et al. (1973) revealed a statistically significant
correlation between blood lead levels and SCOT values, but
it is doubtful that lead may cause significant functional and
morphological changes in the liver. More detailed examinations
in highly exposed subjects may show some minor functional changes.
8.2.2.6 Cardiovascular system
According to Dingwall-Fordyce and Lane (1963) workers who had
been exposed to high levels of lead in the years before
270
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retirement showed higher risk of cerebrovascular accidents
than other retired workers who had been exposed to lower lead
levels or not exposed at all. A study by Cooper and Gaffey
(1975) in the United States did not confirm Dingwall-Fordyce
and Lane's results. This may be due to a difference in lead
exposure, i.e. workers were formerly exposed to much higher
levels of lead than is the case now. There may also be other
factors involved, since the workers in the Dingwall-Fordyce
and Lane study who had been exposed to high levels of lead
were selected from a different socioeconomic stratum than other
workers in the same study who had been exposed to lower levels.
The association between hypertension and lead exposure has
not been clarified (Cramer and Dahlberg, 196'); Monaenkova and
Glotova, 1969). There are several reports suggesting that
electrocardiographic abnormalities in man could be caused by
lead (Myersen and Eisenhauer, 1963; Freeman, 1965; Silver and
Rodriguez-Torres, 1968).
8.2.2.7 Endocrine organs
The possible effects of lead on endocrine organs include impair-
ment of thyroid and adrenal function, and disturbance of
tryptophan metabolism (Saridstead et al., 1970; Urbanowiecz
et al., 1969), but the latter effect could not be confirmed
by Schiele et al. (1974). The interpretation of these
findings is difficult at present (Task Group on Metal Toxicity,
1976).
8.3 Carcinogenic, teratogenic and genetic effects
8.3.1 Carcinogenic effects
Although there is no evidence that lead is carcinogenic to man,
there are several reports in which benign and malignant tumors
were produced in experimental animals. In most of the available
studies malignant and benign renal neoplasms were induced in
mice and rats by oral or parenteral administrations of various
types of lead compounds in rather high doses. A report published
by the International Agency for Research on Cancer (IARC, 1972)
concluded that there was no evidence to suggest that exposure
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to lead salts causes cancer in any sites in man. The level of
human exposure equivalent to the levels of lead acetate pro-
c.ucing renal tamor'5 :' , rats would be 810 ing/day (550 mg Pb) .
8.3.2 Teratogenic effects and effects on reproduction
Stillbirths and miscarriages have often been reported as
a possible result of exposure to lead (Cantarow and Trumper,
1944), but- th<" T .s ro epid' niological evidence to support
these claims, o-^-.-iarly, :,here is no evidence tha . lead
affects in any way the in utero development of the fetus in
man, although there are some experimental studies in animals
that indicate that lead may have some effects on litter
size, weight, survi ^1 rate and possibly behavior (Stowe
and Goyer, 1971; Snowdon, 1973).
8.3.3 Genetic effects
The evidence on a possible association of lead exposure and
chromosomal aberrations in man is inconclusive and contradictory.
This may be due to the fact that in several studies exposure
was mixed (Pb, Zn, Cd) (Deknudt et al., 1973; Schwanitz et
al., 1975; Bauchinger et al., 1976). The available experimental
data are too scarce to clarify this question (Muro and Goyer, 1969)
8.4 Modifying factors and interactions
There is some indication that certain biological effects of
lead occur at lower Pb-B levels in children than in adults
(Rolls et al., 1975; Zielhuis 1975; Lin-Fu, 1976). It has
been noted that severe lead poisoning in children occurs more
frequently in summer, but the reasons are not clear (Baetjer,
1959). The evidence favoring an influence of dietary composition
on the susceptibility to lead is almost entirely experimental.
Low phosphorus, calcium and iron enhance lead absorption and
low protein diet appears to increase the susceptibility to
lead poisoning (Six and Goyer, 1970; Goyer and Mahaffey, 1972;
Mahaffey, 1974). Interactions of lead with other metals are
poorly understood. There seems to be a synergistic interaction
between lead and cadmium in experimental teratogenesis (Ferm,
1969), whereas zJ c: appears to be antagonistic to lead
(Willoughby et al ., 1972; Cheh and Neilands, 1973).
272
-------
9. Diagnosis, treatment and prognosis of lead poisoning
9.1 Diagnosis
The value of diagnostic tests in lead poisoning has been recently
reviewed by a WHO group of experts (WHO, 1976). For differential
diagnosis of lead poisoning it is essential to determine lead
in blood and <5-aminolevulinic acid and coproporphyrin in urine.
Other tests including ALA-D activity, hemoglobin, FEP and
basophilic granulation may provide useful supplementary in-
formation.
Subjects who have developed symptoms some months prior to
diagnosis and who have been removed from exposure at the time
of development of symptoms may require calciv:.v-EDTA provoca-
tion tests, since blood lead levels in these cases may have re-
turned to almost normal at the time of diagnosis. If urinary
lead excretion within 24 hours after one gram of calcium-EDTA
intravenous infusion exceeds one milligram, such subjects are
considered to have had abnormally high lead exposure in the
past (Rieders, 1960). According to a technique reported by
Emmerson (1963), the upper limit in healthy adult subjects is
less than 600 ng lead excreted over 4 days after a one gram
injection of calcium-EDTA.
Early detection of health impairment due to occupational
lead exposure has been extensively discussed in a recent
report of a WHO Study Group (WHO, 1975).
9.2 Treatment
The first and foremost measure to be taken in any case of
lead poisoning is, of course, removal of the victim from the
source of exposure. Chelating agents which may be used in
treating cases of both acute and chronic lead poisoning are
BAL (British Anti-Lewisite), calcium-EDTA (monocalcium
ethylene diamine tetra-acetic acid) and D-penicillamine.
Calcium-EDTA is the agent most widely and effectively used.
Abdominal colic and wrist drop disappeared completely after
a few courses of calcium-EDTA injections, leaving no sequel
to the poisoning (Nakasawa et al., 1969). The present author
273
-------
believes that calcium-EDTA has fewer side effects than BAL.
Dose schedules for treatment of lead poisoning by the three
above-mentioned chelating agents are summarized in Table 5.
The daily dose should not exceed 220 mg/kg body weight every
12 hours since calcium-EDTA can cause hazardous effects
(Aronsen et al., 1968). For children, intravenous doses should
not exceed 75 mg/kg every 6 to 12 hours (Chisolm, 1973). Side
effects such as "lacrimation, nasal congestion, sneezing,
muscular pains and hypotension may be seen during or after
treatment by calcium-EDTA (Waldron and Stofen, 1974).
Chronic renal damage with reduced clearance is a contra-
indication for the •T.e of calcium-EDTA or D-penicillamine.
Chelating agents should not be administered orally or
intravenously for preventive purposes. However, in pediatric
emergency, if blood lead level exceeds 80 ug/100 ml, even
though no symptoms are recognizable, immediate chelation
therapy by calcium-EDTA is recommended (Chisolm, 1973) .
For more detailed information on treatment of lead poisoning,
the reader is referred to the handbooks by Krupp and Chatton
(revised annually) and Cecil-Loeb Textbook of Medicine
(revised every 3 years).
9.3 Prognosis
Anemia, gastrointestinal disturbances and neurological
disorders caused by lead poisoning are generally considered
completely curable by proper .reatment if diagnosis is made.
A slight or moderate renal tubular disorder which occurs at
an early stage of lead poi^^ning is considered reversible.
In childhood lead poisoning, residual effects on the central
nervous system are common (NAS, 1972).
In general, if workers who show moderate or subclinical signs
of lead poisoning are removed from exposure, signs or sub-
clinical symptoms will disappear within a few weeks to several
months.
10. Tetraethyllead
One of the alkyl compounds, tetraethyllead (TEL), is widely
used as an anti-knock agent in motor fuels. The amount used
27/1
-------
varies in different countries, but in general is about 0.1%
of the fuel content. The combustion of TEL in motor fuel is
the main source of lead in ambient air. Almost all the TEL
is decomposed by combustion into inorganic lead compounds
such as lead halides and oxides, but very small amounts of
organic lead which have not been affected by combustion escape
into the ambient air. According to a survey conducted by the
U.S. Department of Health, Education and Welfare (1965), TEL
concentrations in ambient air did not reach 10% of inorganic
lead values and were probably considerably less than 10%.
The concentrations of TEL in urban areas at present are too
low to have adverse effects on the health of the general
population.
Since TEL is very volatile, the absorption is usually by
inhalation, but the liquid is easily absorbed by the skin as
well as by the gastrointestinal tract. After absorption TEL
is distributed to various tissues, particularly to the brain
and other organs, decomposing into triethyl lead and minute
amounts of inorganic lead in the tissues and organs, mainly
in the liver, and is excreted rapidly into urine.
Bolanowska et al. (1967) studied the metabolism of TEL using
three accidental cases of acute fatal poisoning. The highest
concentrations of both triethyl and total lead were found
in the liver of all three cases, and in descending order of
content, in the kidneys, pancreas or brain, and heart. The
person who had ingested the TEL showed the highest concen-
tration of both triethyl and total lead. The couple who had
inhaled TEL showed much lower concentrations of triethyllead
in all the above-mentioned organs except the liver. This in-
dicates that TEL is metabolized to triethyllead within a
short time period, i.e. within hours of absorption. Triethyl-
lead may be retained in the body more than 20 days, although
the average concentrations of triethyllead in the tissues
diminish very rapidly. High urinary lead levels (400-800 ug/1)
were observed, indicating that triethyllead is excreted into
urine within a relatively short period of time, partially
metabolized into inorganic lead.
275
-------
The acute toxicity of TEL is much higher and the poisoning
is quite different from that caused by inorganic lead.
Accidental exposure to TEL may result in lack of appetite,
nausea, vomiting, and diarrhea. Complaints of irritability,
restlessness, nervousness, and anxiety may develop before
severe symptoms appear. These acute or subacute symptoms have
seldom been reported in recent years among workers who
produce TEL, because of improvements in production methods,
and also because of early detection of accidental exposure
by the monitoring of lead levels in air and urine. However,
accidents may occur in instances where TEL-containing gasoline
storage tanks are cleaned or where cargos of TEL are transported
by ship.
The earliest symptom of TEL poisoning is insomnia, and the
main organ affected is the central nervous system. The poisoning
is usually acute, developing into toxic psychosis with hallucina-
tions, delusions, excitement, and bad dreams, and may result
in death. If mental symptoms cease and death does not occur,
the patient usually recovers without sequelae after 2 to 3
months. Abdominal pain and peripheral neuropathy, which are
common symptoms of inorganic lead poisoning, have seldom been
observed in cases of TEL poisoning.
Cassels and Dodds (1946) and Kehoe (1942) agreed that if the
urinary excretion of lead is ^ess than 100 /ug/1 at the time
symptoms such as those mentioned above develop, the cause is
probably not the absorption of TEL. If the urinary concentration
is about 150/ug/1, mild symptoms may develop, but TEL poisoning
is usually associated with concentrations of 300 yug/1 or more.
Chronic exposure to TEL in which lead in urine was 64 ± 33
/ug/1 did not give rise to adverse effects on health (Stopps
et al., 1966).
Since organic lead is excreted into urine rather rapidly,
there is little possibility of inorganic lead poisoning
occurring due to exposure to TEL.
276
-------
The most important measure for detecting accidental exposure
and for preventing early effects of TEL is the periodic
monitoring of urinary lead levels and of lead concentrations
in the air of working environments.
277
-------
Table 1. Air lead concentrations in some cities of the
European community 1971-72 (From CEC, 1973) .
Location
Non- urban
Small cities:
residential
areas
traffic areas
Continuous Traffic-hour
measurements measurements
monthly means < 0.5 /ug/iru
daily maxima < 1 /ug/m
3
monthly means < 1 ,ug/m_
daily maxima < 2 /ug/m
monthly means < 3/u
individual
measurements < 8 /ug/m"
Metropolitan
areas:
residential
areas
ug/m individual
ug/m
_ measurements < 4 .ug/m"
monthly means < 2
daily averages
up to 8
traffic areas monthly means ^ 3
up to 6.5/ug/m monthly means <10/ug/m
daily maxima - single measure- 3
up to 10 /ug/m ments up to <20/ug/m
278
-------
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279
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Table 3. Means and standard deviations of lead in blood and
urine and ALA-D in urine (From Tsuchiya, 1976).
Blood lead
(xUg/100 ml)
Urban
Male children
Female children
9
8
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.1+2.4* (74)
Lead in urine
(/ug/1)
5.5+3.1
4.9+2.9
(78)
(66)
ALA-D in urine
(mg/1)
3.3+1.1 (78)
3.1+1.0 (67)
Suburban
Male children 7.9+2.4 (84) 4.8+2.3 (83)
Female children 5.4+1.8 (67) 4.5+1.8 (66)
3.2+1.0 (84)
3.1+0.9 (67)
* Significant difference (P < 0.01) between urban and suburban
children. Number of persons examined is given in parentheses.
280
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282
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Table 5. Dosage schedules for treatment of lead poisoning
(From Waldron and Stofen, 1974) .
Drug
Contra-
Dose Route indica-
tions
BAL 18 mg/kg/24 hr for 2 days Deep Hepatic
12 mg/kg/24 hr for 1 day intraT disease
^ ^ J muscular
6 mg/kg/24 hr for 7 days
Ca-EDTA 50 mg/kg/24 hr for 5 days Intra- Kidney
Allow 2 days before ^nOUS disease
starting a second course ?r,
^ intra-
muscular
D-penicillamine 0.9-1.5 g/24 hr Oral Kidney
disease
?83
-------
HEMATOLOGICAL SYMPTOMS
• ALA-D inhibition in RBC
• PP elevation in RBC
• ALA excr. increased in urine
• CP excr. increased in urine
• Shortening of RBC life span
• Reticulocytosis
• Anemia
OTHER SYMPTOMS
• Subjective symptoms
• Peripheral neuropathy
• Encephalopathy
• Colic
• Kidney function impairment
50 100 150
Pb, )jg/100ml
200
250
Figure 1. Relationship between blood lead levels and the
onset of a number of effects (From Hernberg, 1976)
284
-------
i.NZYMATH
STEPS
INHIBITED
BY Lt.AD
NORMAL PATHWAYS
METABOLITES AND
ABNORMAL PRODUCTS
ACCUMULATED
IN HUMAN
LEAD POISONING
r'Kl i)S
/CYCLE
i Pb
SLCCINYL CoA+GLYClNE
ALAS
INTO SERUM Fo
RETICULO- MAY BE INCREASED
CYTES
1 (IROGENASE
. COPROPOR-
1 PlIYHINOGEN III
7 Pb
HEMOGLOBIN
-ALA SERUM, URINE
URO IN URINE
_COPRO,
IN rbc, URINE
i j COPROGENASE
PKOTOPOIU'llYRIN IX
(PKOTO 9)
IIEME
SYNTHETASE
| EC
HEME
&
- Pb
t
fte
PROTO 9 IN rbc
(TEP)
EERRITIN, To
""MICELLES IN RBC
DAMAGED MITO-
CHONDRIA 8
IMMATURE rbc
FRAGMENTS
(BASOPHILIC
STIPPLED CELLS)
Figure 2. Lead interference with the biosynthesis of heme
during several enzymatic steps, with the utiliza-
tion of iron, and, in erythrocytes, with globin
synthesis (From NAS, 1972).
285
-------
200-
150
^ |3°
^ 100
70'-
a.
O
<
40-
30-
20 -
10
-i-
10 20 30
Pb-B (
40
50
60
Figure 3. Relationship between blood lead concentration (Pb-B)
and erythrocyte ALAD. Open circles, control group.
Solid circles, Pb group. Broken lines indicate the
means of ALAD for every 5 /ug/100 g subcategories of
Pb-B. Transverse dotted line is the lower 95%
confidence limit (two-tailed) (From Sakurai et al.,
1974).
286
-------
40
30
r^-
20 40
Pb-B
60 80
(MQ/IOOO)
100
Figure 4. Relationship between blood lead concentration (Pb-B)
and urinary ALA. Solid circles, data from rubber hose
and automobile tire factory; open squares, data from
storage battery factories (From Sakurai et al., 1974;
287
-------
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MERCURY
Maths Berlin
1. Abstract
Mercury occurs as inorganic and organic compounds (mercury vapor,
mercury liquid, mercury salts, short-chain alkylmercury compounds,
aikoxyalkylmercury compounds and phenylmercury compounds), all
having different toxicological properties.
Mercury can be analyzed in water, air and biological material
by atomic absorption methods and by neutron activation analysis,
and can be detected down to concentrations of a tenth of a ng.
Methylmercury can be detected in biological material at levels of
a few ng by extraction with benzene after strong acidification
with hydrochloric acid, followed by gas chromatographic analysis
of methylmercury chloride.
Mercury is circulated naturally in the biosphere, 30,000 -
150,000 tons being released to the atmosphere by degassing from
the earth's crust and the oceans. In addition, 20,000 tons of
mercury are released into the environment each year by human
activities such as combustion of fossil fuels and other in-
dustrial release. 10,000 tons of mercury are produced yearly
for industrial use, a small part of which is used for synthetizing
organic mercury compounds.
In nature, mainly in the aquatic environment, methylmercury is
produced from inorganic mercury by a microbial activity. In fish,
the major amount of mercury is methylmercury.
The toxic properties of mercury vapor are due to mercury accumu-
lation in the brain causing neurological signs involving an un-
specific asthenic vegetative syndrome (micromercurialism). At
higher exposure levels mercurial tremor is seen, accompanied by
severe behavioral and personality changes, increased excitabi^-
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ity, loss of memory and insomnia. On a group basis, exposure
levels are likely to be reflected in mercury concentration in
blood and urine. Occupational exposure to mercury concentrations
tie
3
in air above 0.1 mg/m may produce mercurialism. Micromercurialism
has not been reported at concentrations below 0.01 mg/m"
The acute and long-term action of mercuric salts, phenylmercury
compounds and alkoxyalkylmercury compounds is likely to be
gastrointestinal disturbance and renal damage - appearing as
a nephrotic syndrome with tubular necrosis in severe cases.
The lethal dose in man is about 1 g of mercuric salt. The
mercury load on the kidney is best determined by analysis of
renal biopsy. Mercury concentrations of kidney between 10-70
mg/kg have been reported in poisoned cases. Levels below 3
mg/kg may be found in normal cases. Occasionally, mercuric
compounds may cause idiosyncratic skin symptoms which may
develop into severe exfoliative dermatitis. A specific form,
called acrodynia or pink disease, is seen in children. Most
cases show increased levels of mercury in urine.
The hazards involved in long-term intake of food containing
methylmercury or occupational exposure to methylmercury are
due to the efficient absorption (90%) of methylmercury in man
and the long retention time - half-time 70 days - with accu-
mulation of methylmercury in the brain. Chronic poisoning re-
sults in degeneration and atrophy of the sensory cerebral
cortex, paresthesia, ataxia, hearing and visual impairment.
Prenatal exposure causes cerebral palsy. Methylmercury concen-
tration in blood and hair reflects the body burden and the
concentration in brain of methylmercury. Intake resulting in
body burdens exceeding 0.5 mg/kg body weight is likely to give
neurological signs. This intake corresponds to blood values
exceeding 200 wg/1 and mercury levels in hair exceeding 50
mg/kg. Cerebral palsy may result from a lesser intake of
methylmercury.
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The history of mercury toxicology has been reviewed by Goldwater
(1974) , the pharmacology and toxicology by Clarkson (1972) , the
toxicology of methylmercury by a Swedish Expert Group (1971),
toxicology and epidemiology by Friberg and Vostal (1972), Task
Group on Jletal Accumulation (1973), Task Group on Metal Toxicity
(1976) and Task Group on Environmental Health Aspects of Mercury
(1976) .
2. Introduction
Mercury is a metal which is in liquid state at room temperature.
In addition to its metallic state, ^ercury occurs in compounds
as monovalent mercurous mercury and divalent mercuric mercury.
Mercury also exists in nature as organometallic compounds in
which mercury is covalently bound to carbon, in compounds of
+ '
the type RHg and RHgR where R and R1 represent the organic
moiety. The carbon-mercury bond is chemically stable due to
the low affinity of mercury for oxygen.
The affinity of mercury for sulfur and sulfhydryl groups is
a major factor behind the biochemical properties of mercury and
mercury compounds. The mercury-containing moiety binds to sulf-
hydryl groups of proteins in membranes and enzymes, thereby in-
terfering with membrane structure and function and with enzyme
activity. Thus mercury compounds which can form mercury-containing
+ ++
radicals or ions of type RHg-, RHg or Hg are generally cyto-
toxic as sulfhydryl groups are ubiquitous in organisms. The
molecular structure of the mercury compound, its stability in
the organism and its routes of biotransformation and excretion
will govern the toxicological properties for the higher or-
ganisms . Thus each mercury compound has its own toxicology
in relation to dose-effect and dose-response relationships.
From the toxicological point of view, it is convenient to divide
the mercury compounds into inorganic compounds and organic com-
pounds . Among the inorganic compounds, elemental mercury and
the divalent mercury salt are the compounds of toxicological
interest. It is doubtful whether mercurous mercury has any
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survival in the organism, although at present the possibility
cannot be precluded that mercurous mercury may be an intermediate
in the redox transformation of elemental and mercuric mercury
or vice versa in the body.
The organic mercury compounds can be divided into mercurials
relatively stable versus those rapidly split in the mammalian
body. Short chain alkylmercury compounds and diuretic mercurials,
pharmaceutically used, which are mainly excreted conjugated or
unchanged by the kidneys, belong to the former group.
Among the organic compounds rapidly splitting in the body and
of toxicological importance are the phenylmercury compounds
and methoxyalkylmercury compounds, both used extensively in
pesticides and preservatives. In the following, the toxicology
of each mentioned group will be treated independently.
3. Physical and chemical properties
Mercury, Hg, atomic weight 200.6; atomic number 80; density
13.6; melting point -38.9°C; boiling point 356.6°C; crystalline
form silver-white metallic liquid; oxidation state 1,2.
Metallic mercury is rather volatile. A saturated atmosphere
of mercury vapor contains approximately 18 mg Hg/m at 24°C.
Mercury vapor is regarded as insoluble in water. However, at
room temperature its solubility is approximately 60 mg/1. Its
solubility in lipids is on the order of 5-50 mg/1. In the
presence of oxygen, metallic mercury is rapidly oxidized
to ionic form. Mercuric salts, like halides, sulfates and
nitrates, are water soluble. In aqueous solutions, an equilibrium
is established between Hg°, Hg2 (mercurous) and Hg (mercuric).
The representation of the three oxidation stages is determined
by the redox potential of the solution and the presence of
compounds which can form complexes with the mercuric ions.
Mercuric ion Hg is able to form many stable complexes with
biologically important molecules or moities such as sulfhydryl
groups. Mercuric mercury forms four different complexes with
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the chlorine, HgCl , HgCl_, HgCl., , and HgCl. in water.
<(• O ^*
Mercurous mercury is rather unstable in the presence of bio-
logical molecules. In the presence of sulfhydryl groups it
undergoes disproportionation to one atom of metallic mercury
and to one ion of mercuric mercury.
The short chain alkylmercuric compounds form salts with the
halogens, which are highly volatile at room temperature, re-
sulting in highly poisonous air concentrations when saturation
occurs. The saturation concentration of methylmercury chloride
at 20Q> C is 90,000 ing mercury/m (Swensson and Ulfvarsson, 1963),
Other salts, such as hydroxide and nitrate of methylmercury,
are less volatile and thus less hazardous. Methylmercury di-
cyandiamide has been used in commercial pesticidal preparations
because of its rather low vapor pressure. Methyl- and ethyl -
mercury chloride have a high solubility in solvents and lipids.
Sulfydryl groups on proteins have a high affinity for the
methylmercuric group. Therefore, methylmercury occurs in the
organism bound mainly to sulfhydryl groups of large molecules.
Phenylmercury salts and methoxyalkylmercury compounds de-
compose readily and release mercury vapor.
4. Methods and problems of analysis
Mercury analysis at concentrations found in the environment and
in biological material (1-2,000 /ag/kg) is complicated, difficult
and requires considerable skill and experience on the part of
the analyst. Colorimetric, flameless atomic absorption and
neutron activation analysis are the three principal types
of methods which have gained general recognition.
The colorimetric method is based on the conversion of mercury
in the sample to a dithizone complex which is extracted by
organic solvents and the amount of dithizonate determined
colorimetrically. This method was formerly used extensively,
but its not so impressive limit of detection, 0.05 mg/kg
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in a 0.01 kg sample (Analytic Methods Committee, 1965), and
its time-consuming nature are disadvantageous.
Flameless atomic absorption and neutron activation method have
replaced the colorimetric methods. The detection limit for
atomic absorption is 1-5 ng of Hg. The reported precision,
expressed as variation coefficient, is generally better than
20% (Burrows, 1973). The detection limit for neutron activation
is 0.1-0.3/ug Hg in a 0.3 g sample; it has high specificity,
and the precision in terms of the variation coefficient is
better than 10%, as is the accuracy (Westermark and Ljunggren,
1972) .
Several interlaboratory comparisons have been published, il-
lustrating the errors encountered in analysis of biological
material under controlled practical conditions (Lindstedt and
Skerfving, 1972). The greatest errors are probably connected
with the collection, storage, transport and handling of the
samples, as mercury is volatile and easily lost. Mercury
vapor diffuses through plastic materials, adsorbs to surfaces
and absorbs into material such as polyethylene, silicone and
rubber. In biological material, bacterial activity can reduce
mercuric mercury, resulting in the loss of mercury vapor.
In aqueous solutions having low concentrations of mercury,
mercury tends to adhere to the surface of the collecting
vessels.
For determination of mercury in air, mercury can be absorbed
in impinger flasks with permanganate, on activated charcoal
filters or on other absorbants. Portable monitoring devices
have been used for direct determination of mercury in air.
In these instruments, the absorption of light emitted from
a mercury vapor lamp is measured. These units are, however,
subject to the interference of substances such as hydrocarbon
solvents often present in the working environment. The presence
of strong electromagnetic fields has also been reported to in-
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terfere with the result. Reactive tubes, Dreger tubes, have
been devised for simple screening (Wolf et al., 1974). Measure-
ment of very low levels of mercury in water requires precon-
centration by, for example, dithizone extraction or electro-
deposition.
Analysis of mercury in biological material may require oxidative
digestion or combustion in oxygen or some kind of extraction.
The method must be selected and adapted to the type of material
analyzed.
Alkylmercury compounds can be identified by thin layer chromato-
graphy or gas liquid chromatography. Quantitative analysis of
methylmercury is carried out using gas liquid chromatographic
techniques after extraction of alky liner cury from the sample
with benzene (Westoo, 1966; 1967). As all techniques used
involve non-destructive extraction of the alkylmercury from
the sample, the recovery has to be checked for every different
type of sample matrix as deficiency of extraction of mercury
will be determined by both the nature of the sample matrix
and the extraction procedures themselves. The detection limit
of the method, according to Westoo, is approximately 1-5 tig/kg
using a 0.01 kg sample. The precision is 3% at the 0.005/ug
level for fish muscle samples. The recovery is generally above
90% but varies with type of sample. Samples such as liver
and kidney are more difficult to extract than fish meat.
5. Production and uses
5.1 Production
Mercury occurs in the earth's crust mainly in the form of various
sulfides. The red sulfide, cinnabar, is the main content of the
mercury-rich ores which are mined, and may contain up to 70%
mercury. The world production in 1973 was about 10,000 tons
(Korringa and Kagel, 1974). In addition to the pure mercury
production, mercury is released into the environment by human
activities like combustion of fossil fuels, waste disposal and
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industrial activities, amounting to about another 10,000
tons per year (Korringa and Hagel, 1974). These figures should
be compared with the release of mercury by degassing from
the earth's crust and the oceans, estimated to fall between
30,000-150,000 tons per year, 30,000 tons being a minimum
figure (Korringa and Hagel, 1974).
Methylmercury is naturally formed in the aquatic environment
from elemental mercury and mercuric mercury. The methylation
is likely to occur in upper sedimentary layers of sea or lake
bottoms (Jensen and Jernelov, 1967, 1969; Jernelov, 1968).
The methylmercury formed is rapidly taken up by living or-
ganisms in the aquatic environment and, by degradation, gases
of (CH_)2Hg are formed and released into the air (Jensen and
Jernelov, 1968). DimethyImercury may be decomposed in the
atmosphere by acidic rainwater to mono-methyImercury compounds
and thereby re-enter the aquatic environment (Jensen and Jernelov,
1972). It may eventually be demethylated, thereby completing
the cycle. Little is known about the quantitative aspects of
these cycles. The local load of MeHg may be considerably in-
creased by industrial release of mercuric compounds. This
has been shown for mercury release from chemical factories
- paper pulp factories and alkaline chlorine factories
(Swedish Expert Group, 1971).
5.2 Uses
Of the more than 10,000 tons of mercury produced yearly, 25%
is consumed by the chlor-alkali industry, 20% is used in
electrical equipment, 15% in paints, 10% in measurement and
control systems such as thermometers and sphygmomanometers,
5% in agriculture, 3% in dental practice, and 2% in laboratories.
The remaining 20% is divided among military uses as detonators,
mercury-containing catalysts, preservatives in the paper pulp
industry, Pharmaceuticals, cosmetic preparations and others
(Korringa and Hagel, 1974). The cytotoxic properties of mer-
cury compounds have given them a widespread usage as germicides
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and pesticides added to Pharmaceuticals, plastics, paints
and other products. Methyl- and ethylmercury have seen extensive
use in seed treatment. Most industrial countries have banned
this use, and the production of alkylmercury compounds has
decreased. Phenylmercury acetate has been extensively used
as a fungicide and algaecide in paints, plastics and other
products. Methoxyethylmercury compounds have replaced the
short chain alkylmercury compounds in seed treatment. Under
the conditions in which they are used, both types of compounds
are unstable and slowly release inorganic mercury.
6. Environmental levels and exposures
6.1 General environment
6.1.1 Food and daily intake
Alkylmercury, formed in the bottom sediment of the ocean and
fresh water systems, is enriched to a high degree in the aquatic
food chain with the highest levels in the predatory fishes.
From the aquatic environment, methylmercury is transformed by
species feeding on aquatic organisms to the terrestrial environment,
However, enrichment has not been seen to the same extent in the
terrestrial food chain. Large tuna fish exceeding 60 kg have
levels up to 1 mg/kg of methylmercury in their muscles
(Peterson et al., 1973), while terrestrial animals rarely
have levels in muscles exceeding 50 ug/kg and generally average
20 pag/kg (Swedish Expert Group, 1971). In areas of polluted
water, levels of methylmercury in fish meat may exceed 1G
mg/kg, with a tendency to increasing levels with increasing
size and age of fishes. Under conditions of agricultural use
of alkylmercury, levels of methylmercury in game birds may
be raised to toxic levels (Swedish Expert Group, 1971).
A large part of the mercury in food, then, at least in animal
products, is likely to be in the form of methylmercury. In
fish, the major amount of the mercury is methylmercury. Since
the mercury concentration in food products excluding fish
varies between a few/i.g to 50/ug/kg (Bouquiaux, 1974),
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the daily intake of methylmercury is mainly dependent on
the amount of fish consumption and the concentrations of
MeHg in consumed fish. Fish consumption may vary between
countries, individuals and ethnic groups, which may have a
fish consumption of from virtually nothing to 500 g or more
per day. The average daily intake of fish flesh in the Swedish
population was estimated at 30 g/day (Swedish Expert Group,
1971). This will result in a daily intake of MeHg of between
1-20 ug/day under conditions of consumption of uncontaminated
fish. In epidemiological studies on the American Samoan
population consuming tuna fish, blood levels have been found
indicating a daily intake of between 200-300 ;ug/day of MeHg
(Clarkson et al., 1973). Should the water be polluted, the
daily intake from fish consumption can rise to toxic levels
as occurred in Minamata and Niigata in Japan, 1953-66 (Swedish
Expert Group, 1971). Concentrations of MeHg in fish of 1-20
mg/kg have been reported to result in a maximum daily intake
in persons with excessive fish consumption (200-500 g/day)
of about 50 mg/day (Swedish Expert Group, 1971).
It should be noted that the daily intake of inorganic mercury
will not likely exceed 10 ug/day, from mercury inhalation,
intake from drinking water and from food in the absence of
occupational exposure. This figure is low in relation to the
possible intake of MeHg mentioned above.
6.1.2 Water
Ground water contains between 10-50 ng Hg/1 (Dall'Aglio,1968),
while surface water in uncontaminated areas may contain up to
200 ng/1 (Durum et al., 1970). In rivers draining industrial
areas, levels around 1 ug/1 may occur (Reichert, 1973). Ocean
water contains less mercury, around 30 ng/1 (Sillgn, 1963).
Mercury levels may increase with increasing depth according
to Hosohara (1961), who reported a threefold increase from
surface to a depth of 3yOOO meters.
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6.1.3 Ambient air
Mercury concentration in the general atmosphere varies from
a few ng/m in remote uncontaminated areas up to around 50
ng/m in urbanized areas (Eriksson, 1967; Williston, 1968).
A fraction of the mercury in the atmosphere may be particle-
bound. Up to 40 ng/m particle-bound mercury has been reported
in the USA in large cities (Goldwater, 1964; Brar et al.,
1969). Near areas of industrial emission or areas where mercury
fungicides are extensively used/ high levels of mercury in
the atmosphere have been reported, values on the order of sev-
eral >ig/m. . From a community close to the mercury mines in
Spain, values of 0.8 mg/m have been reported (Fernandez et al.,
1966). No conclusive evidence as to what amount of the mercury
in water and ambient air is in the form of alkylmercury has yet
come forth.
6.2 Working environment
Exposure to mercury vapor is the most common occupational ex-
posure to mercury. Exposure to mercury vapor occurs in a variety
of industries such as mercury mining, chlor-alkali factories
and instrument manufacturing, as well as laboratories of physics
and medicine. Most reports about hazardous exposure come from
mining and chlor-alkali industries. Air levels of mercury as
high as 5 mg/m have been reported in connection with mining
operations. Human exposure is often related to special opera-
tions or spillage of mercury compounds on the work clothes
from which it evaporates and is inhaled. Although exposure
to mercury vapor is the most common exposure with regard to
inorganic mercury, mixed exposures to organic mercury compounds
in aerosols or mercuric inorganic mercury aerosols occur. In
chlor-alkali industries, the presence of chlorine in combination
with mercury vapor gives rise to the formation of mercuri
chloride aerosols. The handling of mercuric salts in the
chemical industry may also cause exposure to aerosols of
inorganic'mercury.
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Exposure to methyl-- and ethylmercury has been described in
connection with manufacturing and use of these salts in
chemical industrial workers an", in personnel carrying out
seed treatment. Due to the restrictions on the agricultural
applications of alkylmercury compounds, occupational exposure
is likely to oe rare at present in most industrialized countries.
7. Metabolism and toxic effects of elemental mercury and
inorganic mercury compounds
There is a considerable difference in metabolism between metallic
mercury and mercuric mercury. Due to its lipia solubility, mercury
vapor penetrates the membranes of the body and is easily absorbed.
On the other hand, the lifetime of mercury vapor in the body is
very limited due to the rapid oxidation of elemental mercury to
mercuric mercury. The divalent mercuric ion is most likely to bind
to sulfhydryl groups on proteins and has limited mobility in the
body. As the metabolism and toxic properties of metallic mercury,
especially in vapor form, and mercuric mercury differ considerably,
they will be treated separately below.
7.1 Elemental mercury
7.1.1 Metabolism
7.1.1.1 Absorption
Inhalation. Mercury vapor is efficiently absorbed from the al-
veolar air due to the rapid diffusion of mercury vapor through
the alveolar membrane (Berli * et al., 1969) and the capacity
of red cells to bind and oxidize mercury to mercuric mercury
(Clarkson et al., 1961). This process of oxidation can, however,
be inhibited by alcohol and aminotriazole (Nielsen-Kudsk, 1965;
Magos et al., 1974) whereby the absorption by inhalation is
reduced. Considering the effect of dead space, the absorption
of mercury vapor at moderate ventilation rates will be about
80% at concentration levels met in the work environment.
Ingestion. Liquid metallic mercury is poorly absorbed from
the gastrointestinal tract. Mercury vapor is slowly released
from the surface of metallic mercury at a rate which is re-
lated to the surface area present. The tendency of metallic
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mercury to cover itself by mercury sulfide further limits the
amount, of mercury vapor which can be released. As a result
of tnese factors, the amount of mercury released from metallic
mercury ingested is of no toxicological importance. If mer-
cury is broken up into small droplets, the release of mercury
will be considerably increased.
Skin. It is likely that mercury can cross the skin barrier
but no quantitative data on this are available. It is doubtful
whether this route of absorption plays any important role in
comparison with inhalation of mercury vapor from a contaminated
skin surface.
7.1.1.2 Transport, distribution and biological half-time
It has been shown in mice (Berlin and Johansson, 1964) and
in primates (Berlin et al., 1969) that after single exposure
to mercury vapor ten times more mercury is retained in the
brain than after intravenous injection of the same dose of
mercuric mercury. It was suggested (Berlin et al., 1966) that
this observation was due to physically dissolved mercury vapor
in blood being transported to the brain, or to the release
of mercury vapor from blood cells by reduction of ionic mercury
bound to the cells. Magos (1968) confirmed the findings of
Berlin et al., and showed, by intravenous injection of mercury
vapor and by recovering, within 30 sec, 19% of the injected
dose in the exhaled air of the animal, that physically dissolved
mercury would be enough to explain the uptake of mercury in
the brain. It has been shown (Clarkson, 1972) that mercury
vapor, in contrast to mercuric mercury, also penetrates the
placental barrier, causing an accumulation of mercury in the
fetus when the mother is exposed to mercury vapor. Mercury
vapor has, however, a limited survival time in the body as
it is rapidly oxidized to mercuric mercury in the tissue and
behaves then as mercuric mercury. Little is known about steady
state distribution during long-term exposure to mercury vapor.
Attempts have been made in animal experiments to produce steady
state under exposure to mercury vapor. However, the reaching
of steady state has not been proved. Berlin (1975) exposed
squirrel monkeys to 1 and 2 mg/m of mercury vapor for six
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hours five days a week for up to two months. They failed to
obtain steady state in the brain, although mercury in blood
seemed to reach steady state during this time span.
animal studies (Berlin and Ullberg, 1963; Berlin and
Johansson, 1964) with a single exposure to mercury vapor or
injection of mercuric mercury salt, it has been shown by auto-
radiography that mercury is distributed in the mammalian or-
ganism specifically to certain types of cells. Mercury has
a special affinity for ectodermal and endodermal epithelial
cells and glands . Mercuric mercury is thus accumulated in the
epithelial lining of the intestinal tract, the squamous epitheli-
um of the skin and hair, in glandular tissues like the salivary
glands, thyroid, liver, pancreas, and the sweat glands, and
in the kidney as well as epithelial organs, like the testicles
and the prostate. These studies have also revealed that the
retention time of accumulated mercury varies widely among dif-
ferent organs . Biological half-times vary from a few days to
months. The organs with the longest retention times are the
brain, kidneys and testicles. These organs are thus likely
to show accumulation of mercury at repeated exposure and dominate
the distribution at steady state. This has been confirmed in
the human brain in cases of occupational exposure to mercury
vapor (Takahata et al., 1970; Watanabe, 1971). Little is known
about the detailed distribution of mercury in the brain of
man or the primates at steady state or after long-term exposure
to mercury vapor. Available data from long-term exposure of
squirrel monkeys (Berlin et al . , 1975) and a few clinical
cases of occupational exposure (Takahata et al., 1970; Watanabe,
1971) indicate that mercury is accumulated in the cerebral
cortex, especially in the occipital and parietal cortical areas.
The evidence from animal experiments is that the detailed dis-
tribution in the kidney and other organs accumulating mercury
after exposure to mercury vapor, is similar to that seen after
exposure to mercuric salts, and will thus be discussed further
in section 7.2.1.2.
7.1.1.3 Elimination and excretion
The elimination of mercury after exposure to mercury vapor
occurs mainly by excretion of mercuric mercury. However, ex-
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halations of small quantities of mercury vapor have been demon-
strated in animals. (Clarkson and Rothstein, 1964) and man
(Hursh et al., 1975). It is unclear whether this mercury vapor
is a result of reduction of mercuric mercury excreted into
the airways or by diffusion of vapor through the alveolar membrane.
The routes of excretion of mercuric mercury are via feces,
urine, and by salivary, lacrimal and sweat glands. The mechanism
and details of renal excretion are discussed in section 7.2.1.3.
The rate of excretion is dose-dependent and a considerable
species difference has been observed. The best mathematical
model seems to be a multicompartmental model with at least
2 or more excretion rates and with one small compartment including
the brain with a very long biological half-time (Task Group
on Metal Accumulation, 1973). The limited data from human studies
indicate that the bulk of mercury is excreted with a biological
half-time of about 60 days (Hursh et al., 1915; Piotrowski
et al., 1975). Part of the mercury accumulated in the brain
is slowly eliminated with a biological half-time which may
exceed a year.
7.1.2 Symptoms and signs in poisoning caused by exposure to
mercury vapor
7.1.2.1 Acute poisoning
The lung is the critical organ upon acute accidental exposure
to high concentrations of mercury vapor. The mercury vapor
causes erosive bronchitis and bronchiolitis with interstitial
pneumonitis. The patient will eventually succumb in respiratory
insufficiency. The symptoms of respiratory distress may be
combined with signs caused by effects on the central nervous
system, like tremor or increased excitability.
7.1.2.2 Chronic poisoning
Upon long-term exposure to toxic levels of mercury vapor, the
central nervous system is the critical organ. Little is known
about the pathogenesis of the brain dysfunction seen upon exposure
to mercury vapor. With an increasing dose, signs appear which
can be characterized as an unspecific, asthenic-vegetative
syndrome involving symptoms like weakness, fatigue, anorexia,
loss of weight, and disturbance of gastrointestinal functions.
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This syndrome has been called micromercurialism (Trachtenberg,
1969; Friberg and Nordberg, 1972). At higher exposure levels,
the characteristic mercurial tremor appears as fine trembling
of the muscles interrupted by coarse shaking movements every
few minutes. It begins in peripheral parts like fingers, eyelids
and lips and is intentional. It disappears during sleep. In
progressive cases it may develop into a generalized tremor
involving the entire body, with violent chronic spasms of
the extremities. Parallel to the development of tremor, mercurial
erethism develops. This is characterized by severe behavioral
and personality changes, increased excitability, loss of memory
and insomnia, which may develop into depression. In severe
cases, delerium and hallucination may occur.
In addition to the central nervous system signs, cases of severe
poisoning may display inflammatory changes of the gums with
ptyalism, which may be severe, with salivation of liters per
day.
It is still unknown to what degree renal damage may occur in
connection with chronic exposure to mercury vapor. Severe nephrot-
ic changes have not been described in patients exposed only
to mercury vapor. In patients exposed to a combination of mercury
dust and vapor, such changes have been reported (Friberg et al.,
1953j Kazantzis et al., 1962). Studies using more refined
renal function testrmethods have not been described with regard
to mercury vapor exposure.
7.1.3 Indices of exposure and concentration in the critical
organ
Conclusive studies about the relation between levels of exposure
to mercury vapor and concentrations in biological media are
scarce. It seems, from epidemiological studies (Smith et al.,
1970), that mercury concentration in blood may, on a group
basis, reflect recent exposure. As mercury concentration in
urine is closely related to mercury concentration in blood,
urine mercury, on a group basis, may also serve as an index
of recent exposure. This is also supported by the results of
Smith et al. The variations of urine and blood concentration
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render these indices useless fordiagnostic purposes in individual
cases. At present, no index of mercury concentration in the
critical organ or in the kidney is known. Under conditions
of continuous exposure, animal experiments (Berlin et al.,
1975) have shown that levels in blood or urine do not correlate
with levels in brain or kidneys as recent exposure is the most
important factor determining mercury concentration in blood
and urine. (Berlin and Gibson, 1963). Studies on the relation
between bloodmsrcury and levels of mercury in the critical
organ under conditions of no exposure are still lacking.
7.1.4 Dose-response relationships
Studies on dose-response relationships have been made in which
the dose has been determined by the degree of exposure or by ab-
sorbed dose as expressed by concentration of mercury in blood or
urine. Results from all three approaches will be summarized below.
It is, however, uncertain to what extent levels of mercury in air
reflect actual exposure. Factors such as the release of mercury
vapor from mercury-contaminated clothes, temporary and spot-wise
exposure to high levels in connection with special work operations,
and variations in physical load that change the rate of lung
ventilation limit the value of mercury concentrations in the air
as measurements of exposure. Mercury concentrations in blood and
urine are influenced by recent exposure and by the body burden of
mercury from earlier exposure. The relative contribution of these
two parameters determining levels of mercury in blood and urine
is still poorly understood. Physiological variation in metabolism
also affects the level of mercury in urine.
7.1.4.1 Relation between mercury in air and effect
Data on concentrations of mercury in air necessary to produce
acute lung changes are scarce. In one report (Milne et al.,
1970), it was reported that an exposure of more than 1-3 mg/m
for a few hours caused acute mercurial pneumonitis in four
cases. Available epidemiological investigations (Friberg and
Nordberg, 1972) indicate that at long-term exposure to mercury
concentrations in air of 0.1 mg/m and above, the probability
of persons manifesting typical mercurialism with tremor and
behavioral changes will increase. At concentrations of 0.1
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rng/m and less, the probability of meeting cases of micromer>-
curialism or the asthenia syndrome decreases. There is as yet
no substantial accumulation of evidence or any one conclusive
report about incidence of poisoning at exposure to concentrations
below 0.01 mg/m mercury in air. The prevalence of certain
medical findings in relation to mercury exposure in the study
by Smith et al. (1970) is shown in Figure 1.
7.1.4.2 Relations between mercury in urine or blood and effects
Although recent exposure to mercury vapor shows a close relation
to mercury levels in blood and urine, most epidemiological in-
vestigations on exposed populations have not revealed more than
a weak association between blood or urinary concentrations of
mercury and the occurrence of clinical signs, or the degree
of effects, for individual subjects. On a group basis, on the
other hand, high levels of mercury in urine and blood may be
associated with prolonged exposure to high concentrations of
mercury vapor and thus a greater likelihood of occurrence of
signs of poisoning. In animal experiments (Berlin and Gibson,
1963) and in epidemiological studies (Benning, 1958; Smith et
al., 1970), a close correlation has been shown between levels
of mercury in urine and in blood. Levels exceeding 300 ug/liter
in urine indicate dangerous exposure but effects may well appear
even at lower concentrations (Friberg, 1951; Bidstrup et al.,
1951) . The level of 300 lig/1 in urine corresponds on a group
basis to about 100 ug Hg/1 in blood (Smith et al., 1970).
The association between mercury in blood and in urine and
between mercury in air arid blood as found in the study by
Smith et al. (1970) is seen in Figure 2 and 3,respectively.
7.1.4.3 Relation between mercury in the critical organ
and effects
Reliable data on concentrations of mercury in the lung upon
acute hazardous exposure to mercury vapor have not been found
in the literature. Data on mercury concentration in brain upon
exposure to mercury vapor are also scarce. Brigatti (1949) re-
ported concentrations of 6-9 mg/kg in the brain of two persons
exposed for several years to mercury vapor, but who died of
other causes. Both had shown pronounced signs of mercurialism
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some years before. Concentrations exceeding 0.5 mg/kg in the
brain are not likely to occur in man in the absence of known
mercury exposure. The highest reported level (Takahata et al.,
1970) of mercury in brain associated with non-fatal mercurialism
is 34 mg/kg in the occipital cortex in a person who died of
other causes. The highest value published (Takahata et al.,
1970) in a person without known signs of classical mercurialism
is 18 mg/kg in substantia nigraj the mercury concentration
ranged from 5-18 mg/kg in the rest of the brain. In studies
on the rabbit (Ashe et. al., 1953), a concentration of 1-2
rr.g/kg was reported to be associated with mild pathological
changes in the brain, between 3 and 17 mg/kg with moderate
pathological changes and below 0.5 mg/kg no morphological changes
were observed. In squirrel monkeys, levels up to 8 mg/kg in
the occipital cortex were observed (Berlin, 1975) in the absence
of any definite morphological changes in the brain. However,
the possibility of behavioral disturbances at these levels
could not be precluded.
7.2 Mercuric mercury
7.2.1 Metabolism
7.2.1.1 Absorption
Inhalation. No data are available.
Ingestion. Acute poisoning due to accidental or intentional
intake of mercuric chloride was not uncommon at the beginning
of this century. Data from reports of such cases (Sollman and
Schreiber, 1936) and experimental studies (Rahola et al., 1973)
indicate that less than 10% of ingested mercuric chloride can
be absorbed. Upon high intake, the corrosive action of mercury
chloride may alter the permeability of the gastrointestinal
tract, enhancing the absorption.
Skin. It has been demonstrated that upon application of mercuric
mercury to the human skin, penetration of mercury occurs, but
the mechanism is unknown. Factors such as type and concentration
of mercuric compound as well as the condition of the skin determine
the rate of absorption (Wahlberg, 1965). In animal studies
(Friberg et al., 1961), up to 8% of the mercuric chloride applied
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to the skin was absorbed in 5 hours. The available data are
insufficient for evaluating the importance of skin absorption
relative to absorption by inhalation under conditions of occupa-
tional or pharmaceutical exposure.
7.2.1.2. Transport and distribution
Mercuric mercury is divided in blood between erythrocytes and
plasma in about equal amounts (or more in plasma). In the erythro-
cytes, mercury is probably to a large extent bound to sulfhydryl
groups on the hemoglobin molecule. In plasma, mercury binds to
sulfhydryl groups on plasma proteins. The distribution between
different plasma protein fractions varies with dose and time after
administration. Mercuric mercury does not readily cross the
blood-brain barrier or the placental barrier. The rate of uptake
from blood in different organs varies widely, as does the rate of
elimination from different organs. The distribution of mercury
within the body and within organs will thus vary widely with dose
and time lapse after absorption. So far, no one has attempted to
2+
describe the steady state distribution. The distribution of Hg in
the body is highly differentiated to specific organs and, within
the organs, to specific cells. This is likely to be related to the
occurrence of ligands with affinity to mercury. Under all conditions,
however, the dominating mercury pool ^n the body is the kidney.
In view of animal data, other organs or cells where mercury is
likely to accumulate are the liver, the mucous membranes of
the intestinal tract, and the epithelium of the skin, the spleen,
the interstitial cells of tie testicles, and some parts of
the brain. In animal experiments, the placenta and fetal membram. ~
have also been observed to accumulate and retain mercury (Berlin
and Ullberg, 1963).
In the kidney, most mercury is found in the renal tubules
(Taugner, 1966; Taugner et al., 1966). In the liver, the highest
concentration is seen in the peripheral part of the liver lobule
around the bile ducts (Berlin and Ullberg, 1963). In the brain,
most mercury is seen in gray matter, more in some nuclei in
the brain stem and some parts of the cerebellum (Nordberg and
Serenius, 1969; Berlin et al., 1969).
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7.2.1.3 Excretion
As has been mentioned in section 7.1.1.3, mercuric mercury
is excreted by the kidney, by the fecal route, by sweat glands,
lacrimal glands and mammary glands, and by salivary glands.
The major part of absorbed mercuric mercury is excreted in
urine and feces. Partition between these two routes is dose-
dependent and data indicate a larger fraction excreted by urine
upon administration of higher doses.
Little is known about the mechanism behind mercury excretion
in the intestinal tract. Except for the excretion by saliva,
mercury is excreted by the liver through the bile and also
by the mucous membranes of the small intestines and colon.
Nor is the mechanism of urinary excretion of mercury known.
It is still uncertain whether small amounts of mercury are
filtered through the glomerular membranes. The evidence is
that less than 1% of the mercury in the plasma is in ultrafil-
trable form. To what extent a small fraction is filtered remains
a subject of conflicting reports. The major part of the mercury
in the kidney is taken up from the blood and stored in the
kidney, a process not necessarily linked to the process of
excretion. Animal experimental data indicate that excretion
is more correlated to blood concentration of mercury than to
the mercury load in the kidney (Berlin and Gibson, 1963). Transfer
of mercuric mercury through the proximal tubules has been demon-
strated in the avian kidney (Vostal and Heller, 1968) . Most
experimental data from mammals point to some kind of transfer
of mercury through the tubular wall. Some authors have reported
the existence of a protein water-soluble component in the kidney
with high affinity to mercury and increasing in the presence
of mercury exposure (Piotrowski et al., 1974). Others have
reported the binding of mercury to glutathione in the kidney
(Richardson and Murphy, 1975).
The total excretory capacity of the body is illustrated by the
elimination rate from the whole body. It has been demonstrated in
rats (Rothstein and Hayes, 1960) that the elimination curve is
best described as a multi-phasic exponential curve, having a rapid
phase with a half-time of about 5 days, another phase with a half-
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time of about a month and still another with a half-time of about
3 months. Experimental studies do not contradict a similar human
elimination pattern, although only the more rapid phases have been
followed thus far. Rahola et al. (1971) found a half-time of 42
days for 80% of the absorbed amount after an oral tracer dose in
man. The half-time of the remaining 20% could not be determined.
7.2.2 Symptoms and signs in poisoning due to mercuric salts
7.2.2.1 Acute poisoning
Upon accidental or suicidal ingestion of sublimate or other
mercuric salts, the critical organs are the kidney and the
intestinal tract. The corrosive effect of concentrated mercuric
salt solution on the mucous membranes of the gastrointestinal
tract causes extensive precipitation of proteins. Gastric pain
and vomiting may ensue. If the salt is allowed to pass farther
down, general abdominal pain and bloody diarrhea, with necrosis
of the intestinal mucosa, will occur. This may lead to circulatory
collapse and death. If the patient survives the gastrointestinal
damage, the critical organ will be the kidney. Within 24 hours,
renal failure due to necrosis of the proximal tubular epithelium,
which develops into anuria and uremia, occurs. A part of the
mechanism behind the tubular necrosis may a local vasospasm.
7.2.2.2 Chronic poisoning
Chronic poisoning due exclusively to mercuric mercury salts
is unlikely. Most chronic exposure involves a mixture of mercury
vapor and mercuric mercury, lenal damage with nephrotic syndromes
has been described in such mixed exposures. It is possible
that exposure to mercuric mercury is the main cause of those
signs since the kidney is the critical organ in prolonged
exposure to mercuric mercury in animals (Skerfving and Vostal,
1972). Other signs which may be expected are increased salivation,
inflammatory changes of the gums and black lines on the gums.
Mercuric compounds locally applied to the skin may cause idio-
syncratic skin symptoms like erythema and more severe exfoliative
dermatitis, involving the whole body. A specific form of hyper-
sensitivity is seen in children between 4 months and 4 years of
age. This syndrome, called acrodynia or pink disease, is char-
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acterized by a general rash over the body. Other symptoms are
chilis, swelling and irritation of the hands, feet, cheeks and
nose, usually followed by desquamation, loss of hair and ulcera-
tion. In addition to the skin symptoms, the disease features
irritability, photophobia, sleeplessness and profuse perspiration,
which may lead to dehydration. The perspiration is accompanied
by dilated and enlarged sweat glands and desquamation of the
soles and palms. Hyperplasia and hyperkeratosis of the skin in
the peripheral parts of the extremities are seen. If mercury
exposure is eliminated, the signs disappear gradually. Acrodynia
cases of mercury etiology usually show increased levels of mercury
in urine ( >50 ug/1) (Warkany and Hubbard, 1948,1951,1953).
7.2.3 Diagnostic indices of exposure, body burden and
concentration in critical organ
There are no data available relating concentrations of mercury
in blood and urine to data on exposure and absorption of mercuric
mercury. From theoretical considerations, it can be assumed
that, as is the case for exposure to mercury vapor, concentration
of mercury in blood and urine may, on a group basis, be related
to the degree of absorption of or the exposure to mercuric
mercury. Renal biopsy has been used as a diagnostic procedure
to discover mercury concentration in the critical organ (Kazantzis
et al., 1962).
i 9 A Dose-effect and dose-response relationships upon exposure
/ * £ • T
to mercuric salts
Data on dose-effect and dose-response relationships upon ex-
posure to mercuric salts are scarce. The lethal dose upon acute
poisoning is on the order of 1 g, judging from old clinical
reports about suicide cases . Severe poisoning has been reported
after ingestion of less than 1 g. Some data are available on
the relation between concentration of mercury in the kidney
and kidney damage. In persons not exposed to mercuric mercury
in addition to the daily intake by food, water and air, the
mercury concentration in the kidney can be expected to range
between less than 0.1 mg/kg and 3 mg/kg (Berlin, 1972). In
cases of poisoning due to mercuric salts, 10-70 mg/kg mercury
in the kidney has been reported (Clennar and Lederer, 1958j
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Kazantzis et al., 1962). These values tally with the concentrations
seen in kidneys of mercury-poisoned rats (Ashe et al., 1953).
8. Metabolism and toxic effects of organic mercury compounds
8.1 Organic compounds relatively stable in the mammalian body
Organic mercury compounds which resist chemical degradation
by the biochemical processes in the body are the short chain
alkyl compounds and some mercurials used in pharmaceutical
practice. Among the alkyl compounds, methylmercury compounds
occur naturally and it is to them that most accumulated knowl-
edge pertains. Available data indicate that ethylmercury com-
pounds have toxicological properties similar to those of the
methylmercury compounds. This presentation will therefore be
limited to methylmercury compounds, which will be abbreviated
to MeHg. For the toxicology of the organic mercury compounds
used for pharmaceutical purposes, the reader is referred to
handbooks on toxicology (e.g. Goodman and Gilman, 1970).
8.1.1 Metabolism
8.1.1.1 Absorption
Inhalation. MeHg compounds can be absorbed by inhalation.
Vapors of MeHg salts easily penetrate the membranes of the
lung and the absorption rate can be estimated at around 80%.
In cases of exposure to alkylmercury salt aerosols, the absorp-
tion rate would be dependent on particle size and the rate
of deposition in the respiratory tract.
Ingestion and skin. MeHg ingested with food or ingested in
connection with food is likely to be bound to proteins in the
intestinal tract. It is efficiently absorbed through the intestin-
al tract in experiments on man (Aberg et al., 1969; Miettinen,
1973) and primates (Berlin et al., 1975).
Absorption of alkylmercury compounds by the skin is likely
to occur. The rate will be dependent on the type of compound,
the concentration and the condition of the skin. Friberg et
al. (1961) and Wahlberg (1965) have demonstrated skin absorp-
tion of an aqueous solution of MeHg in guinea pigs. Cases of
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poisoning due to local application of MeHg-containing oint-
ment to the skin have been described (Suzuki et al., 1970).
To what extent the absorption can be explained by inhalation
cannot be estimated from the reports.
8.1.1.2 Transport and distribution
MeHg absorbed into the body is bound to protein sulfhydryl
groups or, to a lesser extent, to sulfhydryl groups of amino
acids,or peptides,like cysteine and glutathione. Thus, in blood
plasma, MeHg is bound to plasma proteins mainly and transported
through the cell walls by some unknown mechanism. In the blood,
MeHg is accumulated to a large extent - more than 90% - in the
red cells. MeHg is slowly distributed from the blood to the
organism. Equilibrium between blood and body is not reached
until after four days in the monkey (Berlin et al., 1975). The
adult brain and the fetal brain show a special affinity for
MeHg in squirrel monkeys, with levels of alkylmercury at least
3-6 times higher in brain than in blood, depending on dose (Berlin
et al. , 1975) . In studies of the distribution of MeHg after
tracer doses of radioactively labeled MeHg in man,
Aberg et al. (1969) found 10% of the body burden
of MeHg in the head. Miettinen (1973) found about 1% in one
liter of blood. These values correspond to about six times higher
MeHg concentrations in brain than in blood. The uptake in brain
is slower than in other organs as has been demonstrated in the
mouse (Berlin and Ullberg, 1963). In the rest of the body, MeHg
is rather evenly distributed in the tissues compared to other
mercury compounds, with an intercellular distribution. MeHg
undergoes biotransformation to inorganic mercury by demethylation
in the body, the mechanism of which is still unknown. Considerable
levels of inorganic mercury have been demonstrated in kidney,
liver, feces, bile and urine after administration of MeHg in
primates (Berlin et al., 1975). Biotransformation is unlikely
to occur in the brain as more than about 95% of mercury in brain
has been demonstrated to be in the form of MeHg upon exposure
to MeHg. The distribution in the fetus is close to that of the
mother, although fetal brain levels of mercury may be higher
(Berlin and Ullberg, 1963).
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8.1.1.3 Elimination and excretion
The main routes of elimination of MeHg are via the liver into
bile and via the kidney into urine. The net excretion in humans
amounts to about 1% of the body burden, corresponding to a bio-
logical half-time of 70 days, when this burden is non-toxic
(Swedish Expert Group, 1971). Clinical observations from MeHg
poisoning epidemics in Japan (Swedish Expert Group, 1971) and
Iraq (Bakir et al., 1973 support an elimination in man under
conditions of intoxication of the same order of magnitude. The
major part of the excretion is by the fecal route. Much of the
MeHg excreted in the bile is absorbed in the gut, producing
an enterohepatic circulation of MeHg. However, a part of the
mercury in bile - about 30-80% - in the monkey (Berlin et al.,
1975) is inorganic mercury, derived from the demethylation of
MeHg in the body. This part, less effectively absorbed in the
gut, is excreted. The relative amount of inorganic mercury in
bile may be dose-dependent. About 90% of the total excretion
of MeHg in man is by the fecal route. MeHg is also excreted
in breast milk, the concentration being about 5% of the concen-
tration in the maternal blood (Skerfving, 1973; Bakir et al.,
1973). 20% of the mercury in breast milk is MeHg provided the
load of MeHg is non-toxic (Skerfving, 1973). Bakir et al. (1973)
reported 60% MeHg in Iraqi cases of MeHg poisoning; thus, the
fraction of MeHg may be dose-dependent.
The capacity for MeHg elimination varies in the population.
Analyses of consecutive hair segments from MeHg exposed popu-
lations in Iraq (Al-Shahristani and Shihab, 1974) suggest that
a part (10%) of the population eliminates MeHg at a rate con-
siderably less (biological half-time 110-190 days) than 1% per
day. Whether this may be due to the existence of genetic enzyme
anomalies in the population or to other causes is as yet unknown,
8.1.2 Symptoms and signs in poisoning caused by exposure to
alkylmercury
Available data point to great similarities in symptoms and signs
of poisoning due to ethyl mercury and MeHg. Most detailed in-
formation has to do with MeHg. There is no sharp difference
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between acute and chronic poisoning from exposure to MeHg
compounds. Once a toxic dose has been absorbed in the body,
it is retained for a long time, causing functional disturb-
ances and damage. On the other hand, a single toxic dose does
not produce signs or symptoms until after a latency period,
which may vary from one to several weeks. Signs and symptoms
from poisoning due to MeHg show large species differences,
mainly due to differences in rate of excretion and distribution.
Two clinical types of intoxication may be discerned, a prenatal
and a postnatal type. These give rise to different kinds of
signs and symptoms.
8.1.2.1 Prenatal poisoning
The clinical picture in prenatal MeHg poisoning is that of
an unspecific infantile cerebral palsy (Swedish Expert Group,
1971), involving ataxic motor disturbances and mental symptoms.
Upon autopsy, the brain is found to be hypolastic with a sym-
metrical atrophy of cerebrum and cerebellum. Decreased numbers
of neurons and distortion of the cytoarchitecture in the cortical
areas are histological features. The changes coincide with
those of cerebral palsy of unknown etiology. Similar findings
have been reported in cases of ethylmercury poisoning (Bakulina,
1968).
8.1.2.2 Postnatal poisoning
The clinical signs of postnatal intoxication due to MeHg are
characterized by sensory disturbances with paresthesia in
the distal extremities, in the tongue and around the lips.
These are early signs, occurring with light intoxication.
In more severe intoxication, ataxia, concentric constriction
of the visual fields, impairment of hearing and extrapyramidal
symptoms may appear. In severe cases, clonic seizures have
been observed. The pathological changes in the central nervous
system are characterized by general neuron degeneration in
the cerebral cortex with gliosis, most pronounced in the calcarine,
the precentral and postcentral areas. These changes are accom-
panied by atrophy of the cerebral cortex. In the cerebellar
cortex, a loss of granular cells is engendered, also leading
to atrophy.
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8.1.3 Indices of exposure and concentration in the critical organ
Experimental studies in man and primates have shown that mercury
concentration in blood is linearly correlated to intake of MeHg
and to the concentration of MeHg in the critical organ, the brain,
at non-toxic body burdens. As more than 90% of MeHg in blood i3 to
be found in the erythrocytes, mercury concentration in red cells
is the most reliable index of MeHg body burden and brain concentra-
tion.
MeHg is deposited in the hair at the formation of the pile. The
deposition of MeHg in the pile is proportional to the mercury
concentration in blood at the time of pile formation. Thus the
mercury concentration in the hair pile constitutes a calendar of
mercury concentrations in blood, which have occurred during the
formation of the pile. MeHg concentration in the hair can be used
as an index of mercury concentration in blood, in the critical
organ, or body burden of mercury, provided that allowance is made
for the growth rate of the hair pile, about 1 cm a month, and the
time lag between hair formation and extrusion. Under occupational
conditions, the possibility of external hair contamination should
be kept in mind.
As urinary excretion of MeHg is very small, MeHg concentration
in urine is easily masked by the inorganic mercury present. Thus,
urine concentration of MeHg is not a good index of MeHg body bur-
den or of MeHg concentration in the critical organ.
Under steady state conditions, the quotient between hair levels
and blood levels of MeHg is around 250 (Skerfving, 1974; Tonkelaar
et al., 1974).
8.1.4 Dose-response relationships
Most of our knowledge about dose-response relationships in MeHg
poisoning is derived from studies of the epidemics of MeHg poison-
ing in Iraq (Bakir et al., 1973) and Japan (Swedish Expert Group,
1971), and studies on populations eating mercury-contaminated
fish (Skerfving, 1973; Clarkson et al., 1973). When considering
the dose-response relationships in MeHg poisoning, three main ef-
fects can be discussed - the neurotoxic effect, the embryotoxic
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effect, and the genetic effect as shown in chromosomal aberra-
tions of the lymphocytes. The dose-response relation for each
of these effects will be discussed separately below.
The dose of MeHg can be expressed in terms of level of intake,
amount absorbed as reflected by concentration of MeHg in blood
or hair, and finally in terms of concentration in the critical
organ, the brain. Each approach will be used below for each
effect whenever data are available.
8.1.4.1 Incidence of signs and symptoms related to intake
or body burden of MeHg
Assuming a 70-day half-time for MeHg, Bakir et al. (1973) esti-
mated the body burden of MeHg causing a 5% risk of paresthesia.
They used data from 58 persons who had consumed a known amount
of bread containing MeHg. They arrived at the figure of 0.5-0.8
mg/kg body weight. The body burden corresponding to a 5% mortality
risk was about 10 times higher. However, little is known about
the biological half-time for MeHg at toxic dose levels. It may
be longer than assumed. In a survey of 926 persons from heavily
affected villages in Iraq (Al-Mufti et al., 1974), 427 persons
known to have consumed MeHg-contaminated bread were selected,
and the frequency of paresthesia was reported for different
cohorts with different intakes of MeHg. An estimate of the
body burden corresponding to the 5% risk of paresthesia based
on these data tallies well with the data of Bakir et al, (1973).
8.1.4.2 Incidence of signs and symptoms of MeHg poisoning
related to concentration of MeHg in blood
A thorough review of data from Japanese epidemics of MeHg poison-
ing by a Swedish Expert Group (1971) resulted in the conclusion
that the lowest blood level connected with signs of MeHg poisoning
reported in Japan is around 200 ug/1. Insufficient numbers of
victims were subjected to blood analysis to allow an estimate
of risk at that level. Bakir et al. (1973) reported blood values
in an exposed population in Iraq 65 days after cessation of
exposure. They also reported the frequency of signs of different
cohorts with different levels of blood concentration of MeHg.
An estimate of the blood concentration of MeHg - assuming a
329
-------
log-linear relation between incidence rate and MeHg in blood -
corresponding to a 5% risk in this population, gives a value
for blood concentration between 200 and 300 ug/1 65 days after
cessation of exposure.
8.1.4.3 Incidence of signs and symptoms of MeHg poisoning
related to concentration of MeHg in hair
The lowest mercury concentration found in hair in connection with
symptoms in the Niigata epidemic of MeHg poisoning was 50 mg/kg
The available data indicate that the risk at this level is less
than 10% and possibly not greater than 5%.
In a study on 843 exposed persons in the Iraqi epidemic of MeHg
poisoning, the lowest hair value associated with symptoms or signs
was 120 mg/k.g (Al-Shahristani et al., 1974). The data do not per-
mit any calculation of risk at this level of hair concentration.
8.1.4.4 Incidence of signs and symptoms of MeHg poisoning
related to concentration of MeHg in the brain
Few data on concentrations of MeHg in the brains of fatalities from
the epidemic in Japan have been reported. Almost no data are available
from the extensive epidemic in Iraq. The lowest data reported
from Japan (Swedish Expert Group, 1971) are on the order of 5
mg/kg in brain tissue. This value can be estimated to correspond to
about 800 ug/1 in blood, 200 mg/kg in hair. These values are
rather low in comparison with dose-response levels for early signs
like paresthesia. No basis for estimation of mortality rate exists
at this level.
8.1.5 The embryotoxic effect
In the Minamata epidemic of MeHg poisoning, 23 cases of prenatal
intoxication were encountered. A larger number probably occurred
in the Iraqi epidemic. Among the Japanese cases, the mothers of
the affected children had commonly shown no clinical signs of poi-
soning. Scanty data available on mercury levels in biological
materials like blood and hair (Swedish Expert Group, 1971) in-
dicate that the difference in sensitivity between the fetus and
the adult organism is less than a factor of 5 and closer to a
330
-------
factor of 2. The report from the Iraqi epidemic supports this
estimate (Ainin-Zaki et al., 1974a). The data do not permit
the estimation of a dose-response relationship for this effect.
8.1.6 The genetic effect
Although MeHg has been proved mutagenic under experimental condi-
tions (Ramel, 1972), little evidence of such an effect is available
from clinical experience. Skerfving et al. (1974) reported dose-
related chromosome aberrations in lymphocytes of consumers of MeHg-
contaminated fish. They found such aberrations at blood MeHg levels
of around 100 ug/1. However, studies on intoxicated persons in the
Iraqi epidemic have not revealed any greater incidence of chromo-
somal aberrations compared to a control population (Baghdad meet-
ing, 1974).
8.2 Organic mercuric compounds unstable in the mammalian body
There are two main mercurials of practical importance which belong
to the group of organic mercury compounds unstable in the mammalian
organism - the phenylmercury compounds and the alkoxyalkylmercury
compounds, chiefly the methoxyethylmercury compounds.
8.2.1 Metabolism
8.2.1.1 Absorption
Ingestion. Animal experiments indicate that phenyl Hg salts are
absorbed more efficiently than mercuric salts in the gastroin-
testinal tract (Prickett et al., 1950). There are no data on
the absorption of phenyl Hg salts or alkoxyalkyl Hg compounds
after ingestion in man.
Inhalation. Both phenyl Hg compounds and alkylalkoxy Hg compounds
are absorbed via inhalation of aerosols (Hagen, 1955). Determining
factors for the degree of absorption will be particle size and
solubility of the salt aerosolized.
Skin. There is clinical evidence that phenyl Hg compounds applied
on the skin (Biskind, 1935) or locally in the vagina (Eastman
and Scott, 1944) are absorbed. Data are not sufficient for any
quantitative conclusions. No data are available on the skin
absorption of methoxyethyl Hg compounds.
331
-------
8.2.1.2 Transport and biotransformation
The phenyl Hg and methoxyethyl Hg compounds are decomposed,
mainly in the liver/ to inorganic mercury (Daniel et al., 1971,
1972; Gage, 1975). Experimertal evidence indicates that the
rate of biotransformation of methoxyethyl Hg is more rapid than
that of phenyl Hg. Most organic mercury is transformed to mercuric
inorganic mercury, within 24 hr in the case of methoxyethyl Hg
and within the first four days in the case of phenyl Hg compounds
in the rat. Phe:.yl Hg evidently penetrates cell lembranes more
2+
easily than Hg . Thus/ about 90% of phenyl Hg in blood is found
in the red cells (Berlin, 1963; Goldwater et al., 1964). However,
neither phenyl Hg nor methoxyethyl Hg is transferred through
the blood-brain barrier or the placental barrier to a larger
2+
extent than Hg (Ulfvarsson, 1962; Berlin and Ullberg, 1963) .
8.2.1.3 Distribution
Mercury distribution after long-term exposure to phenyl Hg or
methoxyalkyl Hg is likely to be close to distribution after
2+
Hg exposure. However, in the case of phenyl Hg, one import-
ant difference should be emphasized. As recent exposure deter-
mines the mercury level in blood, under conditions of exposure
to phenyl Hg, a large fraction of the mercury in blood will be
found in the red cells in contrast to what can be expected in
exposure to mercuric mercury (Goldwater et al., 1964).
8.2,1.4 Excretion
Judging from animal experinu nts, phenyl Hg may be more effici-
2+
ently excreted by the liver in bile than Hg . It is unclear
to what extent methoxyethyl mercury is excreted unchanged. Con-
clusive data from observations in humans are not available for
either phenyl Hg or methoxyethyl Hg.
8.2.2 Indices of exposure or concentration in critical
organs
Occupational exposure to phenyl Hg compounds or methoxyethyl
Hg compounds is likely to be a mixed exposure due to the in-
stability of these mercurials. Indices generally useful for
evaluating exposure levels or body burden of mercury will be
difficult to find. Reports from Goldwater et al. (1964), however,
332
-------
suggest that under similar exposure conditions mercury levels
in urine and blood may be indicative of levels of exposure to
phenyl Hg compounds.
8.2.3 Signs and symptoms due to poisoning by phenyl Hg compounds
and methoxyethyl Hg compounds
Both types of compounds may cause local damage in the lung from
inhalation or on the skin from contact with concentrated solu-
tions . Sensitization has been described for phenyl Hg compounds
in single cases (reviewed by Nordberg and Skerfving, 1972).
Cases of intoxication due to long-term exposure are few and the
reports are conclusive to a limited degree as to type of exposure
and dose absorbed. There is no clear evidence that the clinical
pattern deviates from that expected for intoxication by mercuric
salts. The higher level of mercury in the liver seen in animal
experiments after exposure to phenyl Hg compared to inorganic
mercury salts may tally with the observations described by
Cotter (1947). This author found liver damage in ten subjects
exposed to phenyl Hg salts. Other substances may also have been
involved, however. Renal damage and intestinal complaints
have been reported upon intoxication due to phenyl Hg compounds
and methoxyethyl Hg compounds (reviewed by Skerfving and Vostal,
1972).
8.2.4 Dose-response relationships
The quantitative data available do not permit extensive con-
clusions about dose-response relationships in exposure to phenyl
Hg or methoxyethyl Hg compounds. However, available clinical
reports, especially those concerning phenyl Hg poisoning,
suggest that these compounds are not more toxic than mercuric
salts in long-term exposure, but rather less toxic.
9. Prognosis and treatment of intoxication due to mercury
compounds
The prognosis of poisoning due to mercury compounds is dependent
on the type of mercury compound involved and the dose. All specific
therapy is aimed at lowering the concentration of mercury at the
site of action in the organism and to remove the mercury compound
from th~ organism. This can be achieved by different methods common
to all kinds of mercury poisoning. In all severe cases, the first
333
-------
choice should be hemodialysis and infusion of chelating agents for
mercury, such as cysteine or N-acetyl penicillamine. In less severe
cases, mobilization and redistribution of mercury can be achieved
by aid of chelating agents such as BAL (dimercaptopropanol) and
N-acetyl penicillamine. These methods can only be used in selected
cases and not in all types of mercury compounds. The excretion of
mercury can be increased by surgical establishment of gall bladder
drainage, thereby breaking the enterohepatic circulation of mercury.
This method is most efficient with regard to those types of com-
pounds for which enterohepatic circulation plays an important role.
9.1 Mercury vapor
The prognosis in pronounced intoxication by mercury vapor involving
severe tremor and mental changes is, according to the literature,
remarkably good with complete regression if exposure ceases. Whether
the regression is due to a compensatory mechanism - remaining neur-
ons taking over the function of damaged ones - or is a complete
regression is not possible to answer with present knowledge, nor is
it known whether mercury deposited in the brain can be mobilized
by therapeutic measures, or whether regression is due to mercury
eliminated from the brain or converted to and deposited in an inert
form.
9.2 Inorganic mercuric mercury
Severe sublimate poisoning with renal tubular damage is a fatal
condition, but this prognosis can be considerably improved by
therapeutic measures. In acute, poisoning, BAL (dimercaptopropanol)
will efficiently mobilize mercury from the kidney and redistribute
it in the body (Berlin and Lewander, 1965). It should therefore be
used in this kind of poisoning in combination with hemodialysis with
cysteine infusion to remove the mercury from the body. The experi-
mental evidence is that the damaged tubules can regenerate to a
considerable degree.
9.3 Short chain alkyl Hg
Signs and symptoms of intoxication with alkyl Hg compounds do not
appear until several weeks after absorption. Moreover, the appear-
ance of signs of intoxication is secondary to severe damage of the
334
-------
cerebral cortex. If exposure is stopped, considerable regression
of signs and symptoms may occur according to the experiences in
the Iraqi epidemic (Damluji et al., 1974). To date, therapeutic
improvement of the prognosis upon manifest intoxication has not
been seen clinically. Good experimental and clinical evidence
shows that hemodialysis with cysteine infusion can drastically
reduce the concentration of alkyl Hg in the brain and the body
(Kostyniak et al., 1974, 1975; Al-Abassi et al., 1974). This
therapy should be the first choice in any progressive state
of intoxication. This treatment can be followed by continuous
therapy with N-acetyl penicillamine to reduce the body burden
of alkyl Hg further (Shapiro et al., 1973). If hemodialysis
cannot be applied, gall bladder drainage is a must, with oral
replacement of the bile salts and electrolytes lost in the
drain.
9.4 Phenyl Hg compounds or methoxyethyl Hg compounds
Severe renal damage due to these types of compounds should be
treated with hemodialysis. BAL is contraindicated as it forms
lipid soluble complexes with the organic mercury compounds and
redistributes to the brain whereby it may cause severe disturb-
ance in the central nervous system. In cases of acrodynia or
pink disease, N-acetyl penicillamine should be used for mob-
ilization of mercury from the body.
335
-------
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60-
50
40
30
20
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LOSS OF WEIGHT
APPETITE LOSS
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OBJECT. INSOMNIA SHYNESS
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1 _. Control
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OIASTOLIC FREQUENT HISTORY DIARRHEA
•IOOD COIOS NERV.
PRESS.
Figure 1. Percentage prevalence of certain signs and symptoms
among workers exposed to mercury in relation to
degree of exposure (From Smith et al., 1970). Data
on diastolic blood pressure probably mean % below a
certain level. This level is not given in the article.
336
-------
Urine Hg levels
(mg/l)
1.00n
0.75-
0.50-
o
0.25-
0
0.05 0.10 0.15 0.20 0.25 0.30 035
Hg Air levels (mg/m3)
Figure 2. Concentrations of mercury in urine (uncorrected for
specific gravity) in relation to time-weighted
average exposure levels (From Smith et al., 1970).
337
-------
Urinary Hg levels
(AJQ/I)
1,000 -i
750
500
250
o
50
100
150 200 250
Blood Hg (/ug/l)
Figure
3.
Relationship of concentrations of mercury in blood
and in urine (uncorrected for specific gravity)
(From Smith et al., 1970).
338
-------
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344
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MOLYBDENUM
Lars Friberg
1. Abstract
Soluble molybdenum compounds are readily absorbed via inges-
tion and inhalation. The highest molybdenum concentrations
are found in kidney, liver and bones. The excretion, primarily
via the urine, is rapid. The biological half-time is probably
from a few hours in small laboratory animals up to a couple
of weeks in humans.
Molybdenum is an essential element. Its metabolism is related
to copper and sulfur metabolism. Copper generally has a bene-
ficial effect on the symptoms caused by excessive molybdenum,
but the action of sulfur compounds, especially sulfate, is
not so clearly understood. Both positive and negative effects
have been reported, depending upon the copper status.
In livestock chronic molybdenum poisoning known as "teart
disease" is caused by a diet high in molybdenum and low in
copper. Symptoms include anemia, gastrointestinal disturb-
ances, bone disorders and growth retardation. In laboratory
animals excessive molybdenum may give rise to morphological
and functional changes in the liver, kidneys and spleen. It
has a growth depressive action and deformities of bone may
occur.
A few cases of pneumoconiosis have been reported among workers
exposed to metallic molybdenum and molybdenum trioxide. In-
creased blood uric acid values and gout-like symptoms have
been reported among workers exposed to molybdenum in a copper-
molybdenum plant as well as among the general population living
in an area with high molybdenum and low copper content in soil
and vegetables.
A review on the transport and biological effects of molybdenum
has been made by the Molybdenum Project (1974) and a general
review on molybdenum has been given by Friberg et al. (1975).
345
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2. Physical and chemical properties
Molybdenum, Mo, atomic weight 95.9-, atomic number 42; density
10.2 (20°); melting point 2617°C; boiling point 4612°C;
crystalline form silver-whita metal or gray-black powder, cubic;
oxidation state 2,3,4?,5?,6.
More than 50 inorganic forms of molybdenum are known and organo-
metallic forms also exist. Inorganic compounds to be mentioned
in this chapter are ammonium molybdate, calcium molybdate,
molybdic oxide, sodium molybdate, molybdenum disulfide and
molybdenum trioxide.
3. Methods and problems of analysis
Colorimetric methods, among them the thiocyanate and the dithiol
methods, have been used for decades for the determination of
molybdenum. During later years neutron activation, atomic ab-
sorption and X-ray fluorescence have been widely employed. For
detailed discussion on the determination of molybdenum reference
is made to reviews by Meglen and Glaze (1973, 1974) . Duval
(1971) in a comparison of different methods found detection
limits for the thiocyanate and polarographic methods to be
0.01 mg/kg dry weight, for atomic absorption 1 mg/kg and for
neutron activation 0.02 mg/kg. No data on the accuracy of i:he
methods for the determination of molybdenum in animal tissues
and body fluids are available.
4. Production and uses
4.1 Production
Molybdenum does not occur naturally in the native state, but is
obtained from the ores molybdenite,wulfenite, ferrimolybdate
and jordicite. The overwhelming majority comes from molybdenite,
the largest deposit of which is at Climax, Colorado, USA. The
production of molybdenum (in countries excluding the USSR and
some other countries in the Eastern hemisphere) increased from
about 30,000 tons in 1960 to about 60,000 tons in 1969 (Minerals
Yearbook, 1969).
4.2 Uses
The primary use of molybdenum is as a steel alloy. As such it
is utilized in the weapons industry, in aeronautical engineering,
346
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and in the automobile industry. Of the US consumption in 1969,
84% was in alloys (Minerals Yearbook, 1969). In the chemical
industry molybdenum compounds are used as catalysts and as
chemical reagents. There are also many pigments that contain
molybdenum compounds. Since molybdenum is an essential element
in plant and animal nutrition, its uses include its addition
to soil, plants and water to achieve various enrichment or
balance effects.
5. Environmental levels and exposures
5.1 Food and daily intake
Daily intake of molybdenum can be estimated to be between
100 and 500 ng (Schroeder, 1970; Smolyar, 1972; Tipton and
Stewart, 1970; Wester, 1971). In areas where molybdenum ore
is mined, considerable contamination may occur, which can cause
high concentrations in drinking water and daily intakes of more
than 1,000 ug. The variations in foodstuffs, especially plants,
are greatly dependent on species and soil characteristics.
Generally, high concentrations are found in leafy vegetables
and legumes, whereas edible roots have a lower content. Animal
products are generally low in molydenum.
5.2 Water, soil and ambient air
Molybdenum in the ocean has been found to be around 0.01 mg/1
(Sugawara et al., 1962; Muzzarelli and Rocchetti, 1973). Ameri-
can rivers ranged from 5 to 30 mg/1 (Turekian and Scott, 1967).
Molybdenum in normal soil seems to vary between 0.1-10 mg/kg
(Reddy, 1964). In mining areas and near molybdenum-emitting
industries considerably higher values have been reported
(Chappell, 1974). Molybdenum in sewage sludge was found to vary
between 2 and 30 mg/kg dry weight (Berrow and Webber, 1972) .
In ambient air in urban areas, molybdenum ranged 0.01-0.03
3 3
ug/m and at nonurban sites 0.0001-0.0032 ug/m (Schroeder,
1970) .
6. Metabolism
6.I Absorption
6.1.1 Inhalation
Guinea pigs did not show any noticeable absorption after an
3
inhalation exposure to 285 mg Mo/m as molybdenum disulfide while
347
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hexavalent molybdenum compounds were absorbed to an appreciable
extent, even though this was not possible to quantify (Fairhall
et al., 1945).
There are no human data on absorption of molybdenum after in-
halation.
6.1.2 Ingestion
The gastrointestinal absorption is high in animals as well as
in humans.
Animal data are from single exposure studies only. Hexavalent
molybdenum is readily absorbed from the gastrointestinal tract,
40-85% in guinea pigs, rats and goats (Fairhall et al., 1945;
Neilands et al., 1948; van Campen and Mitchell, 1965; Anke et
al., 1971).
Tipton et al. (1969) found an absorption of more than 50% in
two subjects and an absorption of probably less than 50% in one
subject who participated in a balance study for over 50 weeks.
An absorption of about 50% was also found by Wester (1974a).
6.2 Distribution
Studies of the distribution of molybdenum in guinea pigs and
rats after a single oral exposure to molybdenum trioxide show
an ^mmediate accumulation ir. kidney, liver and bones. The same
distribution is also seen alter prolonged exposure in rats,
cows and goats. The highest values are found in the kidneys
(Fairhall et al., 1945; Robinson et al., 1964; Huber et al. ,
1971; Anke et al., 1971). In mice, after a single intravenous
injection, the highest concentrations were found in the kidneys,
liver and pancreas 1-24 hours after exposure. A decrease with
time took place in the kidneys and pancreas while the concentra-
tions of molybdenum in liver remained constant during the ob-
servation period (Rosoff and Spencer, 1973).
6.3 Excretion
Limited animal data indicate a low retention and a more or less
complete excretion of molybdenum, primarily via urine, during the
348
-------
first two weeks after single exposures in guinea pigs, rats,
goats and swine (Fairhall et al., 1945; Neilands et al., 1948;
Bell et al., 1964; Anke et al., 1971; Kselikova et al., 1974).
Excretion via urine was shown to have a half-time of 20 hours in
cows (Robinson et al., 1964). In that same species, the main
excretion route was reported to be feces by Bell et al. (1964).
An important excretion route in connection with the gastro-
intestinal excretion is the bile (Caujolle, 1937). Small amounts
are excreted via milk and hair, in goats about 2% and 0.2%
respectively (Anke et al., 1971).
Excretion in man was studied by Rosoff and Spencer (1964)
after a single intravenous injection of radioactive molybdenum.
99
The cumulative Mo excretion in 10 days was 24% in one subject
and 29% in another, while the corresponding fecal excretion
was 6.8 and less than 1% respectively.
The total excretion of molybdenum in man during "normal"
steady state conditions is not known. Data from Tipton et
al. (1969) tend to show that 25-50% of the ingested amount
is excreted via urine.
6.4 Biological half-time
The biological half-time has not been specifically studied. Data
referred to above concerning excretion as well as the rapid
clearance from liver, kidney, spleen and bones in animal studies
show that the biological half-time, at least for the major part
of the absorbed molybdenum, must be on the order of hours to a
maximum of about one day in laboratory animals (Fairhall et al.,
1945; Neilands et al., 1948) and perhaps up to a couple of
weeks in humans (Rosoff and Spencer, 1964).
The concentration of molybdenum in blood decreases rapidly
after a single subcutaneous injection in rats. After 24 hours
only about 1% of the maximum concentration remained. During the
next 10 days concentrations in blood diminished with a half-time
of about 7 days (Kselikova et al., 1974).
?• Normal levels in tissues and biological fluids
In normal adults, median values for liver, kidneys and adrenals
349
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(spectrographically) have been found to be 1 mg/kg, 0.3 mg/kg and
0.7 mg/kg wet weight, respectively (Tipton and Cook, 1963).
Plantin (1973) determined molybdenum in liver and kidney cortex
by neutron activation in 8 autopsy cases in Sweden, 51-63 years
of age. The average concentrations were 0.88 and 0.2 mg/kg wet
weight. Pribluda (1964) reported the molybdenum concentration
in liver and kidney of 80 subjects aged 17-77 years in the USSR.
Arithmetic mean values for liver (thiocyanate method) were 0.5-
0.6 mg/kg and for kidneys about 0.2 mg/kg wet weight.
An increase of molybdenum with age up to age 10-20 seems to
take place in liver (Tipton and Cook, 1963; Schroeder et al.,
1970) .
Estimations of blood levels in different individuals show a wide
scatter, but most data support a normal value of a few jug/1
whole blood (Butt et al., 1964; Morgan and Holmes, 1972).
Data on daily urinary excretion of molybdenum in "normal"
human subjects have been given by Meltzer et al. (1962) and
Wester (1974b). On the average, the excretion in the groups
varied between 49 and 71 ug/day.
8. Effects and dose-response relationships
Molybdenum is an essential element. It is a constituent of three
mammalian metalloflavoproteins, xanthine oxidase, aldehyde oxi-
dase and sulfite oxidase. No deficiency states in human beings
have been reported.
8.1 Local effects and dose-response relationships
8.1.1 Animals
Inhalation of molybdenum compounds in high concentrations may
be irritating to the upper respiratory tract. A few reports
on inhalation or intratracheal administration have been
published. Pneumoconiosis-like effects in the lungs have
been reported in rats and rabbits. In one study rabbits were
given intratracheally a suspension of powdered molybdenum
of: 70-80 mg/kg. In 9 months diffuse pneumoconiosis with
interstitial pneumonia was observed upon histological examina-
tion (Mogilevskaya, 1963; Dzukaev, 1970).
350
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8.1.2 Humans
Pneumoconiosis with X-ray findings and subjective symptoms
has oeen reported in 3 out of 19 workers exposed to metallic
molybdenum and molybdenum trioxide (Mogilevskaya, 1963).
Exposure varied between 1-19 mg/m for 4-7 years.
8.2 Systemic effects and dose-response relationships
8.2.1 Laboratory animals
Acute as well as prolonged exposure to excessive molybdenum
may give rise to morphological changes in the liver, kidneys
and spleen of rats, guinea pigs and rabbits. Proteinuria has
been reported as well as different functional disturbances
of the liver. Molybdenum has a growth depressive action. Other
symptoms after prolonged exposure are anemia, diarrhea, and
deformities of joints and long bones as well as mandibular
exotoses (Ferguson et al., 1943; Arrington and Davis, 1953;
Halverson et al., 1960; Dasler and Milliser, 1961; Ostrom et
al., 1961; Valli et al., 1969; Mills and Mitchell, 1971).
Mandibular exostoses, growth retardation and anemia were found
in rats on a diet containing 400 mg/kg of molybdenum as sodium
molybdate for 5 weeks (Ostrom et al., 1961). Van Keen (1959)
reported reduced growth and mandibular exostoses in rats fed
50 mg Mo/kg diet (given as Na^MoO.) plus a low sulfate supply.
8.2.2 Livestock
Evidence of chronic molybdenum poisoning has been seen in cattle
and is known as "teart disease". This effect occurs after ex-
posure to a diet high in molybdenum and low in copper. Symptoms
include anemia, gastrointestinal disturbances, bone disorders,
growth retardation, and impaired reproduction.
The molybdenum levels in typical teart pastures range from 20-100
mg/kg on a dry basis, compared with normal levels of 3-5 mg/kg
(Ferguson et al., 1938; Ferguson et al., 1943; Hogan et al.,
1971) .
The disease has been possible to reproduce experimentally in
cattle (Ferguson et al., 1943; Britton and Goss, 1946; Cook et
al., 1966; Huber et al., 1971).
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8.2.3 Humans
Increased blood uric acid values were reported in 34 out of
37 workers in a copper-molybdenum plant who complained of
arthralgia (Akopajan, 1964).
A high incidence of a gout-like disease was reported in an
area of Armenia having 77 mg Mo/kg and 39 mg Cu/kg in the
soil (Koval'skiy et al., 1961; Yarovaya, 1964; Koval'skiy
and Yarovaya, 1966). Based on copper and molybdenum levels
in different food products, the intake in the exposed area
was calculated to 10-15 mg molybdenum and 5-10 mg copper versus
1-2 mg molybdenum and 10-15 mg copper in the control area.
In this region of the USSR more than 50% of the diet is based
upon locally grown products. A medical survey of 400 subjects
from two villages in the molybdenum-rich area revealed a
prevalence of symptoms similar to gout in 31% in one of the
villages and 18% in the other. The authors claimed that sim-
ilar symptoms normally occurred in 1-4% of the population of
the USSR. The symptoms were characterized as arthralgia in
the knee-joints, hands and feet. Joint deformities were also
reported as well as increased values of molydenum and uric
acid in blood and urine. There are difficulties in interpreting
the data due to possibilities of bias in connection with the
selection of groups to be examined, but the data fully moti-
vate further studies, not only in the USSR but also in regions
of other countries where the exposure to molybdenum via the
diet is high.
From the theoretical standpoint, effects like those reported
in Armenia might well appear. Molybdenum exposure could give
rise to an increase in xanthine oxidase activity which in turn
should give rise to an increase in uric acid formation (Yarovaya,
1964; Gusev, 1969).
In humans, molybdenum has been shown to influence copper metab-
olism (see Chapter on Copper).
8.3 Interaction with copper and sulfur
There is a complex relationship between molybdenum, copper
and sulfate, and probably also some other sulfur compounds.
Species differences exist, e.g. sheep are more susceptible
352
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to imbalances between these elements than pigs. Copper gen-
erally has a beneficial effect on the symptoms caused by
excessive molybdenum but the action of sulfur compounds,
especially sulfate, is not so clearly understood, both
positive and negative effects having been reported (Ferguson
et al., 1943; Neilands et al., 1948; Arrington and Davis,
1953; Dick, 1953; Mills et al., 1958; Davis et al., 1960;
Halverson et al., 1960; Compere et al., 1965; Lukasev and
Siskova, 1969; Marcilese et al., 1969). Reference is also
made to the monograph by Underwood (1971).
353
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Berrow, M.L. and Webber, J. (1972). J. Sci. Food Agric. 23,
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SILVER
Gunnar F. Nordberg and Bruce A. Fowler
1. Abstract
Silver compounds may be absorbed via inhalation, but there
are no quantitative data on the extent to which this will
take place. Silver salts will be absorbed up to 10% following
ingestion. The highest concentrations of silver are usually
found in the liver and spleen and to some extent in the
muscle, skin, and brain. The biological half-time for silver
is on the order of a few days for animals and up to about 50
days for human liver; it is possible that skin deposits also
have a long half-time, but there are no quantitative data on
this in humans. Excretion of silver from the body is primarily
gastrointestinal.
Silver is a non-essential element. Water soluble silver
compounds such as the nitrate have a local corrosive effect
and may cause fatal poisoning if swallowed accidentally.
Chronic exposure of humans leads to argyria, a clinical
entity characterized by gray-blue pigmentation of the skin
and other body viscera. Repeated exposure of animals to
silver may produce anemia, cardiac enlargement, growth
retardation, and degenerative changes in the liver.
A review of environmental aspects of silver has been published
by Carson and Smith (1975).
2. Physical and chemical properties
Silver, Ag, atomic number 47; atomic weight 107.9; density
10.5; melting point 960.8°C; boiling point 2212°C; crystalline
form white metal, cubic 0.54; oxidation state +1, +2. Pure
silver has the highest thermal and electrical conductivity
of all metals. The metal forms important alloys with copper
and other metals. The compounds of silver to be taken up here
358
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include silver nitrate, silver lactate, silver picrate, silver
acetate and the silver halides.
3. Methods and problems of analysis
There are spectrographic, colorimetric, and polarographic
techniques for measurement of silver. The detection limit
for spectrographic and dithizone colorimetric methods has
been put at 0.01 mg/1 for a 20 ml sample (A.P.H.A. Standard
Methods for the Examination of Water and Waste Water, 1966;
Rooney, 1975). The detection limit for polarographic techniques
is 5-10 M Ag (Cave and Hume, 1952). Atomic absorption
(detection limit 2 ,ug/l) and neutron activation (detection
limit 2 ng) may also be used and are relatively accurate. A
reference listing of detection limits and other comments on
the analysis for silver are given by Carson and Smith (1975).
4. Production and uses
4.1 Production
The main ore from which silver is produced is argentite.
Silver is recovered from this ore by cyanide extraction,
zinc reduction, or electrolytic processes. The world production
of silver has increased from 238,400 million fine ounces in
1964 to 291,400 million fine ounces in 1972. Canada, Peru,
USSR, United States and Mexico are the largest producers of
silver (Carson and Smith, 1975) .
4.2 Uses
Silver is used in the production of coins, jewellery and
tableware. This element is also utilized as a component of
various alloys and solders with copper, cadmium, and lead.
It is extensively used in photographic processing, in the
manufacture of electrical apparatus and mirrors, in dentistry,
and in the treatment of burns (Harvey, 1970; Hartford and
Ziffren, 1972; Sheker et al., 1972). Silver salts, because
of their germicidal properties, are also used as drinking
water disinfectants and as prophylactic agents against
gonorrheal infection in the newborn.
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5 . Environmental levels and exposures
5 . 1 Food, water and
A detailed mapping of various dietary sources of silver is
not available. Ingestion of silver may occur from consumption
of marine organisms containing low concentrations (see
below) and from small amounts released from dental fillings
(Leirskar, 1974) and eating utensils (Harvey, 1970) . Tipton
et al. (1966) found rhat two subjects ingested between 0.02-
0.01 mg/day from food during a 30-day period. Wester (1971),
by neutron activation analysis, found a daily intake from food
of 1-16 ,ug.
Sea water has been reported to contain silver concentrations
of 0. 055-1. 5, ug/1 (Schutz and Turekian, 1965). Much higher
concentrations (0.03 mg/1) have been reported in waste water
effluents entering southern California coastal basins (Galloway,
1972; Young et al., 1973; Bruland et al. , 1974). Silver has
been accumulated in concentrations of 14-20 mg/kg in bottom
sediments in these areas (Galloway, 1972; Bruland et al . ,
1974) . Molluscs collected from coastal areas of the North
Sea have been reported to contain silver concentrations of
up to 2.0 mg/kg (Segar et al., 1971; Dutton, 1973). Drinking
water, not treated with silver for disinfection purposes,
usually contains extremely low concentrations of silver. A
range of non-detectable to S
-------
Coal flyash has been reported to contain up to 15 mg/kg
silver (Headlee and Hunter, 1953) and emission of silver
from coal-fired power plants may lead to its accumulation in
soil of adjacent areas.
5.2 Ambient air and cigarettes
Silver has been measured in air as a result of anthropogenic
activity. Air concentrations of silver over southern California
have been reported to be about 2 ng/m (Bruland et al.,
1974). The emission of silver iodide crystals during cloud
seeding has been estimated to result in a silver concentration
in air of about 0.1 ng/m (Sargent, 1969; Standler and
Vonnegut, 1972). Silver concentrations in rainwater as a
result of this process were estimated to be between 0.04
pg/ml and 5 ng/ml.
Concentrations of silver in cigarettes are low. Because of
its high boiling point, most of the silver in cigarettes is
probably not inhaled.
6. Metabolism
6.1 Absorption
6.1.1 Inhalation
The deposition fraction of 0.5 micron spherical silver
particles in the lung of dogs has been found to be about 17%
(Phalen and Morrow, 1973). Newton and Holmes (1966) studied
the long-term retention in a human who accidentally inhaled
radioactive silver (chemical form not known). Their data
indicated that the liver uptake was maximal less than two
weeks after inhalation, suggesting absorption of alveolarly
deposited silver compounds, although it cannot be excluded
that a part of the silver compounds was cleared to the
gastrointestinal tract and absorbed that way.
6.1.2 Ingestion
The intestinal absorption of silver by mice, rats, monkeys,
361
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and dogs has been recorded at about 10% or less following
ingestion of radioactive silver (Furchner et al., 1968) . No
precise data are ~~ ^ntly a liable for humans.
6.2 Distribution
Dogs exposed to silver by inhalation accumulated most of the
administered dose in the liver, with lower concentrations in
the lung, brain, and muscle (Phalen and Morrow, 1973) .
Studies on rodents have also indicated a high initial concentra-
tion of silver in the liver which decreases greatly within
10 days, while silver concentrations in the spleen and brain
are retained for longer time periods (Gammill et al., 1950;
Furchner et al., 1968). In a human being more than 50% of
the body burden of silver was found in the liver 16 days and
later after exposure (Newton and Holmes, 1966).
6.3 Excretion
Mice, rats, monkeys, and dogs given radioactive silver salts
by oral, intravenous, or intraperitoneal routes were found
to excrete over 90% of the absorbed dose via the feces
(Furchner et al., 1968). The fecal elimination is mainly
explained by biliary excretion (Scott and Hamilton, 1948).
Fecal elimination has also been found to be the primary
excretory pathway following inhalation exposure to silver in
dogs (Phalen and Morrow, 1973) and in humans (Newton and
Holmes, 1966).
6.4 Biological half-time
After rabbits had inhaled 4 micron monodisperse silver-
coated teflon particles, Camner et al. (1974) found an
average of 30% of the deposited part to be cleared from the
lung in one day and another 30% during the rest of the first
week of the exposure. After inhalation exposure, dogs cleared
59% of an administered dose of radioactive silver from the
lungs in 1.7 days (Phalen and Morrow, 1973). The liver had a
somewhat slower clearance of 9 days. A biological half-time
of about 1 day was found by whole-body scintillation counting
in mice, rats, monkeys, and dogs after oral ingestion,
362
-------
mainly due to fecal elimination of unabsorbed silver (Furchner
et al., 1966). Longer biological half-times were observed
for all these species after intravenous injection of silver,
with monkeys and dogs having biological half-times of 1.8
and 2.4 days respectively. Silver injected into rats as
radioactive silver nitrate had a biological half-time of 2.2
days (Habighorst and Buchwald, 1971). The biological half-
time of silver in the lungs of a human exposed to silver has
been estimated to be 1 day while that in the liver was 52
days (Newton and Holmes, 1966). In a carcinoid patient Polachek
et al. (1960) estimated a biological half-time of 48 days in
the liver by external counting after i.v. injection of
radioactive silver. Upon postmortem examination 195 days
after injection the highest concentration of radioactive
silver was found in the liver and the second highest in
skin, indicating a relatively long biological half-time for
skin as well.
7. Normal levels in tissues and biological fluids
The concentrations of silver in kidneys, liver, and spleen
of "normal people" have been reported to be about 0.4, 0.7, and
2.7 mg/kg respectively on a dry weight basis (Indraprasit et
al., 1974). Normal concentration in skin was reported as
0.035+0.015 mg/kg dry weight by Schropl et al. (1968).
Hamilton et al. (1972) reported 0.006+0.002 mg/kg wet weight
in liver, 0.001+0.002 in kidney and 0.002+0.0001 in lung.
Tipton et al. (1966) found between 0.006-0.015 mg/day in
urine and between 0.02-0.11 mg in feces. Wester (1971)
(neutron activation) found 0.9-l,ug/day in urine and 0.9-
97 xUg/day in feces. In urine Bostrom and Wester (1968) found
l,ug/24 h in normal persons and 0 . 7-7 . 5 ,ug/24 h in patients
with untreated hyperthyroidism.
8. Effects and dose-response relationships
8.1 Local effects and dose-response relationships
Silver salts are pronouncedly caustic and have been used
363
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widely in the treatment of warts. Silver salts are used for
the treatment of burns and have a strong antiseptic effect.
Dressings soaked with 0.5% AgNO., have been extensively used
without any evident local or systemic silver toxicity (Hartford,
1972) .
Repeated occupational handling of silver objects, especially
if repeated minor injury is involved, may give rise to so-
called local argyria, which is blueish-gray discoloration of
the skin at the exposed site. This condition is considered
harmless apart from aesthetic considerations (cf. Holzegel,
1970, and others).
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
The primary toxic effects of silver seem to be exerted on the
cardiovascular, hepatic, and hematopoietic systems. Cardiac
enlargement and ventricular hypertrophy have been reported
in turkeys following dietary exposure to 900 mg/kg silver
nitrate for 18 weeks (Peterson et al.f 1973; Jensen et al.,
1974). A 28.6% mortality figure was recorded for treated
animals during the course of the study. Decreased aortic
elastin content has also been observed (Olcott, 1948;
Peterson et al., 1974; Jensen et al., 1974). Centrilobular
hepatic necrosis and ultrar-tructural alteration of mitochondria
and lysosomes have been described in livers of vitamin E
deficient rats exposed t~> silver (Grasso et al., 1970).
Anemia of a microcytic, hyperchromic type is a common finding
among animals chronically exposed to dietary levels of
several hundred mg/kg of silver compounds (Shouse and Whipple,
1931; Peterson et al., 1973; Jensen et al., 1974).
8.2.2 Humans
Acute effects. 50 mg or more of collargol (Ag-salt) has
been reported to be lethal after intravenous injection
for therapeutic purposes. Autopsy findings in such cases
364
-------
have included pulmonary edema, hemorrhage and necrosis of
bone marrow, liver and kidney (Patein and Robin, 1909; Hill
and Pillsbury, 1959) . Intrauterine administration of approximately
25 g of silver nitrate has been reported to be rapidly fatal
to a human (Reinhart et al., 1971).
Chronic effects. Repeated exposure to silver salts or colloidal
silver by inhalation or ingestion brings about effects classically
described as generalized argyria. This clinical entity is
characterized by a gray-blue discoloration of skin, most
pronounced in areas exposed to light (Holzegel, 1970;
Breton et al., 1971; Kugler et al., 1972; Rich et al.,
1972; Buckley and Terhaar, 1973; Lehnert, 1973; Honigsman et
al., 1973; Hanna et al., 1974). Deposition of silver compounds
causing discoloration and sometimes also functional impair-
ment and/or clinical symptoms may also occur in other organs.
Deposition of silver compounds in the cornea and the anterior
capsule of the lens as may be detected by slit-lamp examination
(Larsen, 1927; Velhagen, 1953; Koelsch, 1956) causes some
impairment of vision in exceptional cases.
Argyrosis of the respiratory tract, liver, kidney and gastro-
intestinal tract has been reported and may be associated
with certain clinical symptoms such as chronic bronchitis
(Montaudon, 1959) and abdominal discomfort (Franken and
Langhof, 1964). However, since these case reports have not
been properly evaluated in relation to reference groups, it
is impossible to say whether there is a true causal relationship
between exposure to silver and these symptoms.
The exposure conditions giving rise to argyria have not been
well defined. Evaluation of the older literature (Hill and
Pillsbury, 1959) indicated that a total dose of 1-8 g Ag
would be required to induce the condition in a long-term
inhalation exposure situation.
The dosage required to induce argyrosis by ingestion seems
to be somewhat higher, i.e. between 1-30 g of soluble silver
365
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salts (Lehnert, 1973). Silver in metallic form is harmless.
Blond people are considered more susceptible than others.
The tissue concentrations leading to argyrosis have not been
extensively studied; Schropl et al. (1968) found 63+8 mg/kg
dry weight in skin samples from persons with argyrosis.
Ultrastructural examination of skin biopsies from patients
with argyrosis has demonstrated silver deposition in the
basal lamina of the various skin layers (Honigsman et al.,
1973) as well as in the sweat glands (Lehnert, 1973).
8.3 Interactions with selenium, copper and vitamin E
Dietary administration of silver acetate has been found to
antagonize selenium toxicity (Diplock et al., 1967). Conversely,
addition of selenium, copper and vitamin E to the diet in
varying concentrations has been reported to decrease the
toxicity of silver (900 mg/kg in diet as silver acetate) to
turkey poults (Jensen et al., 1974). Addition of selenium to
the diets of rats exposed to silver in drinking water prevented
growth retardation but increased hepatic and renal concentra-
tions of silver (Wagner et al., 1975).
9. Treatment
There is no recognized effective treatment for argyrosis.
The condition seems to be relatively stationary when exposure
to silver is discontinued. Chelation therapy is considered
ineffective (Lehnert, 1973).
366
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369
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TELLURIUM
V.E. Vouk
1. Abstract
There is no quantitative information on the absorption of
inhaled tellurium compounds. About 10-20% of ingested tellurite
ion is absorbed and first distributed in blood and soft
tissue, mainly kidney and liver. Accumulation of tellurium
in the bone is slow but 90% of the body burden in man is
found there. Tellurium is also deposited in the neural and
glial cells, and penetrates placenta. Ingested tellurium
compounds are largely eliminated in feces; the absorbed
fraction is excreted mainly in urine but also in feces. Very
small amounts are excreted by exhalation as methyl telluride.
The estimated half-times for blood, liver and kidney of the
rat range from 9-23 days; for bone it is very long, a
rough estimate being two years or more.
There is no evidence that tellurium is essential either to
man or animals.
Organs most affected in acute and subacute poisoning of ani-
mals are the liver, kidney, nervous system, lungs and the
gastrointestinal tract. The effects of tellurium on the
nervous system of rats include paralysis of hind legs,
alteration of conditioned reflexes and reduced learning
ability. There is no evidence of carcinogenicity but hydro-
cephalus was found in rats born to mothers on a diet containing
high levels of elemental tellurium.
A garlic odor of the breath, sweat and urine, dryness of the
mouth, suppression of sweat, and metallic taste in the mouth
are the main symptoms and signs of occupational exposure to
tellurium compounds. A few cases of non-occupational fatal
poisoning by sodium tellurite have been reported. There is
no specific antidote for tellurium poisoning.
370
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Inhalation is the main route of exposure under occupational
conditions; for the general population the main source of
tellurium is food.
Reviews of tellurium toxicology were published by Cerwenka
and Cooper (1961), Sandrackaja (1963), Browning (1969) and
Izrael'son (1973).
2. Physical and chemical properties
Tellurium, Te, periodic system group VIb; atomic weight
127.6; atomic number 52; density 6.2 (20°C); melting point 449.5°C;
boiling point 989.8 C; in elemental state it is a coarsely
crystalline silver-white solid with metallic lustre;
amorphous tellurium is a fine black powder. Its chemistry is
similar to that of selenium, but tellurium has more pronounced
metallic properties. Tellurium forms compounds in oxidation
states~2, +2, +4 and +6. Of toxicological interest are
elemental tellurium, hydrogen telluride and tellurium hexa-
fluoride, both colorless gases; tellurium dioxide; tellurous
and telluric acids; and sodium and potassium tellurites and
tellurates which are soluble in water. There are many organometallic
and complex compounds of tellurium.
3. Methods and problems of analysis
The most promising analytical techniques for tellurium in
environmental and biological samples are atomic absorption
spectrometry and neutron activation but they require further
development. The limit of detection of AAS in air-hydrogen
flame at 214.3 nm is about 0.1 mg/1 (Chakrabarti, 1967;
Severne and Brooks, 1972). Estimated limit of detection for
slow neutron activation (n, y-reactions) is of the order of
0.1-0.2,ug (Parsons, 1976). The available information is
inadequate to assess the precision and accuracy of these
methods. Kinser (1966) reported a relative standard deviation
of about +5% for AAS with wet ashing of tissue samples. The
inaccurate pretreatment of biological samples can result in
considerable analytical errors (Nason and Schroeder, 1967) .
The separation of tellurium from selenium and other elements
can be achieved by several procedures, including chromatography
(Fishbein, 1973) .
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4. Production and uses
4.1 Production
There are no ore deposits which could be mined for tellurium
only and its recovery is linked with the production of
copper, lead, and other metals. The estimated world production
oc tellurium in 1971 was of the order of 200 tons (Kudryavtsev,
1974). Electrolytic copper refining is the source for 80% of
tne world's supply of tellurium. The remainder is recovered
from slimes and slags of lead refining, and from pyrite and
pyrrhotite burned in pulp and paper mills and sulfuric acid
plants.
4.2 Uses
The estimated tellurium consumption in metallurgy is 79%;
in chemical, rubber, plastics and glass industries 18%; and
for electrical and electronic uses 3%. In ferrous and non-
ferrous metallurgy it is used to improve the technological
properties of steels, cast iron, and copper and lead base
alloys. Powdered tellurium is a secondary vulcanizing agent;
in combination with some other organic compounds tellurium
diethyldithiocarbamate is an excellent accelerator for butyl
rubber. Tellurium is also used in catalysts, metal finishing,
explosives, antioxidants, infra-red transmitting glasses,
and in thermoelectric and other electronic devices (Kudryavtsev,
19V4). Some tellurium compounds found therapeutic applications
(Browning, 1969).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food
Schroeder et al. (1967) have found the following mean values
in food samples (in mg/kg): - meats 4.2; dairy products
4.8; cereals 2.8; fats and oils 1.8; vegetables and fruits
1.1; hospital diets 0.44. Most of these values are probably
too high (about 80%) and should be considered as a rough
372
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approximation' only (Nason and Schroeder, 1967). After revising
the results of Schroeder et al. (1967), Nason and Schroeder
(1967) estimated the daily intake at about 100 /ug.
5.1.2 Water and ambient air
4
Tellurium concentrations in water are probably very low as
no Te could be detected in 20 samples of tap water from one
location in the USA (Schroeder et al., 1967). No spectro-
graphically detectable quantities of tellurium were found in
the principal USA rivers (Durum, 1960).
Tellurium in ambient air originates from industrial emissions
and coal combustion. An estimate has been made that coal
combustion in the USA releases about 40 tons of Te in fly
ash (Davidson and Lakin, 1972) . Seljankina and Alekseeva
(1971) found about 2,ug Te/m at 2 km from an electrolytic
copper refining plant.
5.2 Working environment
Since the production and use of tellurium is linked with
other metallurgical and industrial processes, there is
a possibility of multiple occupational exposures which may
involve lead, zinc, arsenic, selenium, cadmium and thallium.
There is little information on the levels of exposure and on
the chemical form of tellurium in the working environment. Ir.
addition to elemental tellurium, occupational exposures may
include tellurium dioxide and hydrogen telluride (Izrael'son,
1973). Steinberg et al. (1942) reported air levels of tellurium
in an iron foundry ranging from 0.01 to 0.1 mg/m with 70%
of the results falling between 0.01 and 0.05 mg/m .
6. Metabolism
Data on tellurium metabolism have been summarized by ICRP
(1968). There is practically no information on the meta-
bolism of tellurates.
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6.1 Absorption
6.1.1 Inhalation
There is no quantitative information on the respiratory ab-
sorption of tellurium compounds.
6.1.2 Ingestion
The absorption of ingested elemental tellurium and of tellurium
dioxides cannot be quantified on the basis of available
information (De Meio, 1946; De Meio and Jetter, 1948) .
Gastrointestinal absorption of tellurites is completed
within two hours and takes place, in rat, mainly in the
duodenum and jejunum (Slouka and Uradel, 1970). Absorption
estimates vary from 10-15% (Rollins, 1909) to 25% (Slouka
and Hradil, 1970). In swine as in sheep, sodium tellurite is
absorbed from the colon but not from the small intestine
(Wright and Bell, 1966).
6.2 Distribution
The method of administration (i.v. and i.p. injection, oral)
does not significantly change the pattern of soft tissue
distribution of tellurium given as sodium tellurite or tellurous
acid in HCl solution (De Meio and Henriques, 1946; Moskalev,
1960; Rollins, 1969; Slouka, 1970; Slouka and Hradil, 1970).
A short term equilibrium is reached within 1-2 hours; the
organs of highest concentration include the kidney, liver,
lungs, thyroid, spleen and the blood. The uptake by skeletal
muscles is much slower, and in the long-term tellurium seems
to accumulate in the bone (Hollins, 1969; Slouka, 1970).
About 90% of blood tellurium in the rat is contained in the
erythrocytes, probably bound to hemoglobin (Sandrackaja and
Krasovskij, 1963; Hollins, 1969; Slouka, 1970; Agnew and
Cheng, 1971). The same applies to swine but not sheep where
only a small fraction of tellurium was found in washed blood
cells following oral and intravenous administration of
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sodium tellurite (Wright and Bell, 1966). Tellurium deposited
in various tissues of the rat is bound to soluble proteins
(58-96%) (Agnew and Cheng, 1971).
Agnew et al. (1968) demonstrated that tellurium readily
crossed the blood brain barrier of the rat. In rats main-
tained on a diet with high concentrations of elemental
tellurium (3000 mg/kg), fine needles of tellurium were found
in the lysosomes of the brain neurons (Cravioto et al.,
1968). A similar observation was made by Mizuno (1969) on
rabbits which received an i.m. injection of elemental tellurium
suspended in olive oil.
Transplacental uptake of tellurium was shown by Agnew (1972)
in rats receiving i.p. injections of radioactive tellurous
acid in 0.9 M HC1.
6.3 Excretion
Injected tellurium (i.v. and i.p. as sodium tellurite) is
excreted by the rat mainly with urine (14-27% within 24
hours, 33% within one week). Fecal excretion amounts to
about 6% in 24 hours and 14% in one week. Tellurium is
transferred to the intestine by biliary excretion (Rollins,
1969; Slouka, 1970). About 11-16% of i.v. injected Te (as
sodium tellurite) was excreted by female dogs within one
hour, and 23% within 6 days (De Meio and Henriques, 1947).
About 60-80% of ingested sodium tellurite and tellurium
dioxide was rapidly eliminated by rats and swine in feces
(De Meio and Henriques, 1947; Sandrackaja and Krasovskij,
1963; Wright and Bell, 1966; Slouka and Hradil, 1970; Chertok
and Lake, 1971). Urinary excretion is highest within 7-24
hours; it amounts to 3-9% in 6-11 days in rats and female
dogs, and to 17-20% in 1-2 days in swine (De Meio and
Henriques, 1947; Sandrackaja and Krasovskij, 1962; Wright
and Bell, 1966; Chertok and Lake, 1971).
375
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During the first 4 days after a single feeding of Te
(chemical form not specified), 0.3-0.5% was excreted in
sheep milk. This is very close to the value reported for
dairy cows (0.5% in 6 days) (Casey et al., 1963).
A very small amount of absorbed tellurium is exhaled (about
0.1%) presumably as dimethyltelluride producing a garlic-
like odor noted in animals and man after exposure to elemental
tellurium and tellurium (IV) compounds (Steinberg et al.,
1942; De Meio, 1946; De Meio and Henriques, 1947; Amdur,
1958; Popova et al., 1965; Rollins, 1969). Schroeder et al.
(1967) consider that tellurates are not methylated in the
organism.
6.4 Biological half-time
The whole body retention of tellurium in rats after i.p. or
i.v. injection of tellurous acid in HC1 or sodium tellurite
can be described by a sum of two exponential functions with
biological half-times of about 19 hours (42-49% of dose) and
13-15 days (51-58%) (Rollins, 1969; Slouka, 1970). After
gavage of the same compounds a third exponential term (half-
time of 3-7 hours) has to be added to account for the rapid
elimination of the non-absorbed fraction (70-80%) (Rollins,
1969; Slouka and Hradil, 1970). The whole body retention model
for man (ICRP, 1968) assumes a biological half-time of about
3 weeks.
Rollins (1969) estimated '-^e biological half-times for the
major sites of retention of tellurium as 9.2 days (blood),
10.2 days (liver), 17.7 days (muscle) and 23 days (kidney).
His results for femur suggest that bone practically does not
release deposited tellurium; a very crude estimate of the
half-time is 600 days with a standard error of 5000 days.
7. Normal levels in tissues and biological fluids
There is no reliable information on the "normal" values in
man. Data reported by Schroeder et al. (1967) and revised by
Nason and Schroeder (1967) are a very crude approximation
376
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because of the analytical inconsistencies admitted by the
authors themselves. It is nevertheless of interest to note
that the skeleton was estimated to contain more than 90% of
the total body burden (about 500 mg, based on neutron activation
data).
8. Effects and dose-response relationships
There is no evidence that tellurium is essential either for
man or animals.
8.1 Local effects and dose-response relationships
8.1.1 Animals
Inhalation of elemental tellurium and tellurium dioxide
aerosols (10, 50 and 100 mg/m , 2 hours daily, 13-15 weeks)
produced in rats catarrhal desquamatory bronchitis and lobar
pneumonia (Sandrackaja, 1962a; Izrael'son, 1973). Inhalation
of tellurium hexafluoride (50 mg/m , 1 hour) resulted in
pulmonary edema in rabbits, guinea pigs, rats and mice
(Kimmerle, 1960) .
Long-term ingestion of sodium tellurite and tellurate (1-50
mg/kg body weight, 3-7 months) was accompanied by dark
inclusions and degenerative changes in the small intestines
of rats and rabbits (El'nicnik and Lencenko, 1969) but pekin
ducks kept on a diet of tellurium tetrachloride (50-1000 mg
Te/kg, 2-4 weeks) showed only a gray-black discoloration of
the intestines (Carlton and Kelly, 1967) .
Tellurium dioxide caused inflammatory processes when in
contact with rat's digits (De Meio and Jetter, 1948).
8.1.2 Humans
Exposures to tellurium vapor and hydrogen telluride have
been reported to cause irritation of the respiratory tract
(Popova et al., 1965; Izrael'son, 1973).
The evidence of local effects on the skin following occupations^
exposure to fumes and dust containing tellurium dioxide is
not conclusive (Shie and Deeds, 1920).
377
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8.2 Systemic effects and dose-response relationships
8.2.1 Animals
The signs of systemic toxicity of tellurium and its compounds
observed in acute and subacute studies include listlessness,
decreased locomotor activity, somnolence, anorexia, loss of
weight, and gastrointestinal disturbances; changes in fur
coat, and occasionally, epilation and paralysis of hind legs
were noticed in rats (De Meio, 1946; De Meio and Jetter,
1948; Amdur, 1958; Sandrackaja, 1962a). Life-time exposure
of rats to sodium tellurite and of mice to sodium tellurite
and tellurate (2 mg Te/1 drinking water) had no effect on
growth and survival rate of males, but tellurite reduced
the life-span of female mice (Schroeder and Mitchener, 1971
and 1972) .
8.2.1.1 Liver
Pathomorphological changes in the liver reported as resulting
from exposure to tellurium compounds range from simple
cellular swelling to hydropic and fatty degeneration and
cell necrosis. Such observations were made by De Meio and
Jetter (1948) (rats, tellurium dioxide ingestion, 375-1500
mg/kg diet, 24-128 days), Sandrackaja (1962b) (tellurium
dioxide, inhalation exposure, 50 mg/m , 2 hours daily, 13-15
weeks), Lencenko (1966) and El'nicnik and Lencenko (1969)
(rats and rabbits, sodium t:ilurite, gavage of 5 and 10
mg/kg body weight for 3 months, and of 0.5 mg/kg for 7
months) and Carlton and Kelly (1967) (pekin ducks, 50-1000
mg/kg diet as tellurium tetrachloride, 2-4 weeks).
Impairment of glycogen function, detoxifying functions and
of protein metabolism as indicated by dose-related reduction
of galactose tolerance, hippuric acid excretion, decrease of
albumin/globulin ratio in serum, urinary bilirubin excretion,
inhibition of cholinesterase, etc. were observed by Sandrackaja
(1962b) (rats, inhalation exposure to tellurium dioxide),
Lencenko (1966) and Lencenko and Plotho (1969) (subacute and
chronic studies in rats and rabbits, oral administration of
sodium tellurite, 0.5-10 mg Te/kg body weight).
378
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8.2.1.2 Kidney
Inhalation exposure of rats to tellurium dioxide (condensation
aerosol, 10 and 50 mg/m , 2 hours daily, 13-15 weeks) caused
focal vacuolization of cells and hemorrhage in the glomeruli,
accompanied by albuminuria and hematuria (Sandrackaja,
1962a, 1962b). Ingestion of tellurium dioxide (375-1500 mg
Te/kg diet, 24-128 days) induced changes ranging from cellular
swelling to frank necrosis, accompanied in some rats by
oliguria and anuria, indicating severe lesions in the proximal
tubular epithelium (De Meio and Jetter, 1948). Kidneys were
soft, swollen, grossly hemorrhagic and distinctly necrotic
in guinea pigs after a single i.m. injection of 75 mg tellurium
dioxide; these effects were probably enhanced by BAL administered
to some animals together with TeO-. No kidney lesions were
reported in subacute and chronic studies with sodium tellurite
in rats and rabbits (El'nicnik and Lencenko, 1969).
8.2.1.3 Blood
Sandrackaja (1962a, 1962b) reported normochromic, possibly
hemolytic, anemia in rats exposed to tellurium dioxide and
elemental tellurium aerosol (50-100 mg/m , 2 hours daily,
13-15 weeks), indicated by dose-related reductions in hemo-
globin and erythrocytes, and hematuria. No significant
changes in the peripheral blood were noted by De Meio and
Jetter (1948) in feeding experiments on rats (tellurium
dioxide, 375-1500 mg/kg diet, 24-128 days), and by Lencenko
(1966) in subacute and chronic experiments in rats and
rabbits (0.0005-1 mg Te/ kg body weight, 3-7 months).
8.2.1.4 Heart
Carlton and Kelly (1967) observed myocardial hemorrhage,
hydropericardium and areas of necrosis confined to myocardium
in pekin ducks maintained on a diet containing tellurium
tetrachloride (50-1000 mg Te/kg diet, 2-4 weeks).
8.2.1.5 Nervous system
Weakness and/or paralysis of hind legs in rats observed b^
several authors under different experimental conditions
379
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(De Meio and Jetter, 1948; Amdur, 1958; Sandrackaja, 1962a,
1962b; for definitions of exposure see previous sections)
was recently confirmed by Lampert et al. (1970) and Lampert
and Garret (1971) who administered 1-1.25% of elemental
tellurium to young rats for 1-8 days. These authors consider
that the paralysis is caused by demyelinization of sciatic
nerves resulting from degeneration of Schwann's cells.
Morphological changes in the pyramidal cells of the brain
cortex were found in rats ingesting sodium tellurite and
tellurate for 3-7 months (Lencenko, 1966; El'nicnik and
Lencenko, 1969). Focal as well as more extensive areas of
necrosis were observed in the brain of pekin ducks fed
tellurium tetrachloride for 2-4 weeks (100, 500 and 1000 mg
Te/kg diet; Carlton and Kelly, 1967).
These morphological changes are either preceded or associated
with functional and biochemical changes, including impaired
conditioned reflexes (Lencenko, 1966), increased chronaxie
(Sandrackaja, 1962a, 1962b) and inhibition of cholinesterase
and free thiol groups in the gray matter of the brain (Lencenko
and Plotho, 1969). A severe impairment of the learning
ability resulted from exposure of weanling rats for 6 months
to elemental tellurium (3000 mg/kg diet).
8.2.1.6 Miscellaneous biochemical effects
Sodium tellurite given orally to rats for 7 months at daily
doses of 0.005 mg Te/kg or more reduced the activity of
catalase and free thiol groups in the blood (Lencenko,
1966). Inhibition of catalase in the erythrocytes was noted
also by Sandrackaja (1962a, 1962b) in rats exposed to tellurium
and tellurium dioxide aerosols. Tellurite ion (1 mM) added
in vitro to the mitochondria of rat's kidney and liver
selectively inhibited the oxidation of NAD dependent substrates
(Siliprandi et al., 1971). Administration of sodium tellurite
(150 ,ug Te/kg body weight/day) for 11-30 months to weanling
rats in diet and drinking water increased serum cholesterol
in male but not in female animals (Schroeder, 1968) .
330
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8.2.2 Humans
8.2.2.1 Occupational exposures
Shie and Deeds (1920) examined 13 subjects working around
blast furnaces where the slime of an electrolytic lead
refinery was treated. No data are available on the level of
exposure, but the authors consider that tellurium could have
been present in the form of hydrogen telluride as well as
tellurium dioxide dust. Seven out of 13 examined workers
showed evidence of tellurium absorption by garlic odor of
the breath, sweat and urine, dryness of the mouth and metallic
taste. Five had a considerable inhibition of the sweat
function, and 3 of them had a dry and itchy skin, anorexia,
nausea, some vomiting, depression and somnolence which were
regarded by the authors as signs and symptoms of mild tellurium
poisoning. Steinberg et al. (1942) found garlic odor of
breath in 84 and of sweat in 30 out of 98 workers exposed to
tellurium-containing fumes in an iron foundry (0.01-0.1 mg
Te/m , 22 months). Tellurium was found in urine of all
exposed workers (0.01-0.06 mg/1) but not in any of the
control group. The workers complained of garlic odor of
breath and sweat, dryness and metallic taste in the mouth,
somnolence, loss of appetite and occasional nausea. Similar
signs and symptoms were found by Amdur (1947) in 3 laboratory
workers accidentally exposed to tellurium-containing fumes
for not more than 30 minutes. Tellurium was present in urine
(0.008-0.016 mg/1).
Popova et al. (1965) described two cases of non-fatal occupational
poisoning by tellurium vapor, but no information was given
on the possible level of exposure. Signs and symptoms included
general weakness, cough, shivering, amnesia, pallor of the
skin, and black-green discoloration of mucosa of the tongue
and nasopharynx. Temperature and pulse rate were increased,
and moderate leukopenia, neutrophilia and leucocytosis were
present. The breath smelled of garlic. The EEC showed transient
diffuse changes in the electrical activity of the myocardium.
381
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8.2.2.2 Accidental non-occupational exposure
Keal et al. (1946) described 3 cases of accidental tellurium
poisoning where sodium tellurite solutions were given instead
of potassium iodide during retrograde pyelography. In two
cases the dose was about 2 g (~30 mg/kg). Two patients died
after about 6 hours; death was preceded by vomiting, renal
pain, stupor, loss of consciousness, irregular breathing and
cyanosis. Autopsy revealed deposition of black tellurium in
the mucosa of the bladder and of the ureter, and congestion
of lungs, liver, spleen and kidneys and fatty change of the
liver. All tissues emitted a strong garlic odor.
8.3 Carcinogenicity, teratogenicity and mutagenicity
Schroeder and Mitchener (1971, 1972) exposed rats to sodium
tellurite and mice to sodium tellurite and sodium tellurate
for life (2 mg Te/1 drinking water). There was no evidence
that such exposure changed either the tumor incidence or the
time-to-occurrence of tumors.
Tellurium was found to induce hydrocephalus in newborn rats
of mothers fed high concentrations of elemental tellurium
(Garro and Pentschew, 1964; Agnew et al., 1968; Duckstt,
1971, 1972). Sixty to 100% of litters had hydrocephalus with
an incidence of 25-100%. The sensitive period of teratogenic
vulnerability was between day 9 and 15 of gestation (Duckett
et al., 1972; Agnew and Currv, 1972). It seems that tellurium
acts directly on the embryo (Agnew, 1972) .
There are no animal studies on the mutagenicity of tellurium
compounds. A significant increase of chromosome breakage
incidence was, however, observed in human leukocytes treated
—8
in vitro with sodium tellurite (1.2-10 M) and ammonium
tellurite (2.4-10~7M) (Patton and Allison, 1972).
9. Diagnosis and treatment
Garlic odor of the breath and urine, and the presence of
tellurium in urine are sensitive indicators of tellurium
absorption. Garlic odor of the breath was noticeable in 5
382
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volunteers who ingested 3 mg tellurium (compound not specified)
in 10 ml water each day for 8 days (Lencenko, 1966), corresponding
to a daily intake of about 40,ug/kg.
There is no specific antidote for poisoning by tellurium
compounds. The use of BAL or ascorbic acid is not recommended
(Amdur, 1958).
383
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THALLIUM
George Kazantzis
1. Abstract
Following rapid, almost total, absorption from the gastro-
intestinal tract, soluble thallium salts are widely distri-
buted in the body, the highest concentrations being attained
in the kidney. Excretion occurs in both urine and feces, the
disappearance of thallium from the tissues following first
204
order kinetics. The biological half-time of Tl in the rat
has been calculated at three to four days. In man, thallium
may be found in urine and feces for several weeks following
absorption. Excretion also occurs via hair, which in unexposed
subjects has been shown to contain the highest concentration
of thallium in any tissue. In the rat, 21 days after dosing,
up to 60% of the remaining body burden was found in the
hair. There are similarities in the ionic transport of
thallium and potassium through cell membranes, but once
intracellular, thallium is less rapidly released than potassium.
Thallium salts have caused acute and often fatal poisoning
as a result of accidental, criminal or suicidal ingestion.
Fatalities have also occurred following the therapeutic
administration of thallium. Following industrial exposure a
number of cases of chronic poisoning have been observed.
Gastroenteritis, peripheral neuropathy and collapse are the
principal features in acute poisoning, but with longer
survival, alopecia becomes characteristic. In chronic poisoning
the main features are vague ill health, paresthesias and
alopecia. The widespread use of thallium as a pesticide has
been responsible for the death of domestic and wild animals
and their natural predators.
2. Physical and chemical properties
Thallium, Tl, atomic weight 204.4; atomic number 81;
388
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density 11.9; melting point 303.5 C; boiling point 1457 C;
crystalline form blue-white metal, tetragonal; oxidation
state, 1, 3. Compounds to be taken up in this treatise are
thallous sulfate, thallous nitrate, and thallium acetate.
Other common compounds are thallium (I) oxide, thallium
(III) oxide, thallous carbonate and thallous sulfide.
Thallium shares group Illb of the periodic table with indium,
gallium, aluminum and boron. It is softer than lead. Thallium
metal forms a brownish-black oxide upon exposure to air.
Thallium is highly reactive, readily soluble in acids and
forms monovalent thallous and trivalent thallic salts, the
latter of which are less stable.
3. Methods and problems of analysis
Thallium can be readily identified spectrographically, as
described by Truhaut (1959) and Downs et al. (1960) . Thallium
in body fluids or tissues can be precisely estimated by
atomic absorption spectrophotometry following conversion to
thallic bromide (Savory et al., 1968). The limit of detection
of the method is 3.5 mg Tl/50 1 sample of urine and 3.5 ,ug
Tl/5 ml sample of serum. A coefficient of variation of 6.9%
has been given for duplicate analyses of thallium in urine
specimens containing 100 to 300 ,ug/l. The method is free
from appreciable interference by other elements. Thallium
has been estimated in urine using a carbon rod atomizer and
atomic absorption spectrophotometry (Kubasik et al., 1973).
Thallium in small samples on the order of 0.1 to 2 g of
liver or kidney has been estimated by pulse polarography
(Reinhardt and Zink, 1973). Care is required with the purity
of the reagents to obviate interference from lead. The
detection limit in such samples is 0.1 mg/kg,which level may
be indicative of poisoning. Thallium poisoning has been
detected from single hair and toenail samples by means of
neutron activation analysis (Henke and Fitzek, 1971). The
detection limit of the method has been given as 10~ mg/kg. Two
simple colorimetric methods for the determination of thallium
in urine are the Rhodamine B method (Duvivier et al., 1964;
Bank et al., 1972) and the methyl violet method (Rieders,
1971), the latter having a detection limit of 0.15/ug thallium.
389
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4. Production and uses
4.1 Production
Thallium is found in Texas and Brazil, in the minerals
lorandite and crooksite. However, it is usually recovered
from flue-dust residues from zinc and lead smelters and as a
by-product of cadmium production. Thallium, which is present
as a sulfate, is separated by electrolysis. It is also
obtained from the residues in the production of sulfuric
acid by the lead chamber process. Total production is unlikely
to exceed a few thousand tons per annum.
4.2 Uses
Thallium has been used on a large scale as a pesticide,
mainly as a rodenticide, but has been replaced in some
countries by safer compounds. However, in some areas, following
the development of warfarin resistance in rats, the use of
thallium has recently increased. Thallium compounds have
uses in infra-red and other optical systems on account of
their high refractive index. They are also used in scintillation
counters. Thallium has been alloyed with silver and with
lead, has been used as a catalyst and included in fireworks.
Thallium solutions have been used in mineralogical analysis.
The industrial uses of thallium are at present limited, but
may increase.
5. Environmental levels and exposures
5.1 General environment
Thallium is fairly widely distributed over the earth, mainly
in rock formations, in very low concentration. It also
occurs in potash, lead and zinc ores and in fossil fuels.
Levels ranging from 0.3 to 3.0 mg/kg have been recorded in
coal and 50 to 90 mg/kg in airborne material collected
within 100 m of coal combustion sources (Natusch et al.,
1973). Concentrations of 0.7 to 88,ug/liter were reported
390
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in river water draining a metal mining area in New Brunswick
(Zitko et al., 1970). In algae and moss from these rivers
concentrations ranging between 9.5 and 162 mg/kg dry weight
were found. In Japan, thallium sulfate has been sprayed over
forest areas to kill rats and other pests, but has not been
found in samples of water taken over a period of one month
after spraying (Kitayama and Saito, 1972).
The use of thallium to kill rodents implicates its spread to
their natural predators such as foxes, weasels and martens.
Furthermore, wild and domestic animals may feed on the
poison directly.
Although pesticides containing thallium are no longer being
sold in some countries, they can still be found stored in
many homes. As a result of such storage, accidental contamination
of food has occurred. Thallium has also been used in the
past for therapeutic purposes, as for example to produce
hair fall in the treatment of ringworm. Domestic contamination
could therefore occur from stored medicines and ointments.
Colorless and tasteless thallium compounds have also been
used for homicidal purposes.
5.2 Working environment
Inhalation of thallium has resulted from the handling of
flue-dusts and of dusts from the roasting of pyrites. Inhala-
tional exposure may also occur in the extraction of the
metal, in the manufacture of thallium-containing rodenticides,
thallium-containing lenses and in the separation of industrial
diamonds (Richeson, 1958). Glomme and Sjostrom (1955) considered
skin contact as the route of absorption of thallium in a
group of workers manufacturing rodenticides.
6. Metabolism
6.1 Absorption
Absorption of thallium compounds is rapid following ingestion,
inhalation or skin contact and may be complete following
391
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ingestion. In experiments on the rat, Lie et al. (1960)
204
administered Tl as a thallous nitrate solution by six
different routes, oral, intratracheal, subcutaneous, intra-
peritoneal, intramuscular and intravenous. Whatever the
route of administration, the body burden, as a proportion of
the administered dose, was similar at any one time and
followed a single exponential function extrapolating to 100
per cent at zero time. From these data, the authors deduced
that complete absorption had occurred from the gastrointesti-
nal tract following ingestion and from the respiratory tract
following intratracheal injection. The rapidity of absorption
from the gut of the rat was shown by Lund (1956) who observed
thallium in the urine within one hour of oral administration
of thallous sulfate.
6.2 Distribution
Thallium is widely distributed in the body following its
rapid absorption in animals. Acute and chronic studies are
in agreement that the highest concentration is found in the
kidney. In the rat study reported above (Lie et al., 1960)
the kidney concentration was 5 1/2 times the next highest
concentration in the salivary gland. This was followed by
testis, muscle, bone, lymph nodes, gastrointestinal tract,
heart, spleen and liver all of which had relatively small
differences in concentration between them. There was little
variation in the relative thallium concentrations in these
tissues on successive days during the first week, with the
exception of hair. This latter increased with time so that
after 21 days it contained up to 60% of the body burden. The
relative organ concentrations remained constant whatever the
route of administration. Blood contained very little thallium,
indicating rapid equilibration with tissues. Thallium could
not be detected in blood 20 minutes after injection and only
in very low concentration two to three hours after intratracheal
instillation. In chronic feeding experiments in the rat,
Downs et al. (1960) found the highest concentration in the
kidney, followed by bone, liver, lung, spleen and brain.
392
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In man, too, thallium is widely distributed in the tissue,
with the highest concentration in the kidney. However, the
proportionate distribution has shown considerable variation.
In the fatal case reported by Cavanagh et al. (1974) the
second highest concentration was found in the heart. The
concentration in grey matter was found to be three times
that in white matter, although brain ranked low in order of
tissue concentrations. Barclay et al. (1953) in their single
case found the highest concentration in hair, followed by
kidney and heart muscle.
6.3 Excretion
Thallium is excreted by the kidney and intestine, and also
in small part by salivary gland, hair and into milk. It is
also able to cross the placental barrier (Heyroth, 1947). In
the rat study described above (Lie et al., 1960) excretion
maintained a similar pattern regardless of the route of
administration. Again, by whichever route thallium was
administered, fecal exceeded urinary excretion during the 21
days of the study, the fecal to urinary ratio rising from 2
to 5, due to a gradual decrease in thallium excreted in the
urine. Thyresson (1951) and Barclay et al. (1953) in observations
in rats also found fecal excretion to exceed urinary. From
observations in the rat following the intraperitoneal injection
of 10 nag thallous sulfate per kg body weight, Lund (1956)
found the principal routes for the elimination of thallium
to be the gut and the kidney. Concentrations of the metal in
gastrointestinal secretions corresponded with those in the
plasma. In rabbits given an intravenous infusion of thallous
nitrate, 0.5 g/1, thallium was shown to be excreted by
glomerular filtration, about half the filtered amount being
reabsorbed in the tubules. With the addition of 1% potassium
sulfate to the infusion, the renal clearance of thallium was
doubled, believed to result from the simultaneous tubular
secretion of thallium and potassium (Lund, 1956). Rauws
204
(1974) gave intravenous T1SC>4 to a small group of rats
and simulated thallium kinetics on the basis of a three-
compartment model. He concluded that a significant exchange
393
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of thallium occurred between the tissues and the intestinal
contents, which he described as an entero-enteral cycle.
Few observations have been made in man. Barclay et al.
(1953) gave radioactive thallous nitrate and thallous sulfate
to one patient with metastatic osteogenic sarcoma and found
the rate of excretion in the urine to be 3.2% per day of the
amount remaining in the body. Thallium excretion in both
urine and feces may persist for many weeks in spite of low
plasma levels in poisoned patients. In unexposed persons,
the highest tissue concentration of thallium has been found
in hair, throughout its length (Weinig and Zink, 1967) (See
Section 7). In the long-term, therefore, hair and to a
lesser extent nail, provides an important route for the slow
excretion of thallium from the body.
6.4 Biological half-time
The body burden as a percentage of administered dose was
204
determined in rats following the administration of Tl by
a variety of routes over a period of 21 days (Lie et al.,
1960). Body clearance was found to occur exponentially with
a half-time of 3.3 days whatever the route of administration.
At the end of 21 days, the total period of observation, 1%
of the administered dose remained. As, except for hair,
there was no day to day variation in relative organ concentration,
individual organs were considered to have similar biological
half-times. With a biological half-time of 3.3 days, it was
calculated that with daily dosing an equilibrium would be
attained at about 20 days. In an industrial situation,
assuming similar clearance rates in man, and with a five day
per week exposure pattern, such an equilibrium may be attained
in about 30 days.
A biological half-time of approximately four days was also
204
found by Rauws (1974) in his observations with Tl given
intravenously in rats and quoted in Section 6.1. In his
three compartment model, Rauws considered the brain as a
compartment on its own, because of its role as a target
394
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organ and because thallium ions penetrate into it more
slowly. He found the brain concentration to be always lower
than the mean concentration in the organism calculated from
body load and body weight.
7. Normal levels in biological tissues and fluids;
indicators of exposure
Few data are available on levels of thallium in normal
subjects. In a study on six people of various ages dying
from unrelated causes, Weinig and Zink (1967) estimated
tissue concentrations of thallium by mass spectroscopy. The
highest values were found in hair, with concentrations
ranging from 4.8 to 15.8 /ug/kg. Concentrations in nail
ranged from 0.72 to 4.93 /ug/kg, and in the wall of the colon
from 0.56 to 5.40 /ug/kg wet tissue. The mean tissue concentra-
tion was calculated as 1.2 /ug/kg, from which it was derived
that the thallium content in a 75 kg person would be of the
order of 0.1 mg. The same investigators found the thallium
concentration in early morning urine samples in nine subjects
to range from 0.13 to 1.69/ug/l. Johnson (1976) in a study
in New Zealand on eleven subjects with no known exposure to
toxic metals, found a mean thallium concentration in liver
of 0.47 mg/kg dried tissue, with a range of 0.4 to 0.9 mg/kg.
Thallium concentration in tissues, urine, feces, hair and
nails provides the only indicator of thallium exposure
available at the present time. Weinig and Zink (1967) considered
that no conclusion on poisoning in forensic practice could be
drawn from tissue or urine levels of thallium less than 50
to 100 times their normal values, briefly quoted above.
8. Effects and dose-response relationships
8.1 Humans
Thallium compounds are cumulative in their effect and extremely
toxic. In general, acute poisoning is characterized by
gastroenteritis, with nausea, vomiting, diarrhea and abdomina"!
pain within hours of absorption. Involvement of the nervous
system then becomes apparent, with paresthesias, muscular
395
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pain and weakness, mental confusion or delirium, convul-
sions, respiratory and circulatory involvement followed by
death. When the period of survival extends beyond one week
or so, a varied neurological picture may develop with head-
ache, ataxia, tremor, paresthesias and muscular atrophy
predominating. There may also be cranial nerve involvement,
with ptosis, retrobulbar neuritis or facial paralysis. After
an interval of one to three weeks, alopecia develops, sparing
pubic and axillary hair, and also the medial third of the
eyebrows. Recovery may be complete or neurological defects
may remain with mental abnormality, ataxia and tremor (Reed
et al., 1963; Grunfeld and Hinostroza, 1964; Smith and
Doherty, 1964; Matthews and Anzarut, 1968; Bank et al.,
1972; Cavanagh et al., 1974).
Three cases, two of which were fatal, were described in
detail by Cavanagh et al. (1974). The more acutely affected
of these was initially diagnosed as a case of Guillain-Barre'
polyneuritis. This case showed little evidence of neuronal
degeneration, but the second fatal case showed extensive
distal degeneration of all nerve fibers examined, with
chromatolysis of motor nerve cells. Neuronal degeneration
was of the distal, dying-back type and was still continuing
three weeks after the onset of paresthesia. In the second of
Cavanagh's two fatal cases, the concentration of thallium in
the kidney was 20 mg/kg •, heart 13 mg/kg; brain (gray matter)
10 mg/kg; skin 6 mg/kg; liver, bone, muscle 5 mg/kg, with
lower concentrations in other tissues. In the survivor,
seven weeks after exposure, thallium could not be detected
in the serum but was present in the urine in a concentration
of 3.0 mg/1. In the fatal case reported by Smith and Doherty
(1964), tissue thallium concentrations revealed 5.2 mg/kg
of brain tissue, 7.8 mg/kg of kidney tissue, the bile contained
7 mg/1 and the urine 2.29 mg/1. The fatal case reported by
Grunfeld and Hinostroza had ingested more than 3 g thallium
sulfate, probably the highest dose to be reported. Tissue
concentrations in mg/kg were as follows: More than 20: colon
and liver; 10-19: stomach, gallbladder, bone marrow, small
bowel; 5-9: brain, lung, adrenal, spleen, cerebellum, kidney,
muscle, pons, all in descending order.
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The minimum lethal dose for soluble thallium salts for an
adult is on the order of one gram thallium (Gettler and
Weiss, 1943). The more acutely affected of the two fatal
cases of Cavanagh et al. (1974) was estimated to have ingested
0.93 g Tl as the acetate in two divided doses, while the
fatal case in which symptoms developed less rapidly had
taken the same total amount but in 3 divided doses. The
survivor had ingested 0.31 g Tl in a single dose. The so-
called therapeutic dose, recommended to produce hair loss in
two to three weeks, was 8 mg Tl/kg but Munch (1934) knew of
six deaths in children given this dose, with evidence of
poisoning in 5.5% of 8006 instances of therapeutic application.
There is in fact no therapeutic dose for thallium salts. The
minimum lethal dose for man is about 8 to 15 mg Tl/kg.
Thallium poisoning has occurred following the accidental
contamination of food. In one outbreak, barley containing 1%
thallium sulfate for pest control gave rise to 27 cases of
poisoning with 7 deaths (Munch et al., 1933). Thallium salts
have been used for suicide and their criminal use has been
reviewed by Prick et al. (1955). Many cases of poisoning in
children and adults, both fatal and with recovery, have
followed the therapeutic use of thallium salts, especially
in the treatment of ringworm. Of the 778 cases reviewed by
Munch et al. (1933), 6 % were fatal.
Industrial thallium poisoning has occurred following absorption
after inhalation of dust or fume, ingestion from contaminated
hands or food or as a result of skin contact. Munch (1934)
recorded 12 cases of industrial poisoning up to 1934. The
principal clinical features in these cases were fatigue,
anorexia, pains in the legs and loss of hair. There were no
deaths, but one worker lost his sight with optic atrophy.
No information on doses is available. Glomme and Sjostrom
(1955) described 4 cases where absorption was thought to
follow skin contact in the manufacture of rodenticides.
Minor degrees of polyneuropathy and varying degrees of alopecia
397
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were noted, with maximal urinary excretion of thallium
between 0.38 and 10 mg/1. Occupational thallium poisoning
usually results from moderate, long-term exposure giving
rise to a mild clinical course characterized by subjective
symptoms, sometimes with polyneuropathy and with partial
alopecia.
8.2 Laboratory animals
In acute poisoning the principal effects are seen in the
digestive and nervous systems with, in addition, a necrotizing
renal papillitis. In chronic poisoning the most striking
feature is loss of hair.
In chronic poisoning, the daily ingestion of thallium acetate
added to the diet of male and female rats was tolerated at
the 10 mg/kg level but was lethal in male rats at the 30
mg/kg level by 15 weeks (Downs et al., 1960). All rats fed
an oral dose of 0.45 mg Tl/kg daily died after a period of 4
months (Hanzlik et al., 1928).
8.3 Domestic and wild animals
Clausen and Karlog (1974) examined 60 wild martens and
badgers in Denmark over a 2-year period and found a thallium
load in 48% of these, with evidence of poisoning in 22% of
the total. Acute hemorrhagic intestinal inflammation was
seen in most of the cases of poisoning. In the 13 poisoned
animals, liver concentrations ranged from 4.7 to 57 mg/kg;
kidney concentrations ranged from 1.8 to 92 mg/kg and intestinal
concentrations from 0.2 to 42 mg/kg. Thallium concentration
was estimated in 34 red foxes in Denmark which had been
found sick or dead during 1971 (Munch et al., 1974). In 4
out of 7 foxes where the cause of death could not be immediately
established a thallium content was found in excess of 1
mg/kg in at least one organ. Of the 27 foxes where an alternative
diagnosis had been made, thallium concentrations were greater
than 1 mg/kg in 5; between 0.5 and 1 mg/kg in 8 and 0.5
mg/kg or less in the remaining 14 animals.
398
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8.4 Interaction with potassium
There are similarities between the ions of thallium and
potassium and there is experimental evidence to suggest that
the biological handling of thallous and potassium ions is
interrelated. Mullins and Moore (1960) found in frog muscle
that potassium and thallium ions traversed cell membranes in
a similar way, and Gehring and Hammond (1964) showed that
the active transport mechanism for potassium into rabbit
erythrocytes also transported thallium. These authors (1967)
studied the relationship between the level of potassium and
the excretion of thallium in rats, dogs and sheep. Infusion
of potassium increased the renal clearance of thallium and
also its mobilization from tissues. It was concluded from
these experiments that the disappearance of thallium followed
a first order kinetic process. However, while the ionic
movements of thallium and potassium ions are related, once
inside the cell, thallium appears to be less readily released
than potassium. Thallium can substitute for potassium in
causing activation of adenosine triphosphatase indicating
that the mechanism involved in the active transport of
potassium cannot differentiate between the two ions. In
rats, an increased potassium intake increased the LD of
thallium, suggesting a translocation away from the toxic
receptor site (Gehring and Hammond, 1967). However, there is
no clear evidence that the administration of potassium is
beneficial in human thallium poisoning, although this is now
generally advocated (Lancet, 1974). The excessive mobilization
of thallium ions with subsequent redistribution in the
tissues may even be detrimental (Cavanagh et al., 1974).
Thallium has other effects on tissues in addition to those
related to potassium transport (Truhaut, 1959).
9. Diagnosis, treatment and preventive measures
The diagnosis of thallium poisoning may be difficult because
it is often unsuspected. The characteristic features are
gastroenteritis, peripheral neuropathy and alopecia, the
last occurring at a late stage. The possibility of thallium
poisoning should be borne in mind in obscure neurological
399
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illnesses, especially where there is neuropathy, and thallium
should be looked for in the urine. A brownish black pigmentation
close to the hair root is characteristic of thallium exposure
and may appear as early as the third or fourth day (Matthews
and Anzarut, 1968; Gerdts, 1974).
The treatment of thallium poisoning is unsatisfactory and
evaluation is difficult. Large doses of potassium chloride
may hasten the excretion of thallium, but may cause a transient
increase in blood levels and a redistribution in tissues
which may lead to a temporary exacerbation of symptoms (Papp
et al., 1969). In one case studied over a two-week period,
the urinary concentration of thallium adjusted for specific
gravity was directly related to the duration of the illness
and unaffected by potassium chloride or by dithizone therapy
(Smith and Doherty, 1964). Some authors have recommended
hemodialysis and forced diuresis as effective in decreasing
the body burden of thallium (Piazolo et al., 1971; Bank et
al., 1972; Loew et al., 1972; Koch et al., 1972; Jax et al.,
1973). Chelating agents have not in general been found to be
useful (Smith and Doherty, 1964). Diethyldithio-carbamate
has been shown to increase the urinary excretion of thallium
in the rat (Schwetz et al., 1966), but Kamerbeek et al.
(1971a) noted clinical deterioration and EEC disturbances
coincident with administration in man. They observed increased
levels of thallium in rat brain due to the formation of a
lipophilic chelate. Kamerbeek et al. (1971b) reported increased
fecal excretion of thallium with clinical improvement in 3
cases by giving Prussian blue (potassium ferric cyanoferrate
II) by mouth, replacing the potassium ion in the Prussian blue
molecule with thallium, thus rendering it unabsorbable from
the gut. Van der Merwe (1972) reported a successful outcome
in 2 patients treated with Prussian blue. Each had swallowed
700 mg thallous sulfate.
Rauws (1974) from his pharmacokinetic studies in the rat
estimated a 70% inhibition of thallium reabsorption from the
gut and considered this was responsible for the decrease of
400
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thallium half-time from 4 to 2 days in rats which had been
pretreated with Prussian blue.
In the prevention of thallium poisoning in industry, substitution
of less toxic compounds should be advocated wherever possible.
Where thallium compounds must be used, strict safety precautions
should be observed to prevent skin contact, inhalation or
unwitting ingestion. Food, drink and cigarettes should be
prohibited at the work site. With regard to poisoning in the
community, the use of thallium-containing pesticides should
be discontinued wherever possible and restrictions placed on
their availability (Lancet, 1974).
10. Prognosis
The estimation of outcome in thallium poisoning is difficult.
In general, cases with a fulminating onset are rapidly
fatal, and the longer the course of the illness, the greater
the chance of survival, although recovery may be incomplete
where there is peripheral neuropathy. In one of the cases
described by Grunfeld and Hinostroza (1964) the only manifestation
of poisoning was nausea and vomiting of 16 hours' duration
in spite of a urinary excretion of 3.65 mg Tl/1 5 days after
ingestion.
401
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TIN
Magnus Piscator
1. Abstract
Inorganic tin compounds are absorbed to only a few percent
from the gastrointestinal tract. Tin is mainly stored in bone,
where the biological half-time in animals is about 100 days.
Excretion is mainly via urine.
Organotin compounds vary in metabolism depending on number
and type of organic radicals attached to the tin. Short chain
alkyl compounds have a relatively high gastrointestinal absorp-
tion, whereas long-chain alkyl compounds are absorbed to a very
small degree. Distribution, biotransformation and excretion
differ among the organotin compounds.
Tin has not been shown to be an essential metal for humans.
Experimental data indicate that 1-2 mg tin per kg diet promotes
growth in rats.
The toxicity of tin after inhalation or dietary exposure is
low. In exposed workers tin oxide accumulates in high con-
centrations in the lungs and causes "stannosis", a benign
pneumoconiosis without tissue reaction or pulmonary dysfunction,
Acute gastrointestinal disturbances have been common after in-
gestion of food packed in tin cans, especially acid juices.
About 50 mg of tin may cause nausea and vomiting. Long-term
exposure to smaller amounts has not caused any ill effects.
Some organotin compounds are highly toxic, especially triethyl-
tin. Trialkyl compounds, especially triethyltin, cause an
encephalopathy due to brain edema. Several deaths due to brain
lesions have been reported among people treated with "Stalinon"
a preparation containing diethyliodide contaminated with tri-
ethyltin. Triphenyltin compounds have caused liver damage in
exposed workers. Long-chain alkyl compounds, e.g. octyltin,
405
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There is no evidence that inorganic or organotin compounds can
give rise to carcinogenic or teratogenic effects.
For further information, see reviews by Barnes and Stoner (1959)
and Piver (1973). Both WHO and NIOSH are preparing criteria
documents on tin; the latter will deal exclusively with organo-
tin.
2. Physical and chemical properties
Tin, Sri, atomic weight 118.7; atomic number 50; density 5.8-
7.3; melting point 231.9°C; boiling point 2260-2270°C; cryst-
alline form, three variations: gray, cubic (tin gray), white
metallic, tetragonal (tin white) and white rhombic (tin brittle);
oxidation state 2, 4.
Transition from the gray allotropic form (a) to the white one
(8) occurs when the temperature sinks below 13 C. The divalent
compounds are designated as stannous and the tetravalent as
stannic. At pH above 6, stannous compounds are easily oxidized.
Tin does not occur in ionized form, but rather in colloidal
complexes. In the organotin compounds, one to four carbon atoms
may be bound directly to tin.
Tin forms a large number of inorganic and organic compounds.
The inorganic tin compounds to be taken up here are tin oxide,
tin tetrachloride, stannous chloride, stannic chloride, sodium
chlorostannate, sodium pentachlorostannite, stannous fluoride
and sodium pentafluorostannite. The organic compounds to be
discussed include ethyl, butyl, octyl, phenyl, and cyclohexyl
tin.
3. Methods and problems of analysis
The quantitative determination of small amounts of tin has al-
ways presented problems, as reflected in the large number of
methods proposed. The merits of various methods have been dif-
406
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ficult to evaluate owing to the lack of interlaboratory com-
parison .
There are many spectrophotometric methods available for the
analysis of tin, among which are the dithiol, catechol violet
and quercetin methods (Kirk and Pocklington, 1969j Adcock and
Hope, 1970; Engberg, 1973). Atomic absorption is widely used
at present for the determination of tin in different media.
Most reports agree that the detection limit is not satisfactory,
this being but one of several difficulties(Engberg, 1973). Tin
oxide is not readily broken down in the flame, a problem which
may be overcome to some extent by using special flame systems.
This procedure may bring the limit of detection down to around
15 mg/1 solution.Emission spectroscopy (Tipton et al., 1966),
spark source mass spectrometry (Hamilton et al., 1972/1973a),
neutron activation (Bowen, 1972) and X-ray fluorescence (Rudolph
et al., 1973) have also been employed for analysis of tin in
body fluids, tissues and food. The last three methods seem to
be able to determine tin in concentrations of 1-100 ug/kg, but
there are no interlaboratory comparisons available.
A variety of methods for identification and determination of
organotin compounds is also available. Extraction steps, tedi-
ous and demanding great care, with solvents such as benzene
and hexane, must often be performed to separate different organotin
compounds before analysis. Chromatographic methods are generally
used for the analysis itself (Fishbein, 1973).
4. Production and uses
4.1 Production
Tin is obtained mainly from cassiterite and to some extent
from other ores in combination with other metals. In 1973
the total production of tin was more than 185,000 metric tons,
Malaysia being the leading producer with 72,260 metric tons.
USSR, Thailand and Indonesia are other important production
countries in the eastern hemisphere. In the western hemisphere
Bolivia is the main producer (28,568 metric tons). Tin is
recycled to a considerable extent (Heindl, 1972).
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4.2 Uses
Tin is used in tin plating (50%), solders and alloys, and in
food cans (35%). Pewter, which contains 90-95% tin, 1-8%
antimony and 0.5-3% copper, is widely used in trays, tankards,
plates and the like (Heindl, 1972). Only about 4% serves for
producing chemicals. Inorganic tin compounds play a role in
a variety of processes from glass production to textile printing.
Stannous chloride has been claimed to have a cariostatic action
and has been added to toothpaste. Organotin compounds are used
as stabilizers in plastics and as catalytic agents. Dioctyltin
compounds are allowed as stabilizers in PVC-plastics used for
food wrapping. Triphenyl tin salts and many alkyltin compounds
have been utilized as pesticides (Ross, 1965; Piver, 1973).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
In meat, cereals, and vegetables, concentrations of tin were
usually less than 1 mg/kg in a study by Schroeder et al.,
(1964), using atomic absorption spectrophotometry. A diet
based on such products was figured to give a daily tin intake
of about 1 mg. In adults in the U.K. Hamilton et al. (1972/1973b)
estimated an average daily tin intake of 187 ug. In meat, fats,
cereals, and vegetables the concentration of tin averaged less
than 0.1 mg/kg. Tipton et al. (1966, 1969) found an average
daily intake of from 1.5 to ^.8 mg in long-term studies on 4
subjects. Estimates of the fecal output in the same study
showed values from 1.6 to j. 6 mg. The daily intake of tin may
be increased considerably if a good deal of canned food is
eaten. The release of tin into canned food depends on many
factors, such as presence of other chemicals, e.g. nitrates,
pH and storage temperature (Bielig and Treptow, 1973). Canned
tomato juice made from tomato plants treated with nitrate
fertilizers has been linked with an outbreak of acute tin
poisoning (Barker and Runte, 1972). Juices which have a high
acidity may cause the release of tin from the plating resulting
in very high concentrations, 100-500 mg/kg. The tin content of
the stored food also increases considerably when an opened can
is kept for a few days. 408
-------
The risk for tin contamination may be reduced considerably
by lacquering the cans (Bielig and Treptow, 1973). Still
another source of an increased tin content in canned food
is the use of stannous salts as additives. The stannous ion
prevents other metals from being released and helps to maintain
the ascorbic acid level.
Organotin compounds, e.g. dioctyltin, may be released into
food from plastic bottles but the resulting concentration
is generally less than 1 mg/kg (Carr, 1969).
5.1.2 Water, soil and ambient air
Several attempts to measure tin in various types of water
have failed, probably due to analytical difficulties. When
concentrations have been reported, they are usually around
1 ug/1 or less. In municipal drinking water higher concentra-
tions have sometimes been found. It has been suspected that
some tin could be released into such systems from e.g. bronze
fittings. It is not known whether organotin compounds occur
to any large extent in water. Tin concentrations in soil vary
greatly, from a few mg/kg to several hundred mg/kg (Schroeder
et al., 1964). In sewage sludge Berrow and Webber (1972) found
40-700 mg/kg, on an average 160 mg/kg. In air, concentrations
from < 3-300 ng/m have been reported from the United States,
the lowest values found in rural and suburban areas (Tabor
and Warren, 1958). High volume samplers and a spectrographic
method were used. In the Heidelberg area in Germany, Bogen
(1973) reported levels around 100 ng/m ; the method was neutron
activation. At a distance of 700 m from an industrial plant,
levels of 3.8-4.4 ug/m have been recorded in Japan (Environment
Agency, 1974).
5.2 Working environment
Exposure can be expected in the industries referred to in section
4. Oyanguren et al. (1958) found tin levels of 14.9 and 8.6
mg/m near two respective foundry furnaces.
6. Metabolism
6.1 Inorganic tin
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6.1.1 Absorption
6.1.1.1Inhalation
There are no data from animal experiments or from studies
on human beings on deposition or absorption of inhaled
inorganic tin.
6.1.1.2 Ingestion
Studies on animals (Durbin et al./ 1957; Kutzner and Brod,
1971; Hiles, 1974; Furchner and Drake, 1976) and on human
beings (Galloway and McMullen, 1966) show that the absorption
of ingested tin is only a few percent. In rats, Hiles (1974)
estimated that the absorption of Sn (II) was about 4 times
that of Sn (IV), 2.8 and 0.6% respectively.
6.1.2 Distribution
In animals given oral doses of tin the highest concentrations
have been found in kidneys, liver and bone (Durbin et al.,
1957; Hiles, 1974; Furchner and Drake, 1976). Most of the
tin initially distributed to soft tissues was eliminated
relatively rapidly therefrom. The main deposit of tin was in
the skeleton which in one study contained 35% and 46% of
administered doses of Sn (II) and Sn (IV) respectively
two days after an injection (Hiles, 1974). Long-term oral
administration of tin did not result in an accumulation in
soft tissues, but the levels in bone were higher than after
a single dose (Hiles, 19'/4). In human beings small amounts
of tin have been found in most organs, mainly bone, lungs,
liver and kidney. Tin has a tendency to accumulate in
human lungs with age (Schroeder et al., 1964).
6.1.3 Excretion
Animal data (Durbin et al., 1957; Hiles, 1974? Furchner and
Drake, 1976) indicate that injected tin is initially
excreted mainly via urine, and to some extent via bile. About
one-third of an injected dose of either Sn (II) or Sn (IV)
was excreted via rat urine within 48 hours (Hiles, 1974).
Durbin et al. (1957) found that rats excreted about 50% of
a dose via urine and only 1% via feces 24 hours after
410
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injection. Thirty days after injection, altogether 20% had
been excreted via the gastrointestinal tract, whereas the
percentage excreted via urine remained the same. Furchner
and Drake (1976) studied 5 species and found an average
of from 19.8 % (mice) to 62.8 % (dogs) of the dose had been
excreted via urine within 3 days after intravenous injection
of Sn (II) as the chloride. Via feces, from 5.6% to 10.6%
had been eliminated within the same time period.
6.1.4 Biological half-time
Durbin et al. (1957) estimated the biological half-time in
the rat after an injection of Sn to be 84 days> the half-
time in the skeleton was 100 days. Hiles (1974) estimated
the half-time for Sn (II) in rat liver and kidney to be
10-20 days. In bone both Sn (II) and Sn (IV) had about the
same half-time, 34 and 40 days respectively. In mice, rats,
monkeys and dogs given intravenous or intraperitoneal
injections of Sn (II) Furchner and Drake (1976) found
that the elimination could be described by four components,
the longest one comprising 90-100 days.
6.2 Qrganotin compounds
Data are not available for many of the wide variety of
organotin compounds. This lack is especially notable with
regard to metabolism in human beings.
6.2.1 Absorption
6.2.1.1 Inhalation
There are no data from animal experiments or from studies
on human beings on deposition patterns or absorption for
inhaled organotin compounds.
6.2.1.2 Ingestion
The high oral toxicity of short-chain alkyltin compounds
bears witness to their being absorbed. Quantitative data
are available for monoethyltin chloride only. This compound
is absorbed to about 8% in the rat as shown by Bridges et al,
(1967). Triphenyltin acetate has been shown to be absorbed
411
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to about 10% in cows (Bruggeraann et al., 1964) and in rats
(Heath, 1963). Tricyclohexyltin chloride has an absorption
of not more than 2% in the rat (FAO/WHO, 1971). No data are
available for human beings.
6.2.1.3 Skin
Short-chain alkyltin compounds seem to be absorbed from the
skin to a high degree, as indicated by their high toxicity
after dermal application (Hall and Ludwig, 1972). Triphenyl
compounds do not readily penetrate intact skin (Stoner, 1966).
6.2.2 Distribution
After injection of dibutyl- and diethyltin compounds, the
highest concentrations were found in liver and kidney of
mice and rats. After injection of triethyltin the highest
concentration was found in the liver, with smaller amounts
in kidneys and brain (Barnes and Magee, 1958). After three
months of oral exposure, triethyltin was found mainly
in liver, blood and muscles of rats, with minor amounts in
kidney and brain (Barnes and Stoner, 1959). Species
differences may be illustrated by the finding that triethyl-
tin was absorbed in vitro by the red cells of rats, but
not of rabbits (Barnes and Stoner, 1959). Triphenyltin,
labelled with Sn, has been found in liver, kidneys and
brain both after injection and after oral exposure (Heath,
1963). After long-term oral exposure to tricyclohexyltin
119
chloride, labelled with Sn, minor amounts were found
in the brain, kidney, liver, and muscles of rats (McCollister
and Schober, 1975). In a two year study, dogs and rats were
given tricyclohexyltin chloride orally. In the dog, the
highest concentrations were in liver, kidney and brain.
6.2.3 Excretion
The excretion pattern of triethyltin is not known in detail
but it seems that only a minor part is excreted via kidneys..
It has been shown that diethyltin is excreted via the bile
and monoethyltin via the urine (Bridges et al., 1967).
Triphenyltin has a relatively slow excretion, mainly via urine.
412
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In milk from exposed sheep only minor amounts of tin were
found (Herok and G§tte, 1964). Tricyclohexyltin is
excreted slowly but the major route is not known.
6.2.4 Biological half-time
For triphenyltin, the biological half-time in rat brain
has been estimated to be about 3 days, but it seems to be
considerably longer in the guinea pig (Heath, 1963). The
half-times for tricyclohexyltin compounds in different rat
tissues have been reported to vary from 5 to 40 days, the
longest half-time being in the brain (FAO/WHO, 1971).
There are no data on half-times for alkyltin compounds.
6.2.5 Biotransformation
Tetraethyltin is metabolized to triethyl, and probably
also to di- and monoethyl, tin compounds (Cremer, 1957, 1958)
These processes are governed by enzymes in the microsomes
of the liver (Casida et al., 1971). Diethyltin is
transformed to monoethyltin in the gut (Bridges et al.,
1967). In sheep exposed to triphenyltin, about 90% of the
tin in milk was in organic form while about 10% was in
inorganic form. There are no data on biotransformation of
tricyclohexyltin compounds.
7. Normal levels in tissues and biological fluids
The average concentration of tin in whole blood, determined
by spark source mass spectrometry, was about 5 ug/1
(Hamilton, 1972/73t>) which is considerably lower than values
reported earlier by Kehoe et al. (1940),i.e. 140 ,ug/1 more
than 80% of which was in the cells. Kehoe et al. employed
a colorimetric method. Rudolph et al. (1973), using X-ray
fluorescence, found 37 ug/1 in serum, which better agrees
with Kehoe et al.'s old data. Conclusions as to the true
levels of tin in human blood are not permitted by available
data. The urinary excretion of tin has been reported to be
around 20 ^g/day in three studies (Kehoe et al., 1940;
Perry and Perry, 1959; Meltzer et al., 1962).
413
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In tissues the concentrations of tin are generally less
than 1 mg/kg. The highest concentrations have been found
in bone (ribs), lungs, liver and kidney, i.e. 0.8, 0.8, 0.4
and 0.2 mg/kg wet weight respectively (Hamilton et al.,
1972/73b). These data agree well with earlier data by Kehoe
et al. (1940) who found 0.5, 0.45, 0.6, and 0.2 mg/kg
wet weight in the respective organs.
8. Effects and dose-response relationships
Tin has not been shown to be an essential element in human
beings. It has been claimed that 1-2 mg tin/kg diet is
necessary for growth in rats (Schwarz, 1974).
8.1 Inorganic tin
8.1.1 Local effects and dose-response relationships
8.1.1.1 Animals
Gastric irritation occurred in cats given canned fruit juices
contaminated with soluble tin salts (Benoy et al., 1971).
Eleven cats given orange juice containing 498 mg/1 of tin
did not vomit whereas one of 11 vomited when the tin content
was increased to 540 mg/1. The doses per kg body weight
were 2.5 and 2.7 mg. A concentration of 1370 mg/1, 14 mg/kg
body weight, induced vomiting in three out of ten cats.
This dose did not induce vomiting in dogs.
Inhalation exposure for 10 minutes to tin tetrachloride
at a concentration of 3 g/m was said to be well tolerated
by guinea pigs. Even repeated exposure to this concentration
was claimed to be tolerated (Pedley, 1927). There are no
later data that can support these statements.
8.1.1.2 Humans
Several outbreaks of food poisoning due to tin contamination
in canned food have been reported, see e.g. Benoy et al.
(1971). The lowest concentration reported to have caused
effects (nausea, vomiting and diarrhea) is 250 mg/kg (Benoy
414
-------
et al., 1971). Svensson (1975) examined 85 persons who had
consumed contaminated canned peaches and estimated the doses
that had given rise to effects. The concentration of tin was
413-597 mg/kg peach, and 398 mg/1 syrup. The pH was 3.9.
Of 78 persons who had consumed 100 mg tin or more, 74 showed
symptoms, whereas 2 out of seven who had consumed 50 mg
were affected. Nehring (1972) reported that canned peaches
containing 563 mg tin/kg had caused gastrointestinal symp-
toms. Acute gastroenteritis was seen in 113 persons who had
consumed tomato juice containing 400 mg tin/1 (Barker and
Runte, 1972).
Five volunteers given canned juice with a pH of 3.9 and
containing about 500 jftg tin/1 (1.59-2.65 mg/kg body weight)
did not show any symptoms. A concentration of 1370 mg/1
(4.38-6.71 mg/kg body weight) did result in gastrointestinal
disturbances in the same study (Benoy et al., 1971). No effects
were seen in volunteers after long-term consumption of canned
food containing about 200 mg/kg of tin (Galloway and McMullen,
1966) .
No acute effects have been ascribed specifically to the
inhalation of tin, but "stannosis", a benign pneumoconiosis
caused by long-term exposure to tin oxide dust or fumes, has
been reported in several studies (Pendergrass and Pryde, 1948;
Cutter et al., 1949; Dundon and Hughes, 1950; Schuler et al.,
1958; Oyanguren et al., 1959). In none of these studies has
there been any evidence of a decreased pulmonary function.
Stannosis appears on the radiograph as small shadows, denser
than those of silicosis. The first sign is an increase in
bronchovascular markings and hilar thickening. A fully dev-
eloped stannosis was observed after 3-5 years of exposure
to tin oxide fumes in a foundry. The concentrations in air
3
near two furnaces were 14.9 and 8.6 mg/m respectively
(Schuler et al., 1958; Oyanguren et al., 1958).
A man who died 18 years after his last exposure to tin oxide
fumes and who had stannosis without respiratory dysfunction
415
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was found to have l,100mg tin/kg wet weight in the lungs
upon autopsy. This concentration is more than 1,000 times
the "normal". No tissue reaction to this high concentration
had taken place. Tin was identified in the oxide form (Dundon
and Hughes, 1950).
8.1.2 Systemic effects 'and dose-response relationships
8.1.2.1 Animals
Injected tin compounds have been shown to cause paralysis and
other signs of neurological damage in several species (see
review by Barnes and Stoner, 1959). Conine et al. (1975)
observed neurological damage and renal lesions in rats exposed
to stannous chloride. A subcutaneous dose of 28 mg tin/kg
as stannous chloride increased heme oxygenase activity in the
kidney of rats 20 to 40-fold (Kappas and Maines, 1976). Long-
term studies have been carried out by Schroeder and Balassa
(1961) and Schroeder et al. (1968) in which mice and rats
were given tin as stannous chloride in drinking water (5 mg/1)
from weaning to natural death. In mice no gross effects were
noted, but in female rats a reduced longevity and an increased
incidence of fatty degeneration of the liver were reported.
Special interest has been devoted to sodium pentafluorostannite
owing to its reported anticariogenic activity. In a 30-day
study on rats, sodium pentafluorostannite in a concentration
of 20 mg/kg diet (13 mg Sn/kg) had slight toxic effects, in-
dicated by a tendency toward reduced weight gain. Higher doses
resulted in renal damage, attributed mainly to fluoride
(Conine et al., 1976).
A 90-day toxicity study on rats given tin compounds orally
disclosed a no-effect level of 22-33 mg tin/kg body weight
per day. At higher levels anemia appeared, which could be
alleviated by increased dietary iron ' (de Groot et al., 1973).
8.1.2.2 Humans
In the study by Galloway and McMullen (1966) nine volunteers
were given canned food from military rations with tin con-
416
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centrations of 13, 33 and 204 mg/kg respectively for three
24-day periods. No toxic effects were noted. Absorption of
iron tended to increase when 204 mg tin/kg food was given,
which might have a bearing on the findings by de Groot et
al. (1973) mentioned in the previous section.
8.2 Organotin
8.2.1 Local effects and dose-response relationships
8.2.1.1 Animals
Large single oral doses (4000 mg/kg) of some monobutyltin com-
pounds produced gastrointestinal damage (Pelikan and Cerny,
1970). Similar damage was seen after oral administration of
tributyl compounds (Pelikan and Cerny, 1968a). Some tributyltin
compounds caused skin irritation in rabbits at concentrations
of 0.36 to 0.95 mg/kg. High concentrations caused marked
inflammation and skin necrosis (Pelikan and Cerny, 1968b).
Triphenyltin hydroxide was reported not to irritate rabbit skin,
but was extremely irritant to the eye (Marks et al., 1969).
Klimmer (1964) found that a 10% solution of triphenyltin acetate
in oil in a dose of 150 mg/kg body weight gave a skin reaction
in rats.
8.2.1.2 Humans
In workers handling dibutyltin and tributyltin chlorides skin
lesions, even burns, have been found (Lyle, 1958). The irritant
effect appeared between 1 and 8 hours after contact. Healing
was rapid after removal from exposure. The eyes can also be
affected, as seen in a case described by Lyle (1958) but this
damage was not chronic.
Triphenyltin acetate caused skin and eye irritation in workers,
but the symptoms disappeared without treatment when exposure
ceased (Markicevic and Turko, 1967). Application of 0.5 ml
of a 0.1% emulsion of tricyclohexyltin hydroxide two times
with an interval of 20 days did not produce any skin reaction
or sensitization in 53 women (FAO/WHO, 1971).
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8.2.2 Systemic effects and dose-response relationships
8.2.2.1 Animals
Concerning the alkyltin compounds the highest toxicity is found
among the short-chain trialkyl compounds, i.e. trimethyltin
and triethyltin. The toxicity declines as the number of carbon
atoms in the chain decreases. The trialkyl compounds are gen-
erally more toxic than the dialkyl and monoalkyl compounds
(Barnes and Stoner, 1958j Klimmer, 1969).
After injection or oral exposure organotin compounds have
caused a wide variety of symptoms. Triethyltin compounds produce
an encephalopathy characterized by an edema of the white matter,
while the nerve cells do not suffer damage. This lesion is
distinct from brain lesions produced by other alkyl metals,
i.e. alkyl lead and alkylmercury. The lesion, which is reversible,
could be produced by an intravenous dose of 4 mg/kg in the
rabbit (Magee et al., 1957) as well as by an oral exposure
to in rats.
Other trialkyl compounds had a weaker effect on the brain
(Barnes and Stoner, 1958). Dioctyltin produced no effects when
given to rats in a concentration of 200 mg/kg diet for 4 months
(Barnes and Stoner, 1958). Tri- and dibutyltin compounds caused
mainly liver and bile duct lesions respectively (Barnes and
Magee, 1958-v Pelikan and Cerny, 1968a) .
Triphenyltin compounds gave rise to effects in liver, kidneys
and central nervous system. The no-effect level for triphenyl-
tin acetate in a 2-year study on rats was found to be 0.1
mg/kg/day (FAO/WHO, 1971).
Intraperitoneal injections of 10 mg/kg and higher of tricyclo-
hexyltin hydroxide caused neurological damage in rats (McCollister
and Schober, 1975). The no-effect level in rats has been estimated
to be 3 mg/kg/day in a 2-year study (FAO/WHO, 1971, 1974).
In dogs it was found to be 0.75 mg/kg/day.
8.2.2.2 Humans
In 1954 more than 100 deaths and more than 200 cases of illness
occurred in France due to the ingestion of a preparation (Stalinon)
410
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containing diethyltin diiodide, 15 mg per capsule, for treatment
of furuncles, acne and some other disorders (Alajouanine et al.,
1958; Barnes and Stoner, 1959). The preparation also contained
monoethyltriiodide and triethylmonoiodide, the concentration
of the latter comprising about 10% of the diethyltin compound,
The total dose of ethyltin compounds over a period of 6
to 8 weeks was calculated to be 3 g. The doses of diethyltin
were estimated to be from 45 to 675 mg in non-fatal cases
and from 380 to 675 mg in fatal cases (Barnes and Stoner,
1959).
Symptoms appeared in some cases after only a few days of treat-
ment and consisted of severe headache, vomiting, vertigo and
visual disturbances. Meningism, paresis and convulsions were
sometimes present, but physical signs could be absent even in
some fatal cases. There were no consistent alterations in
encephalograms. Death occurred from coma, respiratory or
cardiac failure. In fatal cases a pronounced edema of the white
matter of the brain was seen (Gruner, 1958). In non-fatal cases
recovery was slow and neurological signs were noted up to four
years after exposure. There have been no reports on further
follow-ups. Even though triethyltin iodide is strongly sus-
pected as being the causative agent, no report has shown
this conclusively.
Priill and Rompel (1970) reported headaches, nausea and visual
disturbances in five workers with acute intoxications from
organotin (compound not stated, but presumably triethyltin).
Electroencephalograms showed general disturbances, dysrhythmia,
and involvement of the occipital cortex.
Liver damage, in one case irreversible, has been reported
in people using triphenyltin acetate as a spray (Horacek and
Demeik, 1970; Mijatovic, 1972). Exposure to other toxic
compounds cannot be excluded.
8.3 Carcinogenic and teratogenic effects
Roe et al. (1964) gave rats inorganic tin compounds via food
for 80 weeks. One group (n = 37) received sodium chlorostannate,
419
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20,000 mg/kg,one group (n = 37) received stannous 2-ethyl
hexoate, 10,000 mg/kg, and one group (n = 40) served as
controls.
In the first group, 3 malignant tumors developed among the
30 rats surviving more than one year, whereas no malignant
tumors were seen in the other two groups. The small number of
animals makes it difficult to draw any conclusions.
Kanisawa and Schroeder (1967) gave stannous chloride in drinking
water, 5 mg/1, to 108 mice for their life-times. The control
group consisted of 198 animals. 86 and 170 autopsies were per-
formed in the two groups whereupon 15 and 6 malignant tumQrs,
respectively, were found.
Triphenyltin acetate was not found to be carcinogenic in an
18 month study on mice (n = 72). The daily dose via food was
0.46 mg/kg body weight (Innes et al., 1969).
Tricyclohexyltin hydroxide given to rats in daily dietary
doses of 12 mg/kg body weight for 2 years did not cause an
increased incidence of tumors (FAO/WHO, 1971).
Teratogenic effects were not seen in pregnant rats given sodium
pentafluorostannite, sodium pentachlorostannite and stannous
fluoride corresponding to tin levels of 125-500, 125-500
and 156-625 mg/kg respectively. In control fetuses the tin
concentration was 0.64 mg/kg while in the exposed it varied
from 0.81 to 1.28 mg/kg. indicating a slight placental transfer
(Theuer et al., 1971).
FAO/WHO (1971) has evaluated studies on tricyclohexyltin
hydroxide. A 3-generation study on rats using an exposure
of 100 mg/kg diet did not reveal any effects on reproduction
or on fetuses. In rabbits given 3 mg/kg/day via food from
day 8 to 16 of gestation, no effects were seen. With regard
to triphenyltin, the data are conflicting. Effects on the
testes and ovaries were brought about in two studies on rats
given 20 mg/kg/day of triphenyltin acetate or chloride for
420
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less than 4 weeks. On the other hand no effects on the
testes were found in three studies when up to 25 mg/kg
diet was given to rats (FAO/WHO, 1971). Gaines and Kimbrough
(1968) found a reversible fertility reduction in male rats given
200 mg/kg diet for 9 months. No abnormalities were noted
in the next generation.
In a 6-month study, an increase in chromosome aberrations
in bone marrow cells was found in rats given gastric doses
of 0.1 mg/kg of dibutyltin sulfide (Mazaev and Shlepnina,
1973) .
8.4. Mechanisms of action
There are no data on the action of inorganic tin. The exten-
sively studied triethyltin has been shown to have a strong
affinity to mitochondria, where it binds to histidine and
inhibits oxidative phosphorylation (Aldridge, 1958; Rose,
1969; Aldridge and Street, 1964, 1970, 1971). Other trialkyl
compounds cause similar effects.
In vivo studies in the rat brain showed that triethyltin
inhibited glucose oxidation (Cremer, 1970). The dialkyl
compounds, with the exception of dioctyl, affect the mito-
chondria by inhibiting the oxidation of 2-keto acids
(Piver, 1973).
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TITANIUM
Maths Berlin
1. Abstract
Titanium compounds common in the environment are little absorbed
upon ingestion and inhalation. Detectable amounts of titanium
can be found in blood, brain and parenchymatous organs; the
highest amount is seen in the lung, probably due to retention
of titanium-containing dust particles. Excretion occurs via
urine and feces. Data on biological half-time are not available
at present.
There is no evidence that titanium has any physiological metab-
olic function. Most animal and human data indicate a low degree
of toxicity for common titanium compounds. However, in animal
experiments, titanium carbide, nitride and hydride have been
observed to cause liver and kidney as well as heart damage.
Organic titanium compounds have been shown to produce cancer
in animal experiments. Long-term administration of soluble
titanate has disturbed reproduction in animal experiments.
2. Physical and chemical properties
Titanium, Ti, atomic weight 47.9; atomic number 22; density 4.5;
melting point 1660°C± 10; boiling point 3287°C; crystalline form
a hexagonal, transition point 3 cubic 838, silver-gray; oxidation
state +2,+3,+4.
Titanium has both metallic and non-metallic characteristics
and occurs mostly in a tetravalent form, titanic, but trivalent,
titanous, and bivalent forms are known, in addition to oxyforms
such as TiOCl , titanyl chloride. Several other inorganic com-
pounds which are referred to in this chapter are titanium
oxide, titanium tetrachloride, titanous chloride, titanium
dioxide, titanium carbide, titanium halide, titanium nitride,
barium tetratitanate, titanium hydride, titanic acid, titanic
oxychloride, titanium oxalate, titanium acetate, titanium sali-
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cylate, titanium tannate, titanium boride. The metal is highly
resistant to many corrosive agents, including concentrated
nitric acid. A number of organometallic compounds with titanium
are known, for example titanocene; the most common are the alkyl
and aryl titanates of the general formula Ti(OR).. Complex organic
coordination compounds of titanium are also known.
3. Methods and problems of analysis
For the determination of titanium in air, water, food and
biological material, a wide variety of analytical procedures
has been employed, such as spectrography {Durum and Haffty,
1961; Eremenko and Mel'Nikov, 1968; Timakin and Bagdasarova,
1969; Chekotilo and Torokhtin, 1970), photometry (Schlenk, 1936;
Yound and White, 1959; Loiko, 1967; Urusova, 1969; Mal'Tseva,
1973a; Mal'Tseva, 1973b), atomic absorption (Beyer, 1969;
Burnham et al., 1970; Carlson and Black, 1970; Hwang, 1972;
Ranweiler and Moyers, 1974), atomic fluorescence spectrometry
(Schiller, 1970; Slavin and Manning, 1963; Kirkbright et al.,
1969; Chakrabarti and Katyal, 1971; Ottaway et al., 1970),
X-ray fluorescence (Shono and Shinra, 1969; Dittrich and Cothern,
1971; Rhodes et al., 1972; Frigieri et al., 1972; Blasius et
al., 1972), spark source spectrography (Crocker and Merritt,
1972; Hamilton and Minski, 1972; Hamilton et al., 1972/1973),
neutron activation (Dams et al., 1970; Zoller and Gordon, 1970;
Harrison et al., 1971; Dams et al., 1972), polarography (Hoff
and Jacobsen, 1971; Petit, 1973), and proton-induced X-ray
emission spectrometry (Johansson et al., 1972, 1974). A
practical limit of detection of about 1 ng for titanium in
air has been achieved by PIXE spectroscopy (Johansson et al.,
1972/1974). The same method has been adapted for water and
has a detection limit of less than 1 ng/drop of water (Johansson
et al., 1972). The detection limit for titanium assay in
human tissue by spark source mass spectrometry was 0.007 g/kg
(Hamilton et al., 1972/1973) and by X-ray fluorescence 0.3
g/kg (Hamilton et al., 1972/1973).
4. Production and uses
4.1 Production
Titanium is the eighth most common element in the earth's
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crust and occurs in a number of minerals. The major titanium
minerals commercially mined are ilmenite and rutile. From these
minerals, the yearly world production of titanium oxide is
about 1.5 million tons, and it is estimated to be doubled by
the year 2000.
4.2 Uses
Titanium metal has extensive applications in aerospace, in-
cluding aircraft and spacecraft. Because of its resistance to
corrosion and its inertness, titanium is widely used in the
chemical industry for tubing and for lining vessels in production
of nitric acid and acetaldehyde. It is also used in the paper
pulp industry. Titanium metal may be a component of surgical
implant material or prothesis. Titanium dioxide is the most
common titanium compound used because of its extreme whiteness
and brightness as well as its high index of refraction. It is
extensively used as a white pigment in paints, lacquers, enamels,
paper coatings and plastics.
Titanium oxide is also used as a color additive in confection,
dairy products and bread flour, replacing the flour bleaching
agent normally used. It serves as a clouding agent for incor-
poration into dry beverage mixes, and in tobacco wrapping
and tobacco substitutes. Due to its effectiveness as a shortwave
ultraviolet sun screen, titanium oxide is included in a variety
of drugs and cosmetics. Another commercially important compound
of titanium is titanium tetrachloride, used as an intermediate
in the production of titanium metal and titanium pigments but
also as a component and catalyst in the chemical industry. Titanous
chloride, TiCl_, is prepared by reducing titanium tetrachloride.
This compound is also used as a polymerization catalyst. Organic
titanium compounds are used as cross-linking agents and cata-
lysts in chemical processes.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Titanium is poorly absorbed and retained by plants and animals
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(Monier-Williams, 1950; Underwood, 1971). Levels of around
1 mg/kg dry weight have been reported for a wide variety of
plants (Mitchell, 1957). However, local contamination by
fly-ash fallout or fertilization of titanium-containing sewage
residues as well as the use of titanium dioxide as a food
whitener may cause higher levels of titanium in food products.
Schroeder et al. (1963) found titanium levels from 1.76 to
2.42 mg/kg wet weight in milled grains, butter, corn oil and
vegetables, especially lettuce. Wheat flour from the US and
Japan was found to contain 0.41 and 0.99 mg/kg titanium respect-
ively. Certain types of cheese contain high concentrations
of titanium due to the addition of titanium dioxide to whiten
the cheese and to accelerate aging (Palo, 1966, 1967; Kosikowski
and Brown, 1969; Leone, 1973).
More than 99% of the total daily intake comes from food and
water, and the daily intake from water is low, around 2 ,ug
(Schroeder et al., 1963). The daily intake from food will vary
widely with food habits. Typical American diets have been
estimated to contain between 3-600 ,ug of titanium (Schroeder
et al., 1963; Poole and Johnston, 1969). The daily intake from
air of titanium has been estimated for American cities (Woolrich,
1973) to be around 4,ug, which constitutes a few tenths of a
percent of the total daily intake.
5.1.2 Water, soil and ambient air
Titanium concentrations between 2-107,ug/l have been reported
for fresh water in the US and Canada (Durum and Haffty, 1961).
Drinking water in the US contains around 2 ,ug/1, range 0.5-
15 /ug/1 (Durfor, 1963). Titanium concentration in sea water
is mostly around 0.6-1 ,ug/1; values up to 9 ,ug/1 have been
reported (Mason, 1958; Bowen, 1966; Ishibashi, 1966; Silvey,
1967).
Soil generally contains between 0.3-6% titanium (Vinogradov,
1959; Monier-Williams, 1950). However, there are many soils with
an exceptionally high titanium content, up to 10% (Vinogradov,
1959; Chilean Nitrate Educational Bureau, 1958).
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Soils in the vicinity of power incineration plants may be
enriched with titanium.
Atmospheric levels of titanium between 0 . 01-0 . 5 ,ug/m in soots
and dust have been reported (Tabor and Warren, 1958; Japan En-
vironmental Sanitation Center, 1968) with about 2-10 times
higher concentration over urban areas compared to non-urban
areas.
5.2 Working environment
Occupational exposure to titanium is mainly found in mining,
production of titanium metal dioxide or carbide. Titanium
exposure is mainly in the form of dust but in connection with
handling titanium tetrachloride, fume and vapor exposures
occur. Concentrations of titanium compounds in air between
20-50,ug/m have been reported by several authors (Mogilevskaya,
1972, 1973; Mezentseva, 1967) in connection with dusty
operations.
6. Metabolism
6.1 Absorption
Data on absorption of titanium compounds are very limited.
Titanium dioxide has been shown to be absorbed to a very low
degree in animal experiments. Rats, given 250 mg/kg in the
diet, excreted more than 90% of the daily intake in feces
(Fournier, 1950). In mice, given 5 mg/kg titanium as a soluble
salt during their entire life span , a five times increase in
organ content of titanium, as compared to control animals, has
been observed (Schroeder et al., 1964).
In humans, about 10 ,ug/l of titanium is found in urine,
which suggests a titanium absorption of about 3% assuming
an intake of 300 ,ug/day (Perry and Perry, 1959; Schroeder
et al., 1963). Data on absorption by inhalation are not
available. Data on metabolism and excretion of titanium are
lacking for the most part. As mentioned above, titanium in
about 10 ,ug/l is regularly excreted in urine in man.
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The mechanism of excretion and the possible amount excreted
by the intestinal route are unknown.
6.2 Distribution
Studies on mice given titanium in food during their life span
have shown the presence of between 2 and 9 ,ug of titanium in
parenchymatous organs such as heart, lung, spleen, liver, and
kidney (Schroeder et al., 1964). In man, the highest titanium
concentration has been found in lung (Tipton and Cook, 1963),
probably as a result of inhalation of titanium particles.
Detectable levels have also been found in blood, brain, and
other parenchymatous organs (Hamilton et al., 1972/1973).
In blood, distribution of titanium between erythrocytes and
plasma has a ratio of 2:3 (Smyshlyaeva et al., 1971).
6. 3 Biological half-time
There are no studies available providing a basis for an estimate
of biological half-time in man or animals.
7. Normal levels in tissues and biological fluids
Levels between 0.03-0.15 mg/kg of titanium in blood have been
reported (Maillard and Ettori, 1936a; Maillard and Ettori,
1936b; Timakin et al., 1967; Hamilton et al., 1972/1973).
Concentrations of 3.7-mg/kg have been reported in the lung,
and 0.8 mg/kg in the brain (Hamilton et al., 1972/1973). In coal
miners, considerably higher levels of titanium have been
reported in the lung (Crable et al., 1967, 1968).
8. Effects and dose-response relationships
The most common forms of titanium used in present-day communities
are titanium metal and titanium oxide. These forms have a low
toxicity as shown in experimental animals and in observations on
exposed humans. Titanium halides have been shown to be irritant
to the respiratory tract (Stokinger, 1963). Titanium nitride has
been observed to cause dystrophy of the liver and the renal tubular
epithelium as well as some fibrogenetic activity in the lung in
exposed animals (Brakhnova and Samsonov, 1970). Titanium boride
and titanium carbide have also been observed to cause fibrogenic
432
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action in the lung and dystrophy of the liver and kidney
as well as of the myocardium (Brakhnova, 1969). In rats, titanium
metal powder, injected intramuscularly, has been observed to
cause fibrosarcomas and lymphosarcomas (Furst, 1971) , and an
organic titanium compound, titanocene (Furst, 1971; Furst and
Haro, 1969), has been shown to be carcinogenic if injected
intramuscularly to rats, causing fibrosarcomas at the injection
site, hepatomas and malignant lymphomas of the spleen. Most
data on toxicity of titanium compounds are derived from animal
experiments. Epidemiological and clinical observations on humans
have not yet revealed any significant toxic effects of titanium
compounds used in industry.
8.1 Local effects and dose-response relationships
8.1.1 Animals
8.1.1.1 Short-term studies
Intratracheal injections of titanium oxide, 20-50 mg to rats
(Mogilevskaya, 1956; Gothe and Swensson, 1970) and up to 400
mg to rabbits (Dale, 1973) have not shown anything other than
non-specific reactions to dust particles. Intratracheal in-
stillation of other titanium compounds such as barium tetra-
titanate, 5% suspension in saline, to guinea pigs and in
50 mg doses as a dust to rats, have not produced signs of
fibrotic reaction (Pratt et al., 1953). A weak fibrogenic
effect was seen after administration of 50 mg of titanium
hydride to rats (Brakhnova and Shkurko, 1972). Rats exposed
to hydrolysis products of titanium tetrachloride by inhalation
for two hours at concentrations from 0.1 to 3 mg/1 showed
fatal injuries in a frequency decreasing with decreasing con-
centration. Mortality was significantly higher than in groups
exposed to equivalent amounts of hydrochloric acid vapor
(Mezentseva, 1967).
8.1.1.2 Long-term studies
Implantation of titanium metal in dogs (Beder et al., 1941;
Gross and Gold, 1957; Shpak and Margolin, 1971) has shown that
soft tissue has a high tolerance to titanium metal, illustrated
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by lack of irritation, good wound healing and the incapsulation
of the metal by fibrous tissue. Rats, which inhaled titanium
oxide dust four times daily five days a week up to 13 months,
did not show any pathological responses in the lungs seven
months following cessation of exposure. In guinea pigs fibrotic
effects and eosinophilic infiltrations have been observed after
repeated titanium oxide inhalation over various time intervals
from five days to four months (Lenzi, 1936). Intratracheal
injections to rats of a suspension of 50 mg metallic titanium
dust or titanium oxide dust, particle diameters less than 2 ,u,
did not show any fibrosis six months or eleven months after
injection (Mogilevskaya, 1956). Weak fibrogenic effects were,
however, observed when titanium hydride was inhaled by rats
for 1-6 months (Shkurko and Brakhnova, 1973).
8.1.2 Humans
Vernetti-Blina (1928) studied men exposed to titanium oxide for
prolonged periods. These studies did not reveal any signs of
clinical or radiological abnormality. Uragoda and Pinto (1972)
investigated the health of 136 workers exposed to ilmenite
and rutile in Ceylon. No significant differences in the
incidence of radiological lesions of the chest were seen in
these workers as compared to the general population. Lung
specimens from three factory workers exposed for nine years
in processing titanium oxide pigments were examined by Elo
et al. (1972). Deposits in pulmonary interstitium with cell
destruction and slight fibrosis were seen. Titanium oxide
particles were found in the lymph nodes, suggesting clearance
via the lymphatic system. The authors characterized titanium
oxide as a mild pulmonary irritant. Splashing with titanium
tetrachloride at 100°C and inhalation of fumes of titanic
acid and titanic oxychloride led to surface skin burns with
scarring (Heimendinger and Klotz, 1956). Congestion of the
mucous membranes of the pharynx, vocal cords and trachea,
with cicatrization as a late sequel with laryngeal stenosis,
was also observed.
8.2 Systemic effects and dose-response relationships
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8.2.1 Animals
Intraperitoneal injections of 25-250 mg/kg body weight to
rats (Huggins and Froehlich, 1966; Sethi et al., 1973) did
not give rise to other changes than could be expected from
inert particles. Titanium nitride (Brakhnova and Samsonov,
1970), boride, carbide (Brakhnova, 1969) and hydride
(Shkurko and Brakhnova, 1973) have been observed to cause
dystrophy of the liver and renal convoluted tubules.
8.2.2 Humans
No data on dose-response or dose-effect relationships
concerning systemic changes caused by titanium compounds
in humans are available. Lack of toxicity of titanium and
its compounds from contact with skin and tissues has been
demonstrated by its use in therapy of skin disorders and in
surgical appliances (titanium salicylate, oxide and tannate).
8.3 Carcinogenic effects; teratogenic effects and effects
on reproduction; genetic effects
Carcinogenicity studies were performed on 50 rats with titanium
metal powder (Furst, 1971). Increased rates of fibrosarcomas
and lymphosarcomas were observed in rats which survived up
to 820 days compared to controls. Titanium oxalate and acetate,
5 mg/1 in drinking water, from weaning to death, were non-
carcinogenic in 150 mice of both sexes as compared to control
groups (Schroeder et al., 1964). The organic compound, titano-
cene (Furst, 1971j Furst and Haro, 1969), has been shown to
be carcinogenic when suspended in trioctanoin and injected
intramuscularly to rats and mice. Fibrosarcomas occurred at
injection site and the animals developed hepatomas and
malignant lymphomas of the spleen.
In reproduction and teratogenicity studies, Schroeder and
Mitchener (1971) found a toxic effect of a soluble titanate
on the reproduction of mice and rats given 5 mg/1 of the compound
in drinking water. Each group was followed through three
generations. In the rats, marked reduction in the numbers of
animals surviving the third generation appeared, and the
435
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male-female ratio was progressively reduced compared to the
controls, which continued to breed for four generations at a
normal rate. Titanium salts have been reported to induce
sticky chromosomes in root stems of allium cepa (Levan,
1945) .
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TUNGSTEN
George Kazantzis
1. Abstract
In the rat, following ingestion in the form of tungstate,
1 0 C
almost one half of the administered dose of W was rapidly
absorbed into the plasma and the greater part of it was rapidly
excreted by glomerular filtration. Transfer occurred to red
blood cells and, following sequestration, to the spleen which
accumulated the highest concentration in soft tissue. After
100 days over 99% of the total body burden (about 0.4% of the
administered dose), was found in bone, with a biological half-
time of about 1100 days, the slowest of a three component
elimination curve.
There is no evidence that tungsten is essential either to man
or animals.
The metabolism of tungsten is related to that of molybdenum
which it closely resembles in chemical properties. Sodium tungstate
antagonizes molybdate in its role as metal carrier for xanthine
oxidase. It is likely that tungsten can preferentially occupy
enzyme sites normally occupied by molybdenum.
Little is known of the toxicity of tungsten compounds, although
the LD n of soluble salts in the rat is relatively high. Tungsten
and its compounds are not an important human health hazard.
Following occupational exposure to tungsten carbide dust by
inhalation, cases of pulmonary fibrosis have been reported,
but this "hard metal disease", as it is often called, is more
likely to be caused by cobalt, with which tungsten carbide is
fused.
2. Physical and chemical properties
Tungsten, W, atomic weight 183.9; atomic number 74; melting
point 3410°C; boiling point 5900°C; specific gravity 19.3;
valence 6,5,4,3 and 2; crystalline form gray-black, cubic.
442
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Tungsten, known also as Wolfram, belongs to Group 6 of the
periodic system, together with molybdenum and chromium. Tungsten
is not oxidized in air at ordinary temperatures and is highly
resistant to acids. Its chemical properties resemble those of
molybdenum. Among the more common compounds are the canary yellow
trioxide, tungstic acid, sodium tungstate, ammonium paratungstate
and tungsten carbide.
3. Methods and problems of analysis
Aull and Kinard (1940) detailed a spectrophotometric method
based on thiocyanate and stannous chloride for the estimation
of tungsten in biological materials. However, nickel and
cobalt may interfere with the estimation if present in
comparable amounts. The detection limit could be improved
to 0.7 mg/kg by a concentration procedure described by Wilson
and Fields (1944). Estimation of trace concentrations of
tungsten occurring in air and in water can be performed by
instrumental neutron activation analysis using automatic
gamma-ray spectroscopy with a high degree of accuracy (Salmon,
1974; Cawse, 1974). The detection limit of their method, using a
14 -2 -1
thermal neutron flux up to 10 n • cm sec for activation,
was 2 ng/kg for industrial air and 10 ,ug/kg for industrial
rainwater. These limits were based on 98% confidence levels
and the precision of the method was estimated at 5-10%.
4. Production and uses
4.1 Production
Wolframite and Scheelite are the common, naturally occurring
sources of tungsten, the richest deposits being found in China,
Alaska and Mexico. The world production in 1973 was 48,230
metric tons. The ore is crushed and ground, concentrated by
various physical processes, converted to the oxide and reduced
to the metal. Tungsten carbide is produced by heating the
finely powdered metal intimately mixed with carbon in an
atmosphere of hydrogen in an electric furnace. In the produc-
tion of tungsten carbide tools, the carbide is sintered with
cobalt which acts as a binder. The sintered material is then
ground to its final shape.
443
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4.2 Uses
Tungsten is a valuable metal because of its high melting
point, great strength at high temperatures and good
conductivity for electricity and for heat. It is used to
increase the hardness and tensile strength of steel; it
plays a vital role in the production of a number of other
alloys noted for their hardness, such as the chromium,
cobalt and tungsten alloy used for tipping and facing lathe
tools. Many drills and cutting edges of tools are tipped with
tungsten carbide which gives them a hardness comparable to that
of diamond. The metal is used for making filaments for incan-
descent lamps, and tungstates are used in X-ray tubes, fluo-
rescent lamps in lasers, and as pigments in dyes and inks.
Tungsten has more recently acquired importance in nuclear and
space technology in the nozzles of rocket motors and protecting
shields for space craft.
5. Environmental levels and exposures
5.1 General environment - Food, water, soil and ambient air
The dietary intake of tungsten, estimated by neutron activation
analysis in 4 subjects, ranged from 8.0 to 13.0,ug/24 hours
over a total of 8 total diet estimations (Wester, 1974).
Drinking water sampled in the 3 largest Swedish cities varied
in tungsten concentration from 0.03 to 0.1-ug/l depending on
the sampling site. Neutron activation analysis was used (Bostrom
and Wester, 1967). In a survey of atmospheric trace elements
in the United Kingdom performed during 1972-73, again by neutron
activation analysis, tungsten was included in the "very low"
category. Concentration in rainwater was found to be less than
1> .ug/1 in 5 out of 7 sampling stations. Total deposition of
/ -2 -1
tungsten was found to be less than 2 ,ug cm year at all
' -2 -1
7 sampling stations and less than 0.1,ug cm year at six
of these. Only very small concentrations of tungsten have been
found in the atmosphere, and these have been related to indus-
trial emissions or to nuclear fallout. Levels have usually
been less than 1 ng/kg air (Cawse, 1974).
'5.2 Working environment
A large amount of dust can be released from the crushing
444
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and milling of the ores wolframite and scheelite. In the loading
and emptying from furnaces of graphite boats containing the
reduced metal, air concentrations of tungsten and of tungsten
trioxide of 10 and 46 mg/m were obtained (Mezentseva, 1963).
In the various processes associated with tungsten carbide man-
ufacture, air concentrations as high as 47 mg/m were measured
(Mezentseva, 1963). Dust may be produced during the mixing
of the components and also in the shaping and grinding of the
products. Coates and Watson (1971) described metal particles
in the atmosphere with a mean diameter of 1.2 to 1.9 mu. In
the tool cutting industry exposure occurs not only to the dust
of tungsten carbide but also to cobalt fume and dust and to
the carbides of nickel, titanium and tantalum.
6. Metabolism
Tungsten has not been shown to be an essential trace metal
in either animal or plant metabolism. The tungstate ion, WO. ,
is the most soluble and frequently occurring form of tungsten
in biological systems.
6.1 Absorption
A detailed study on the absorption, distribution and retention
187
of W has been performed on the rat (Kaye, 1968). The radio-
isotopes in the form of tungstate in alkaline solution were
administered by gastric intubation and followed, in the case
-I Q r
of W for periods up to 254 days. A large part of the ingested
tungsten was absorbed. The rapid absorption of tungsten from the
gut could be demonstrated by the peak value of 17% of the admin-
istered dose in the carcass 1 hour after administration. After
4 hours 9 % had remained in the carcass and 12% had been excreted
in the urine, while after 24 hours only 2% had remained in
the carcass and about 40% had been excreted in the urine. This
activity was due to rapid uptake by plasma followed by clearance
by renal filtration. During the first hour, all the radioactivity
in whole blood was in the plasma, but this was followed by
transfer of tungsten from plasma to cells and by incorporation
at sites of hemopoiesis.
445
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6.2 Distribution
Rats were fed for a period of 100 days on diets in which
..ungsten had bee - i r • •por-a+r ~~ either as the finely ground
metal, tungstic oxide, sodium Lungstate or ammonium paratung-
state (Kinard and Aull, 1945). The principal sites of deposition
were bone and spleen with smaller quantities, of the order
of less than 10 mg/kg of tungsten in kidney and liver. Concen-
trations of tungsten less than 10 mg/kg were reported as a
trace; traces of tungsten were also found in blood, lung, muscle
and testis. No marked difference in distribution of tungsten
was found with the different compounds ingested.
-IOC
Long term studies in rats of W administered by stomach tube
(Kaye, 1968) showed that after 100 days over 99% of the total
body burden (about 0.4% of the administered dose) had been
retained in bone. In soft tissues, the highest concentration
was found in spleen, thought likely to be due to the sequest-
ering action on red blood cells. The next highest concentration
was in hair, but external contamination could not be excluded.
The relatively high concentration of tungsten in the kidney
on the third day correlated well with the large fraction of
the administered dose eliminated in urine and the shape of the
kidney retention curve reflected this.
6.3 Excretion
In 4-he study detailed above (Kaye, 1968) about 40% of the ad-
187
ministered dose of W had been excreted by the kidney in
the first 24 hours. Very little was excreted in the urine sub-
sequently. The further 40% of the administered dose recovered
from the feces by 24 hours is likely to have been accounted
for by unabsorbed tungsten together with tungsten excreted
into the gut with intestinal secretions and with bile. In man,
trace quantities of tungsten are excreted in urine and feces
(see section 7). In a limited study on 4 normal young adults,
the excretion by these two routes over 24 hour periods balanced
the tungsten intake in food, with only small positive and
negative variations (Wester, 1974).
446
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6.4 Biological half-time
In the study by Kaye (1968) elimination of tungsten from the
whole rat was very rapid with a biological half-time of
about ten hours for the initial fast component of the
elimination curve. Elimination from soft tissues was
relatively rapid with a biological half-time of 44 days
n o r
for the spleen. The biological half-time for W in bone
was calculated at 1100 days for the slowest component of a
three component elimination curve.
7. Normal levels in biological tissues and fluids
Information on this aspect is scanty. Kinard and Aull (1945)
were unable to detect tungsten in any of the tissues of their
control group of animals in their oral dosing experiments
referred to in section 6.2.
In man, the mean serum concentration of tungsten, estimated
by neutron activation analysis, was found to be 5.8 ng/ml in
8 healthy subjects, with a standard deviation of 3.5. In 11
patients with hypertension the mean serum level was 11 ± 13
ng/ml before treatment and 16 + 18 ng/ml after treatment with
chlorthalidone. None of these differences were significant
(Wester, 1973).
The urinary excretion of tungsten,again measured by neutron
activation, ranged from 2.0 to 13.0 ug/24 hours in four
subjects over 8 estimations. Fecal excretion in the same
subjects ranged from 1.6 to 5.7 ug W per 24 hours. The subjects
were healthy, young male and female adults in whom tungsten
output did not appear to be affected by calcium intake in the
diet in this small series of observations (Wester, 1974).
In a group of 16 hypertensive patients, the mean tungsten
excretion in the urine was 32 ± 63 (SD)/ug per 24 hours before
treatment, and 36 + 85 (SD) ug for 24 hours during treatment
with chlorthalidone. The levels showed great variability
between individuals and were not influenced by diuretic
therapy.
447
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8. Effects and dose-response relationships
8.1 Respiratory effects
8.1.1 Animals
Tungsten metal and its compounds do not appear to have any
significant effect on the respiratory system of the rat. Upon
intratracheal instillation of pure tungsten carbide and
tungsten metal in rats, Miller et al. (1953) and Delahant
(1955) produced no cellular reaction other than that due
to an inert dust. However, an intense inflammatory reaction
resulted if cobalt was an ingredient in the injected material.
Mezentseva (1963) gave white rats a single intratracheal dose
of 50 mg metallic tungsten, tungsten trioxide or tungsten car-
bide in 0.5 ml saline and sacrificed the animals after 4, 6
and 8 months. Histological changes were limited to the lungs
and consisted of a proliferative reaction of the lymphoid
and histiocytic elements, particularly at the sites of accu-
mulation of the administered dust, with subsequent mild
fibrosis. The walls of small vessels were thickened and their
endothelium swollen.
8.1.2 Humans
A hazard exists in the tungsten carbide industry, which takes
the form of "hard metal disease". The agent responsible for
this disorder is believed to be cobalt, present as a constituent
of the hard metal alloy, but this has not been proven. Studies
in a number of factories manufacturing tungsten carbide based
products have revealed the presence of respiratory symptoms
associated with impaired respiratory function and radiographic
abnormality in a small proportion of those exposed. Moschinski
et al. (1959) investigated 331 hard metal workers and found
evidence of pulmonary fibrosis in 59. The characteristic
radiographic appearances were of increased lung markings in
the lower lung fields with nodular opacities in the more ad-
vanced cases. Ahlmark et al. (1961) described four cases in
men who had not been exposed for more than eight years. Bech
et al. (1962) described the clinical and radiological findings
in six cases of hard metal disease collected over a period
448
-------
of 15 years. Complaints included cough, expectoration, shortness
of breath, and tightness in the chest. In two of six cases
pulmonary function tests showed mild alveolar diffusion
defects, and in one worker who died, diffused pulmonary
interstitial fibrosis was found. There was evidence of
pulmonary fibrosis in the chest radiographs. In addition,
a radiological survey was performed in 255 workers exposed
to hard metal dust. This showed only slight changes in
several of the workers and yielded one of the six cases
described above. Airborne dust concentrations at the time
of the survey were of the order of 0.30 mg/m for particles
less than 5 ,um projected diameter. Gravimetric samples taken
in the sieving room showed 90% tungsten and 6% cobalt in
the incombustible fraction. It was concluded that the cause
of hard metal disease was the inhalation of dust from the working
environment but that the responsible component was likely to
be cobalt rather than tungsten. The absence of cobalt from
the lungs of hard metal workers, which contained both tungsten
and titanium, was attributed to the high solubility of cobalt
in plasma.
Coates and Watson (1971) described 12 cases, including 8
deaths, of diffuse interstitial pulmonary fibrosis in work-
ers processing tungsten carbide. The clinical picture was of
nonproductive cough, exertional dyspnea and weight loss. Res-
piratory function tests showed a restrictive pattern with an
abnormality of gas transfer. The radiological appearances were
characterized by progressive, bilateral nodular and linear
shadowing involving major portions of both lungs. Detailed
histological examination of three cases (Coates and Watson,
1973) showed deposits of collagen and elastic tissue in the
septal areas, and alteration of the alveolar lining cells
(modified type 1 pneumocytes) with swelling and formation
of microvilli. Unidentified, hard, multifaceted crystals were
present in the affected areas of the lung. These authors,
too, attributed the condition to the inhalation of cobalt
containing dust.
449
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8.2 Systemic effects and dose-response relationships
8.2.1 Animals
In a series of feeding experiments, young rats were fed for a
period of 70 days with different concentrations of sodium
tungstate, tungstic oxide and ammonium paratungstate mixed in
Purina dog chow (Kinard and Van de Erve, 1941). Sodium tungstate,
equivalent to 2% W, tungstic oxide equivalent to 3.96% W and
ammonium paratungstate equivalent to 5% W were markedly toxic,
causing initial weight loss followed by the deaths of all
animals in each group within 10 days. In diets having an
equivalent of 0.5% W, sodium tungstate and tungstic oxide
produced death in three quarters of the rats, while ammonium
paratungstate produced no fatalities. The same authors (1943)
in similarly designed feeding experiments administered 2%,
5% and 10% tungsten metal powder over 70 days and found no
effect on weight gain in male rats, but a 15% reduction in
females.
In an extensive life-term study, Schroeder and Mitchener (1975)
added 5 mg/1 as sodium tungstate to the drinking water of rats,.
At this dose level there was little detectable effect as
measured by serum cholesterol, glucose, uric acid and incidences
of tumor formations. However, a slight enhancement on growth
was seen in rats of both sexes and a small but significant
shortening of longevity in the tungsten dosed male rats.
Tungstic acid has been used to produce experimental epilepsy
in laboratory animals (Kusske et al., 1974). 0.02 ml of tungstic
acid gel applied to the surface of the cortex in a series
of cats gave rise to abnormal EEC activity after a 20 to 30
minute interval, which increased to give rise to sustained
ictal activity.
Following the intraperitoneal injection of tungsten oxide
in rats, no cellular reaction has been observed (Frederick
and Bradley, 1946).
8.2.2 Humans
There are no data available on occupational exposures to
450
-------
compounds of tungsten which incriminate these as toxic or
as hazardous agents. Kruger (1912) observed no ill effects
in patients given 25 to 80 g powdered tungsten metal by mouth
as a substitute for barium in radiological examinations.
8.3 Interaction with molybdenum
Sodium tungstate antagonizes the normal metabolic action of
molybdate in its role as metal carrier for xanthine dehydro-
genase. Higgins et al. (1956) showed that sodium tungstate
added to the diet inhibited the intestinal deposition of
xanthine oxidase in the rat and reduced both xanthine
dehydrogenase and molybdenum concentrations in the liver
of the chicken. Owen and Proudfoot (1968) fed sodium tung-
state to goats and cows and showed a reduction in xanthine
oxidase secreted in milk, in some cases to an undetectable
level. They postulated that tungstate can preferentially occupy
enzyme sites normally occupied by molybdate.
Cohen et al. (1973) administered tungstate to rats maintained
on a low molybdenum diet and demonstrated a loss of both
xanthine oxidase and sulfite oxidase activities. The tungsten
treated rats appeared healthy, but were more susceptible to
bisulfite toxicity. Upon exposure to high levels of sulfur
dioxide, the tungsten treated, sulfite oxidase deficient animals
showed evidence of systemic sulfite toxicity and had much shorter
survival times than the controls. Sulfite oxidase appears to be
involved in the oxidative metabolism and thus detoxification
of sulfur dioxide as well as of bisulfite.
Sulfite oxidase activity in rat liver is negligible at birth
but increases rapidly between the fifth and eleventh days after
birth. Activity is considerably impaired by administration of
tungsten for 20 days before delivery (Cohen et al., 1974).
451
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REFERENCES
Ahlmark, A., Bruce, T. and Nystrom, A. (1961). "Silicosis
and Other Pneumoconioses in Sweden." pp 390. Svenska Bokforlaget,
Stockholm.
Aull, J.C. and Kinard, F.W. (1940). J. Biol. Chem. 135, 119.
Been, A.O., Kipling, M.D. and Heather, J.C. (1962). Brit. J.
Ind. Med. 19_, 239-252.
Bostrom, H. and Wester, P.O. (1967). Acta Med. Scand. 181,
465-473.
Cawse, P.A. (1974). Atomic Energy Research Establishment Report
R 7669, H.M.S.O., London.
Coates, E.G. and Watson, J.H.L. (1971). Ann. Intern. Med. 7^5,
709-716. ~
Coates, E.G. and Watson, J.H.L. (1973). J. Occup. Med. 15,
280-286.
Cohen, H.J., Drew, R.T., Johnson, J.L. and Rajagopalan, K.V.
(1973). Proc. Natl Acad. Sci. 70, Pt.l, 3655-3659.
Cohen, H.J., Johnson, J.L. and Rajagopalan, K.V. (1974).
Arch. Biochem. Biophys. j.6_4, 440-446.
Delahant, A.B. (1955). A.M.A. Arch. Ind. Health 12_, 116.
Frederick, W.G. and Bradley, W.R. (1946). Rep. of 8th Ann.
Meeting of Amer. Ind. Hyg. Assoc., Chicago.
Higgins, E.S., Richert, D.A. and Westerfield, W.W. (1956).
J. Nutr. 59, 539.
Kaye, S.V. (1968). Health Phys. 15, 398-417.
Kinard, F.W., Van de Erve, J. and Voigt, D. (1940). Amer. J.
Med. Sci. 199, 668-670.
Kinard, F.W. and Van de Erve, J. (1941). J. Pharmacol. Exp.
Ther. 72., 196-201.
Kinard, F.W. and Van de Erve, J. (1943). J. Lab. Clin. Med.
2Q, 1541-1543.
Kinard, F.W. and Aull, J.C. (1945). J. Pharmacol. Exp. Ther.
83., 53-55.
Kruger, R. (1912). Munchen Med. Wochenschr. 59_, 1910.
Kusske, J.A., Wyler, A.R. and Ward, A.A. (1974). Exp-i- Neurol.
4,2, 587-592.
Lane, W.B. (1963). USAEC Doc. PNE-229P. "Some radiochemical
and physical measurements of debris from an underground
nuclear detonation."
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Mezentseva, N.V. (1963). In: "Toxicology of the Rare Metals."
(Z.I. Izrael'son, ed) pp 28-35. Translated from Russian by
Israeli Program for Scientific Translations, Jerusalem 1967.
Miller, C.W., Davis, M.W., Goldman, A. andWyatt, J.P. (1953).
AMA Arch. Ind. Hyg. _8, 453.
Moschinski, G., Jurisch, A. and Reins, W. (1959). Arch. Gewerbe-
pathol. Gewerbehyg. 16_, 697.
Owen, E.G. and Proudfoot, R. (1968). Brit. J. Nutr. 22, 331-340.
Rieck, G.D. (1967). "Tungsten and Its Compounds." Pergamon Press,
London.
Salmon, L. (1974). Atomic Energy Research Establishment Report
R7859, H.M.S.O., London.
Schroeder, H.A. and Mitchener, M. (1975). J. Nutr. 105, 421-427.
Wester, P.O. (1973). Acta Med. Scand. 194, 505-512.
Wester, P.O. (1974). Atherosclerosis 20, 207-215.
Wilson, S.H. and Fields, M. (1944). Analyst 69, 12.
453
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URANIUM
Maths Berlin and B. Rudell
1. Abstract
Uranium occurs in the mammalian body in soluble form only as
tetravalent uranium or hexavalent uranium as uranyl com-
plexes. Both hexavalent and tetravalent uranium form com-
plexes with carbonate ions and proteins in the body. Oxida-
tion of tetravalent uranium to hexavalent uranium is likely
to occur in the organism. Absorption of uranium salts may
occur by inhalation or by ingestion. 95% of retained uranium
in the body is deposited in bone. Excretion is mainly by the
kidney. There is no evidence that uranium has any metabolic
function in the mammalian organism. As all uranium isotopes
in nature are radioactive, the hazards of a high intake of
uranium are two-fold - chemical toxocity, and irradiation
damage caused by the radioactive emission from the uranium
isotope.
The critical organ for the chemical toxicity is the proximal
tubule of the kidney. The chemical injury reveals itself by
increased catalase excretion in urine and proteinuria in
man. Such changes are likely to occur when uranium con-
centration in the kidney exceeds 1 mg/kg. The concentration
of uranium in the kidney is mainly dependent on the solu-
bility of the uranium compound to which the individual is
exposed.
The daily intake of uranium is of the order of 1.5,ug/day,
mainly derived from food items like vegetables, cereals and
table salt. Occupational exposure involves exposure to dust
particles containing uranium compounds with different solu-
bility and of varying size and density. Uranium concentra-
tions in air up to several 100 ,ug/m have been reported for
some occupational conditions. Insoluble uranium particles
454
-------
may be retained in the lung for a long time and constitute a
radiological hazard there.
The toxicology and radiological hazards of uranium compounds
have been extensively investigated as part of the Manhattan
project during the Second World War. This work has been
summarized recently by Hodge et al. - "Uranium, Plutonium,
Transplutonic Elements".
2. Physical and chemical properties
Uranium, U; atomic weight 238; atomic number 92; density
~18.95; melting point 1132.3 + 0.8°C; boiling point 3818°C;
crystalline form silvery, cubic, radioactive; oxidation
state 3,4,5 or 6.
Uranium occurs in nature in three isotopic forms - U-238
(natural abundance 99.25%), U-235 (0.71%) and U-234 (0.0057%).
q
U-238, half-time 4.5-10 years; a-energies ~4.2 MeV - 100%;
y-energies 0.048 MeV - 0%; U-235, half-time 7.1-10 years;
a-energies 4.8 to 4.56 MeV; y-energies 0.095 MeV - 9%, 0.143
MeV - 12%, 0.185 MeV - 55%; U-234, half-time 2.5-105 years;
a-energies 4.717 MeV - 28%, 4.768 MeV - 72%; y-energies
0.051 MeV - 0%. Pure uranium metal is very reactive as a
strong reducing agent (Hodge et al., 1973).
Uranium occurs in physiological systems in soluble form
only, in a tetravalent or hexavalent state as uranyl ions
+ 2
(UO~) . Both hexavalent and tetravalent uranium form
complexes with carbonate ions and proteins in the body.
3. Methods and problems of analysis
In the determination of the uranium content of biological
samples, the organic material must first be destroyed by
ashing or by acid treatment. Interfering substances may be
removed by ion-exchange or by solvent extraction after the
addition of appropriate chelating agents. After uranium
recovery has been ascertained through these separation techniques,
455
-------
the uranium content of the purified sample may then be
-12
determined by mass spectrometry (detection limit 2-10 g) ,
— 8
fluorimetric method (1-10 g) or radiometric methods
In fluorimetric determination, sodium fluoride is activated
with uranium upon which it becomes very brightly fluorescent
(yellow-green, 5546 A) when illuminated with ultraviolet
radiation of 3650 A (Australian Atomic Energy Commission,
1970) . This fluorescence is specific for uranium (Analytical
Chemistry of Uranium, 1963) .
Many elements such as silver, gold, cerium, cobalt, chromium,
copper, iron, manganese, nickel, lead and thorium produce
marked quenching effects when present in microgram amounts
(Australian Atomic Energy Commission, 1970) . Therefore a
preliminary separation of uranium must be carried out.
Radiometric methods are based on the spontaneous radiation
emitted by uranium and its decay products or the radiation
induced by nuclear reactions caused by particle irradiation.
Depending on the uranium isotope composition of the sample,
the uranium content can be determined by measuring alpha
and/or gamma irradiation combined with pulse height analysis.
It is necessary that a standard containing material of the
same isotope composition as the sample be used.
In neutron activation analysis the uranium or a specific
uranium isotope can be determined by a number of nuclear
techniques including direct a-counting (Campbell, 1955;
Kurtz, 1956; Frigerio, 1970), delayed neutron counting
(Amiel, 1962; Kramer, 1967; Donoghue, 1972), fission track
counting (Carpenter, 1970), and nuclear activation techniques
utilizing Np-239 daughter of U-239 (Edington, 1967; Picer,
1968) , several different fission products of U-235 (Smales,
1952; Buzzelli, 1965; Ikeda, 1969; Weaver, 1974), and a
number of procedures using the nuclear reaction U-238 (n,y)-
U-239 (Sankar Daj, 1962; Decat, 1963; Kramer, 1967; Nozaki
et al. , 1970) .
456
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4. Production and uses
4.1 Production
Uranium is produced in about 15 countries. 80% of the production
outside the Soviet Union and China - about 30,000 tons of
uranium per year - takes place in the United States (14,600
tons), Canada (4,600 tons) and South Africa (4,200 tons)
(World Energy Conference, 1974). Production capacity in the
Soviet Union and China is not known.
Open pit methods are often employed in mining uranium deposits,
but underground mining is currently the principal method
used in Canada, South Africa, and France, and for about half
the production in the United States.
Uranium is soaked from the ore and separated from the leach
solutions by ion exchange, solvent extraction or direct pre-
cipitation. Recovery commonly exceeds 90%. During the process,
the uranyl ion (U0~ ) is converted into uranium hexafluoride
235
(UF,), a gas. The enrichment of UFfi is achieved by membrane
235
diffusion utilizing the mass difference between UF, and
235
hexafluorides of other uranium isotopes. UF, is converted
235
into uranium dioxide ( UO~) , the final reactor fuel product.
Uranium metal is prepared from uranium oxide and uranium
halides by reduction.
4.2 Uses
The main use of uranium is as fuel in nuclear energy plants.
To a smaller extent, uranium compounds have also been used
as catalysts and staining pigments.
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Food products such as potatoes, bakery products, meat and
fresh fish contain uranium concentrations between 10 and
457
-------
100/ug/kg according to Prister (1969). Concentrations of
magnitudes 2 orders lower have been reported by Welford and
Baird (1967) and Hamilton (1972) . Hamilton found that table
salt contained 40 ,ug uranium/kg and contributed considerably
to the uranium content of prepared food. All cited investigators
agree that vegetables and cereals contribute most heavily to
the daily intake of uranium.
Based on analysis of uranium concentration in food products,
Prister (1969) calculated the daily intake of uranium in the
Soviet Union at around 30 /ug. Similar estimates for three
urban areas in the United States gave a daily intake of 1.3-
1.4,ug/day with virtually no difference among the three
areas (Welford and Baird, 1967) . An estimate for the United
Kingdom by Hamilton (1972) resulted in an average uranium
intake of about 1 ,ug/day. Daily intake of uranium in Japanese
urban areas has been estimated at 1.5 ,ug/day by Nozaki et
al. (1970). Yamoto et al. (1974) reported daily intakes up
to 4.55/ug in areas near uranium mines in Japan.
5.1.2 Water, soil and ambient air
High levels of uranium have been reported in drinking water
derived from sources near rock of high uranium content.
Values between 200 ,ug and 7 ,ug uranium/liter have been found
(Novikov and Rezanov, 1962; Berdnikova, 1964). A value of 32
ng uranium/liter has been reported in New York City tap
water (Welford and Baird, 1967). According to Nozaki et al.
(1970) , drinking water in urban centers in Japan contains
4.8 to 11.4 ng/liter.
Uranium is a ubiquitous element, present in the earth's
- - _4
crust in an average concentration of about 4-10 ,%;
concentrations in sea water average around 3.3 /ug/liter
(Keen, 1968). It is absorbed from the soil into plant tissues
to an extent which is dependent upon the species of plant
and the depth of its root system. Uranium occurs in higher
concentrations in some minerals. Sources containing as
little as 0.1 and up to 60% uranium are exploited commercially.
Most ore deposits hold about 1% uranium or more.
458
-------
Measurable concentrations of uranium in ambient air have
been reported from the USA and the United Kingdom. Average
concentration in the New York area was found to be 0.4 ng/m
(Welford and Baird, 1967). Corresponding values from the
United Kingdom of 0.02 ng/m have been reported by Dean
(1967) and Hamilton (1970). Hamilton (1970) has further
-9 3
reported a uranium concentration of 3-4-10 ng/m in air
over the Atlantic Ocean.
5.2 Working environment
Occupational exposure to uranium usually involves mixtures
of different uranium compounds with solubilities in water at
room temperature ranging from 1-400,000 mg uranium/liter.
Dust particles containing uranium may be of varying sizes
and densities. Density ranges from 2.8 to 10.9 g/cm (Hursh
and Spoor, 1973). Changes in particle size distribution and
compound mixtures occur continuously in the work environment.
Uranium concentrations in air of between a few ,ug/m to
3 '
several hundred /ug/m have been reported from different
work environments.
6. Metabolism
Hexavalent uranium can be reduced intracellularly to tetra-
valent uranium. Oxidation of tetravalent uranium to hexavalent
uranium is likely to occur in the organism. On entering the
body, soluble uranium immediately forms complexes with
anions, bases such as bicarbonate, citrate, malate, lactate,
etc. (Dounce, 1949; Dounce et al., 1949; Gindler, 1973).
The uranyl compounds have great affinity for phosphate-
containing molecules and tissues (Rothstein, 1951; Rich,
1970), carboxyl and/or hydroxyl groups such as proteins,
nucleotides and bone tissue.
Absorption, retention and excretion of uranium are dependent
upon its chemical form. The most crucial factor is the
solubility of the compound in biological media. Other factors,
such as particle size and surface characteristics, will
459
-------
affect the rate of phagocytosis and the transportability of
relatively insoluble material in the body. According to
Scott (1973) , uranium compounds occurring in the environment
can be classified as highly, moderately and slightly transportable,
In Table 1 uranium compounds are listed under these headings.
To the highly transportable uranium compounds belong the
water soluble compounds. The moderately transportable compounds
are less soluble but may also be transformed into hexavalent
soluble compounds in the organism.
6.1 Absorption
6.1.1 Inhalation
There is little conclusive data in the literature about the
rate of lung absorption upon inhalation of uranium compounds.
Due to the high density of uranium-containing particles,
most particles would have an aerodynamic size which will not
permit them to be carried to the peripheral part of the
lung. Based on measurements in some uranium plants (Harris,
1961), estimates have been made that only 1-5% of uranium-
containing dust will penetrate to the pulmonary region. The
rest will be deposited in the upper respiratory tract and
will eventually be swallowed. The soluble compounds of
uranium deposited in the alveolar region are likely to be
absorbed to 100%. Less soluble particles can either be
absorbed to a fraction or removed by the lung clearance
mechanism. Measurements of lung burden of uranium in workers
occupationally exposed to high levels of uranium in air
support the conclusion that a low fraction of inhaled dust
penetrates into the alveolar region (West and Scott, 1966,
1969; Schultz, 1968).
Animal data on deposition and absorption in the lung indicate
large species differences (Spoor and Hursh, 1973) .
460
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6.1.2 Ingestion
Experimental data from both animals and man show that absorption
in the intestinal tract varies with the solubility of the
uranium compound. Even of the soluble compounds, only a
small fraction is absorbed. In a clinical experiment on four
patients, given 11 mg uranium in the form of uranium nitrate
hexahydrate, 0.5-5% of the dose was found to be absorbed
(Hursh et al., 1969). If data on daily intake as reported by
Hamilton (1972) for the United Kingdom and Welford and Baird
(1967) for three large American cities are combined with
daily urinary excretion found by the same authors, absorption
can be estimated at 12% in the American data and 31% in the
British data. The dose in Hursh's study is about a thousand-
fold higher than the average daily intake; these data thus
suggest a dose dependence for absorption.
6.1.3 Skin
In animal experiments, water soluble uranium compounds have
been shown to be absorbed by the skin in sufficient amounts
to cause intoxication (Orcutt, 1949). Absorption can also
occur from the conjunctival sac, as has been shown on experimental
animals (Orcutt, 1949) . Water insoluble compounds are not
absorbed in detectable amounts. Human skin absorption data
are not available.
6.2 Transport and biotransformation
Uranium tends to be converted in the mammalian organism into
water soluble hexavalent uranium. Uranium forms soluble
complexes with the bicarbonate ions and with proteins. Thus,
uranium in blood is found complexed with the bicarbonate in
plasma to 47%; 32% is bound to plasma proteins and 20% to
erythrocytes (Chevari and Likhner, 1968) . Tetravalent uranium
introduced into the bloodstream either oxidizes into hexavalent
uranium or forms colloidal uranium oxide in the plasma
(Dounce et al., 1949).
6.3 Distribution
Uranyl compounds introduced into the bloodstream are rapidly
461
-------
distributed throughout the human organism. In experiments in
humans only 6 minutes after intravenous administration, two-
thirds of the injected dose lett the bloodstream; after 20
hrs this figure had risen to 99% (Struxness et al., 1956;
Luessenhop et al., 1958), In animals, the distribution
process was found to be even more rapid (Neuman et al.,
1948). The major part was rapidly excreted by the kidney,
and the rest was deposited in the kidney and in bone. Under
steady-state conditions, 85% of the body burden of uranium
was found in bone provided that uranium deposited in the
lung is excluded (Donoghue et al., 1972). More than 90% of
the remaining uranium was in the kidney, and detectable
amounts could be found in the liver. In case of inhalation
of less soluble uranium compounds, uranium may be found in
the bronchial lymph nodes as well as in the lung itself. In
bone, uranium replaces calcium in the hydroxyapatite complex.
In the kidney, most uranium is found in the proximal tubules.
Walinder et al. (1967a, 1967b) have described a two-phase
distribution with a high amount of uranium in the juxtamedular
part of the renal cortex shortly after administration, and
later a clearance of this zone and relatively higher concentra-
tions in the most peripheral part of the renal cortex.
fi.4 Excretion and retention
Hexavalent uranium is rapidly excreted by the kidney. The
uranyl bicarbonate complex in blood is ultrafiltrable and
filtrated by the glomeruli. Depending on pH of the tubular
urine, some uranium will be reabsorbed in the tubules. At
high pH, small amounts of uranium will be retained in the
tubular walls. At low pH, the carbonate uranyl complex will
be split and the uranyl ion will complex with the proteins
on the walls, whereby the tubular function may be impaired.
This mechanism has been verified in humans by experimental
study (Bassett et al., 1948). More than 90% of hexavalent
soluble uranium salt injected intravenously is excreted by
the kidney and less than 1% by feces. The excretion pattern
is characterized by a two-phase excretion, one very rapid
phase during which 70% of the dose is excreted the first 24
462
-------
hr, and a very slow phase with a half-time exceeding months.
In a study on six patients given intravenous doses of between
6 and 70/ug/kg, Bassett et al. (1948) found that 50% of the
dose was excreted in 3-10 hr, and 70-86% in 24 hr. The
remaining 14-30% was excreted very slowly. Similar figures
were found in another group of patients in a terminal state,
given doses of between 172-900,ug/kg of uranyl salt. Struxness
et al. (1956), Luessenhop et al. (1958) and Bernard et al.
(1956) confirmed the described excretion pattern. The overall
elimination rate of uranium under conditions of normal daily
intake has been estimated to a half-time of between 180 and
360 days (Hursh and Spoor, 1973), assuming that the excretion
of uranium by other routes than by urine is negligible and
that the organism is in steady state under normal conditions.
These estimates were based on the autopsy data collected by
Hamilton (1970), who estimated the body burden of uranium to
be around lOO.ug, and the autopsy data of Welford and Baird
(1967), who estimated the body burden to be around 80,ug.
The authors also determined the daily urinary excretion and
found it to be 0.38 (Hamilton, 1970) and 0.15,ug (Welford
and Baird, 1967) . Assuming a steady state, the fraction of
the whole body burden excreted per day becomes An and
038
' , which corresponds to half-times of 180 and 360 days.
The elimination rate of insoluble uranium compounds deposited
in the lung has been studied in both animal experiments and
by measuring the gamma emission from uranium deposited in
the human lung. The lung burden of uranium has been followed
to determine the elimination curve. It has to be emphasized
that the rate of deposition and clearance of uranium-containing
particles will be dependent on the chemical form and particle
size. In a five-year exposure study on dogs, monkeys and
rats exposed to uranium oxide U02 dust, the overall biological
half-time for uranium deposited in the lung was found to be
around 15 months for monkeys and dogs (Leach et al., 1971).
Reports from human subjects occupationally exposed to insoluble
uranium compounds have been summarized by Hursh and Spoor
(1973). From the available material, it appears to be a two-
463
-------
phase clearance rate with a short phase with a biological
half-time of between 11 and 100 days, and a slow phase with
a long retention time and a biological half-time of between
120 and 1,500 days.
7. Effects and dose-response relationships
There are two hazards connected with exposure to uranium
compounds: the renal damage caused by the chemical toxicity
of the soluble uranium compounds, and the injury caused by
the radioactive irradiation from the disintegration of the
uranium isotopes. Which of these two hazards will be the
limiting factor for exposure to uranium compounds is dependent
upon the solubility of the compound, its route of administration
and its isotope composition. The isotope most dangerous from
the point of view of radiation, Uranium 235, comprises less
than 1% of natural uranium, but is enriched during the
production of nuclear fuels. Higher fractions of Uranium 235
increase the irradiation risk.
As the retention time in the body is the important factor
for the irradiation risk, exposure to insoluble particles
which are deposited and retained in the lung for a long
time, constitutes a radiological hazard. Under these cir-
cumstances, renal uranium load should be low. The chemical
toxicity of uranium will be the limiting factor after exposure
to soluble compounds, when large quantities of the element
will pass through the kidney. The following discussion will
be limited to the chemical hazard; for a detailed discussion
of the radiological hazard, the reader is referred to Hursh
and Spoor (1973).
In experimental animals, the renal injury caused by uranium
manifests itself some days after exposure as a change in the
proximal convoluted tubules. Cell necrosis appears in the
lower portions of the convoluted tubules and may extend to
other parts of these structures. Hyaline casts, or casts
containing shedded necrotic cells, are present at all levels
of the tubular system. If the dose is not lethal, regeneration
464
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of the injured epithelium begins after 2-3 days; regrowth is
complete within 2-3 weeks, but this new epithelial lining
differs morphologically from normal tubular epithelium. The
morphological damage has been described through electron
microscopy by Stone et al. (1961); the appearance of the
regenerating epithelium and the structure of the regenerating
cells has been electron microscopically depicted by Porte et
al. (1963). In animal experiments, a tolerance to uranium
has been observed after exposure to sublethal doses of
uranium compounds. This tolerance has been connected with
the regenerated tubular epithelium, which differs both
morphologically and histochemically from normal epithelium.
If uranium exposure is discontinued, the regenerated epithelium
will gradually be transformed into normal tubular epithelium.
Parallel with the tubular damage, changes in the glomeruli
appear, affecting largely the basement membranes of the
glomerular capillaries, which have been shown electron
microscopically to involve loss of foot processes and dense
deposits between the basement membrane and the epithelium,
as well as hyaline droplets, other cytoplasmic bodies,
myaline figures and cytoplasmic vacuoles in epithelial cells
(Stone et al., 1961). The corresponding functional changes
in the kidney are characterized by proteinuria, impaired
diodrast and PAH clearance, and increased clearance of
animoacids and glucose. Inulin and creatinine often remain
virtually normal, though after severe damage they may decrease.
All changes reflect damage to the lower two-thirds of the
proximal convoluted segment of the proximal tubules.
In animal and human experiments, the earliest observed sign
of renal tubular damage caused by uranium has been an increase
in urinary catalase and albuminuria (Dounce et al., 1949;
Luessenhop et al., 1958). The determination of urinary
catalase is therefore a good control test for kidney function
in uranium exposure. Such tests should preferably be combined
with one for proteinuria.
465
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Neurological signs and pathological changes in the cerebral
and cerebellar cortices have been observed in rabbits exposed
to soluble uranium salts. Verne (1931) and Purjesz et al.
(1930) noted epithelial degeneration of the choroid plexi in
the brains of dogs exposed to toxic doses of soluble uranium
salts.
Five years of exposure to uranium oxide (DO-) has produced
lung tumors in dogs (Leach et al., 1971), probably due to
radiation injury. There is evidence only of renal injury in
humans exposed to uranium compounds.
8. Dose-response relationships for the renal effects
Dose-response data for the toxic effect of uranium on the
human kidney are scarce. The dose can be defined as uranium
concentration in the kidney or as absorbed uranium in the
body or as degree of exposure to uranium compounds. Conclusive
data are available only for concentrations of uranium in the
kidney and amount of uranium absorbed. In animal experiments,
between 1 and 3 mg/kg kidney tissue produces mild renal
damage in more than 10% of the animals (Voegtlin and Hodge, 1953)
In experiments with single intravenous injections of uranium
nitrate to volunteers or terminally ill patients, between
70-100yug/kg body weight produced proteinuria and increased
catalase excretion (Bassett et al., 1948; Luessenhop et al.,
1958) .
9. Indices of exposure and concentration in critical organ
As uranium excretion, distribution and absorption are dependent
upon the type of exposure and the chemical composition of
the compound as well as its solubility, there is no generally
applicable index of exposure or body burden of uranium. How-
ever, urinary excretion of uranium has proved of practical
value under conditions of exposure to appreciable amounts of
soluble uranium salts. Thus, urinary excretion of uranium
may reflect recent exposure levels and can be used for
routine checking of exposure conditions. The establishment
of acceptable levels must be made, in each case, with considera-
tion to the type of exposure. Although it is not unlikely
466
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that urinary excretion of uranium may reflect the concentration
of uranium in the critical organ for chemical toxicity - the
kidney there are as yet no available data confirming this.
In cases of uranium salt retention in the lungs after exposure
to insoluble compounds, the critical organ is the lung, and
the critical effect the radiation injury to the lung. In
vivo measurements of pulmonary uranium burden by whole body
scintillation counting are commonly used for routine control.
10. Prognosis and treatment of chemical injury to the kidney
caused by uranium compounds
Experimental evidence suggests that if death from acute
renal failure can be prevented, the prognosis for regression
and regeneration of the renal tubular damage is good. Cases
of uranium poisoning should be treated by intravenous infusion
of sodium bicarbonate. The bicarbonate ion will complex-bind
uranium in the blood, facilitate excretion and prevent
resorption of uranium in the renal tubules (Newman et al.,
1949). Experimental and clinical data indicate that a certain
tolerance to uranium may develop during prolonged exposure
(MacNider, 1929; Yuile, 1973).
467
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Table 1. classification of uranium compounds according to
transportability (From Scott, 1973).
Highly
transportable
UF6
uo3a)
Moderately
transportable
U3°8a)
Slightly
transportable
uo2a)
«3°8a)
UO(NO)
uo
uranium sulfates uranium nitrates
uranium carbonates
uranium oxides
uranium hydrides
uranium carbides
salvage ash
a) Subjecting a particular uranium compound to higher temperatures
tends to decrease rate of transportability.
468
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Amiel, S. (1962). Anal. Chem. 3_4, 1683.
Analytical Chemistry of Uranium (1963). Academy of Sciences
of the USSR. Israel (Program for Scientific Translations,
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Australian Atomic Energy Commission Research Establishment,
Lucas Heights (1970). In: "Proceedings of a Symposium on the
Analytical Chemistry of Uranium and Thorium." (T.M. Florence,
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Bassett, S.H., Frenkel, A., Cedars, N., Van Alstine, H.,
Waterhouse, C. and Cusson, K. (1948). ESAEC Report UR-37.
Berdnikova, A.V. (1964). Vopr. Pitan. 23, 17-20.
Bernard, S.R., Muir, J.R. and Royster, G.W. Jr. (1956).
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Buzzelli, G. (1965). Anal. Chem. 37, 1405.
Campbell, E.E. (1955). U.S. Atomic Energy Commission Report
LA-1920, June.
Carpenter, B.S. (1970). Anal. Chem. 42, 121.
Chevari, S. and Likhner, D. (1968). Med. Radiol. 13, 52-57.
Dean, M.H. (1967). Personal Communication.
Decat, D. (1963) . Anal. Chem. 35, 845.
Donoghue, J.K., Dyson, E.D., Hislop, J.S., Leach, A.M. and
Spoor, N.L. (1972). Brit. J. Ind. Med. 29, 81-89.
Dounce, A.L., Tishkoff, G.H., Fanta, P. and Ho Lan, T.
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Edington, D.N. (1967). Int. J. Appl. Radiat. Isotop. 18, 11.
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Hamilton, E.I. (1970). Nature 227, 501-502.
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Harris, W.B. (1961). In: "Inhaled Particles and Vapours. I."
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Hodge, H.C., Stannard, J.N. and Hursh, J.B., eds (1973).
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Hursh, J.B., Neuman, W.F., Toribara, T., Wilson, H. and
Waterhouse, C. (1969). Health Phys. 17, 619-621.
Ikeda, N. (1969). Radiochim. Acta 12, 72.
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472
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ZINC
Carl-Gustaf Elinder and Magnus Piscator
1. Abstract
Absorption of ingested zinc is highly variable, from 10 to
90% and is affected by various factors. High zinc concentra-
tions are found in prostate, bone, muscle and liver. Excre-
tion takes place mainly via the gastrointestinal tract. The
biological half-time of retained zinc in humans is in the
order of half a year. Homeostatic mechanisms exist for
gastrointestinal absorption and excretion of zinc.
Zinc is an essential metal, necessary for the function
of several enzymes. Zinc deficiency is easily produced
in animals and has been recorded in humans.
Large oral doses of zinc salts cause gastrointestinal dis-
orders including vomiting and diarrhea. The emetic dose
of zinc as a salt is about 300 mg. Metal fume fever is an
acute disorder seen after respiratory exposure to freshly
generated zinc fumes (mostly as ZnO). The syndrome has
not been seen in working atmospheres with zinc concentra-
tions below 15 mg/m .
Exposure to high concentrations of ZnCl2 may be fatal,
involving acute damage to the mucous membranes of the
nasopharynx and respiratory tract. Chronic zinc poisoning
among humans has not been described.
Reviews on zinc have been made by Athanassiadis (1969) and
Halsted et al. (1974) .
2. Physical and chemical properties
Zinc, Zn, atomic weight 65.4; atomic number 27; density 7.1;
melting point 420°C; boiling point 907°C; crystalline form
bluish-white metal, hexagonal; oxidation state 2.
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Zinc is a relatively soft metal and has a strong tendency to
react with inorganic compounds (as oxides, sulfates, phosphates)
as well as organic OLJS. The compound most commonly used in
industry is zinc oxide, which has a low solubility in most
solvents. Other compounds to be taken up in this chapter are
zinc sulfate, zinc carbamate, zinc chloride and zinc ammonium
sulfate.
3. Methods and problems of analysis
Previously, the most common method for zinc analysis was
the dithizone method. Zinc forms a colored complex with dithi-
zone, which is extracted into an organic solvent and measured
colorimetrically. The detection limit is around 0.7 mg/1 in
water solution (Hibbard, 1937; Sandell, 1959).
Atomic absorption spectrophotometry is at present the most
widely used method for the analysis of zinc, for which it
is well suited as well as having a large capacity. The detection
limit in water is 0.5 to 1 ug Zn/1. The limit of detection of
AAS is sufficient to permit measurements of zinc in air and
in most biological materials such as tissues, blood, serum
and urine (Sunderman, 1973). Other analytical methods in use
are emission spectrography and neutron activation. Due to
the good agreement among zinc concentrations in various materials,
reported by different authors in different countries, the
ace .racy of the zinc analysis employed may be considered as
sufficient (Halsted et al., 1974).
4. Production and uses
4.1 Production
The world production of zinc is at present steadily increasing
at a rate of about 5% per year, from about 0.5 million metric
tons in 1900 to about 5.5 million tons in 1972 (Teworte, 1973).
The principal ores of zinc are sulfides such as sphalerite and
wurtzite (cubic and hexagonal ZnS). Zinc ore is mined to a great
extent in USA, USSR and Japan. During blasting and crushing of
the ore moderate losses of zinc to the atmosphere occur. Treat-
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ment of the crush by means of wet flotation may result in
emissions into water. During smelting there are often large
emissions of zinc into the air, which often also will result
in cadmium emissions. The total emission of zinc into the
atmosphere during smelting activities in the USA during 1969
has been estimated at about 50,000 tons (Davis, 1972). Signi-
ficant zinc contamination of soil is only seen in the vicinity
of point sources (Buchauer, 1973).
Zinc obtained by "recycling" accounts for 16% of the US yearly
production (Fulkerson et al., 1973).
4.2 Uses
Zinc has been used by mankind for more than 2,000 years. The
Romans mixed a zinc ore with copper to yield brass (Dawkins,
1949). At the end of the 18th century zinc began to be produced
on a commercial scale.
Major uses of zinc are in the production of non-corrosive
alloys, brass and in galvanizing steel and iron production.
Zinc undergoes corrosion on the surface and protects the enclosed
metal from degradation. Such products appear widely in e.g.
automobile parts and household appliances.
Zinc oxide used in rubber and as a white pigment accounts
for the largest quantities of zinc. Zinc sulfate is employed
in human medicine in treating zinc deficiency. The carbamate
has been utilized as a pesticide. Even zinc compounds of
high purity may contain significant amounts of more toxic
metals, e.g. cadmium and lead (Smit and Backe-Hansen, 1973).
5. Environmental levels and exposures
5.1 General environment
5.1.1 Food and daily intake
Halsted et al. (1974) summarized studies on the average daily
intake of zinc in different areas and arrived at a figure on
the order of 5 to 22 mg/day. In general, protein-rich foods,
such as meat and marine organisms, oysters in particular, have
475
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high concentrations of zinc (10-50 mg/kg wet weight), whereas
grains, vegetables and fruits are low in zinc, usually less
than 5 mg/kg. Human milk contains about 3 mg/1 (Schlettwein-
Gsell and Mommsen-Straub, 1970).
The refining and preparation of food may result in a decrease
of the zinc content (Schroeder, 1971).
5.1.2 Water, soil and ambient air
In sea and fresh water the concentration of zinc is around 10
ug/1 (Durum et al., 1971; Preston et al., 1972). Drinking water
generally has the same concentration as fresh water. Considerably
higher zinc content (up to 2,000 ug/1) has, however, been recorded
as a result of the passage of water through zincrcontaining
pipes (Schroeder et al., 1967).
The average concentration in the earth's crust is estimated
at 40 mg/kg. In soil the zinc concentration varies between 10
and 300 mg/kg dry weight (Swaine, 1955; Wedepohl, 1972). Con-
tamination by zinc smelters may increase these values consid-
erably. Burkett et al. (1972) found about 50 times higher zinc
concentrations (5,000 mg/kg) in soil close to a smelter compared
with a control area.
Iii. 58 air samples from cities in the USA zinc concentrations
3
range from less than 0.01 to 0.84 ug/m ; in 29 samples from
nonurban areas the corresponding figures were 0.01 to 0.2 ug/m
(Schroeder, 1970/ original data from National Air Sampling
Network, 1968, and Tabor and Warren, 1958/).
5.1.3 Plants
The normal levels of zinc range from 10 to 100 mg/kg in most
crops and pasture plants. Zinc was early established as essen-
tial for the growth of higher plants (Brenchley, 1914). In-
sufficient concentration of zinc is a common micro-nutrition
deficiency in crops (Lindsay, 1972) and zinc addition to soil
with fertilizers is common. Toxicity of zinc among plants is
rarely seen in area? other than those close to some emission
sources.
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5.2 Working environment
Exposure to zinc fumes, particularly ZnO, is a potential risk
wherever zinc oxide is a product or by-product, e.g. in zinc
smelting, manufacture of zinc oxide and powder, production of
brass, and melting of galvanized iron. These processes yield
a dispersion of zinc oxide particles of about 1 u 0 in the
atmosphere (Athanassiadis, 1969). In a Polish shipyard, work-
ing zone averages of ZnO ranged from 1.5 to 18.0 mg/m
(Chmielewski et al., 1974).
6. Biological function and metabolism
6.1 Biological function
Zinc has been shown to be necessary for the function of various
mammalian enzymes. At least 18 zinc metallo-enzymes have been
identified (Parisi and Vallee, 1969), e.g. carbonic anhydrase,
alcohol dehydrogenase and leucine-aminopeptidase. The two former
are necessary for cellular oxidation while leucine-aminopeptidase
is considered to be engaged in protein reabsorption in the proxi-
mal tubule of the kidney (Wachsmut and Torhorst, 1974).
Zinc deficiency decreases the production of DNA and RNA, which
leads to reduced protein synthesis (see e.g. Holt et al. 1970;
Prasad et al., 1974). The role of zinc in carbohydrate metabolism
is still debatable, but one study indicates that zinc is neces-
sary for a normal glucose balance (Macapinlae et al., 1966;
Mills et al., 1969).
6.2 Zinc deficiency
6.2.1 Animals
Zinc deficiency has been described in most ruminants and labora-
tory animals. Deficient diets have usually contained less than
1 mg Zn/kg. Williams and Mills (1970), however, showed that
growth arrest occurred among rats fed with food containing
slightly less than 12 mg/kg of zinc. Typical signs of deficiency
include dermatitis, emaciation, testicular atrophy, retarded
growth, and anorexia. The simultaneous administration of cadmium
enhances some of the effects of zinc deficiency. For example,
Petering et al. (1971) observed a decreased growth rate and
477
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corneal keratinigation among rats fed with a marginal level
of zinc, when 3.4 mg/kg of cadmium was added in drinking water.
The authors also observed that the zinc content of the testes
then decreased.
6.2.2 Humans
Zinc is essential for human beings. The daily requirement for
zinc has been recommended as 15 mg for adults and 25 mg for
nursing mothers (Food and Nutrition Board, 1974).
An endemic zinc deficiency syndrome among young men has been
reported from Iran and Egypt (Prasad et al., 1961j Halsted
et al., 1972). Prominent features were retarded growth, infantile
testis, delayed sexual maturation, anemia, hepatosplenomegaly
and hyperpigmentation. Oral supplementation with zinc (30 mg/day)
had a prompt, beneficial effect.
Acrodermatitis enterohepatica is a familial disease characterized
by skin eruptions, gastrointestinal disorders and low serum
zinc. One causative factor may be a low intestinal absorption
of zinc. Complete cure is achieved by peroral administration
of 135 mg zinc per day given as zinc sulfate (600 mg/day)
(Michaelson, 1974).
There is some contention with regard to zinc and wound healing.
Post workers have found a correlation between low serum zinc
and poor wound healing, and several studies indicate a faster
healing of venous and ischemic leg ulcers after oral zinc
treatment (Hallbook and Lanner, 1972; Haeger and Lanner, 1974).
6.3 Metabolism
6.3.1 Absorption
No data are available which allow a calculation of pulmonary
absorption.
The absorption of ingested zinc is also hard to ascertain since
part of the absorbed zinc is excreted into the gut. As is the
case for iron, some regulation of intake and output of zinc
probably takes place in the intestinal membrane.
478
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In animals, zinc absorption is highly variable and affected
by various factors. Low body weight and poor zinc status
increase absorption, whereas high oral doses of zinc and in-
terfering substances in food such as calcium and phytate reduce
it (Becker and Hoekstra, 1971). Zinc absorption has been reported
to range from less than 10% to over 90%.
In humans, subjected to low doses of ZnCl_ and whole-body
measurements, Lombeck et al. (1975) estimated absorption to
range from 58% to 77% in five controls and from 16% to 42%
in three patients suffering from acrodermatitis enterohepatica.
The whole-body zinc retention was measured for 34 days.
Absorption, by seven volunteers, of radio-zinc occurring as
a contaminant in fishmeat was found to be around 35% by Honstead
and Brady (1967).
6.3.2, Distribution
One week after an oral tracer dose of 2 ug ZnCl,, to mice the
highest concentrations were found in bone tissue followed by
liver and kidney (Ansari et al., 1975).
6.3.3, Excretion
In animals given peroral or parenteral doses, Zn is mainly
eliminated via feces. In mice given 0.3 ug ZnCl intravenously
about 50% of the total dose was recovered in feces within a
week. The corresponding figure in one week for dogs given 6.5
/ug ZnCl_ was about 20%. Urinary excretion during the same time
was well below 5% of the dose in both species (Sheline et al.,
1943). Biliary excretion of zinc in rats was found to be 4%
during 48 hours following a single intravenous dose of 0.1
mg ZnCl0 (Barrowman et al., 1973). Elimination of a single
x- [-
peroral dose of 2 mg Zn increased sharply in rats pretreated
with additions of unlabelled zinc to food, 600 mg/kg, compared
to non-pretreated rats, indicating some homeostatic control
for zinc (Ansari et al., 1975).
The daily elimination of Zn in normal humans is on the order
of 1% per day of absorbed perorally given radioactive zinc
479
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(Sullivan and Heaney, 1970; Lombeck et al. , 1975). About three
quarters of the excretion take place via the gastrointestinal
tract, and the rest, via urine.
Concentrations of 0.6 to 0.7 mg/1 have been found in the urine
of workers exposed to zinc oxide in concentrations between
3 and 5 mg/m (Mass. Div. of Occupational Hygiene, 1970, cited
by ACGIH, 1971). These values are not excessively elevated
compared to normal values (see section 7).
6.3.4 Biological half-time
As stated earlier, elimination of Zn is related to zinc status,
in such a way that additions of zinc in the diet increase the
rate of elimination (see section 6.3.3).
In normal humans, without excessive intake of zinc, the body
burden half-time of absorbed radio-zinc has been estimated
at 162 days (Honstead and Brady, 1967). After parenteral admin-
istration of Zn, half-times ranging from 250 to 500 days
have been reported (Hawkins and Marks, 1976).
7. Normal levels in tissues and biological fluids
The highest concentration of zinc is found in the prostate,
about 100 mg/kg wet weight. High levels of zinc are also found
in bone, muscle, liver, kidney and pancreas. For more detailed
..esults reference is made to the comprehensive review by Halsted
et al. (1974). Levels of zinc in serum and plasma are constant,
around 1 mg/1. The concentration of zinc in whole blood is
about five times higher due to a ten times higher zinc content
in red blood cells (Sunderman, 1973). Normal humans not occupa-
tionally exposed to zinc excrete an average of 0.5 mg/day in
urine (Halsted et al., 1974).
8. Effects and dose-response relationships
8.1 Local effects and dose-response relationships
8.1.1 Animals
Rabbits, rats and cats exposed for 3.5 hours to zinc oxide
3
fumes at concentrations of 110 to 600 mg/m reacted with a
480
-------
transient fall in body temperature followed by a marked leuko-
cytosis. In heavily exposed animals autopsy studies showed
signs of bronchopneumonia (Drinker and Drinker, 1928).
Short-term exposure to zinc sulfate and zinc ammonium sulfate
at about 1 to 2 mg/m produced increased pulmonary air flow
resistance in cats and guinea pigs. However, the sulfate had
the main responsibility for this effect (Kincaid et al., 1953,
Amdur et al. , 1963).
8.1.2 Humans
8.1.2.1 Inhalation
Metal fume fever has been associated with inhalation of zinc
oxide fumes, but other metals have probably been coexisting
causative factors. Symptoms usually occur within a few hours
after exposure, and have a short duration (6-48 hours). The
typical manifestations are influenza-like with headache, fever,
hyperpnea, leukocytosis, sweating, and pains in leg and chest.
The illness is never fatal and affected subjects usually recover
completely within two days (Rohrs, 1957; Stokinger, 1963;
Browne, 1966; Hunter, 1969). The pathogenesis of the syndrome
is not clear, but several indications of an allergic background
have come forth. It has been proposed that zinc enters the
blood circulation and forms a sensitizing complex with plasma
proteins (Jaremin, 1973).
Data on air concentration of zinc oxide and exposure time causing
metal fume fever are insufficient. Sturgis et al. (1927) exposed
two volunteers to air concentrations of 600 mg Zn/m (as ZnO).
Moderate symptoms with typical febrile reaction and leukocytosis
were recorded after 10.5 and 12 minutes'exposure.
Based on an occupational study conducted by Batchelor et al.
(1926) (see section 8.2.2) it has been estimated that metal
fume fever will not occur at air concentrations below 15 mg/m
(Hegsted et al., 1945).
Zinc chloride exposure may result in severe respiratory tract
effects, with pneumonitis and fatal pulmonary edema. Dose-
481
-------
response relationships have not been reported.
It may be speculated that che high toxicity of ZnCl is due
to the formation of hydrochloric acid. Hunter (1969) reported
on 70 workers exposed to an accidental release of ZnCl- from
smoke generators. Ten workers died immediately or within a few
hours and 25 workers experienced severe respiratory inflammation.
Two necrop-ies showed membranes lining the larynx and trachea
and edemateouo oronchi. One case of pulmonary :ibrosis, which
developed within 18 days after accidental exposure to ZnCl_,
has been described by Milliken et al. (1963).
8.1.2.2 Ingestion
Reports of toxic effects following ingestion of zinc are uncommon,
and compared with most other trace metals zinc is fairly non-
toxic.
Food poisoning attributable to galvanized zinc containers in food
preparation has been reported (Brown et al., 1964). Symptoms
occurred within 24 hours and included nausea, vomiting, diarrhea,
in several cases with blood, and abdominal cramps. The emetic
dose of zinc was estimated at 225-450 mg, corresponding to 1-
2 g for the sulfate form.
Murphy (1970) described headache and lethargy in a boy who con-
samed 12 g of elemental zinc. Blood analysis showed elevated
serum amylase, which indi ated some effects on the pancreas.
8.2 Systemic effects and dose-response relationships
8.2.1 Animals
Excessive zinc addition to the food of weanling pigs (around
1,000 mg/kg for periods exceeding one month) produced depressed
rate of growth and food intake. In addition, arthritis, lameness
and inflammation of the gastrointestinal tract were recorded
among the pigs (Grimmet et al., 1937; Brink et al., 1959). Similar
signs of chronic toxicity from high dietary zinc intake have
been found in horses (Willoughby et al., 1972).
482
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8.2.2 Humans
Highly elevated serum zinc has been reported among some patients
treated for renal failure by dialysis. This was brought about
by a direct release of zinc ions from the equipment used into
the blood (Blomfield et al., 1969). No ill-effect related to
zinc was recorded.
Chronic zinc poisoning has not been described in humans. Patients
suffering from venous leg ulcers have been treated for periods
up to half a year with zinc doses on the order of 135 mg/day
as the sulfate without toxic manifestations. Twenty-four
workers occupationally exposed to 3 to 15 mg/m for periods
of two to thirty-five years did not show any signs of chronic
toxicity (Batchelor et al., 1926).
However, it must be remembered that the highly toxic metal
cadmium is closely related to zinc and will be obtained as a
by-product wherever zinc is refined (Fulkerson et al., 1973).
The possibility of cadmium exposure should always be taken into
account when zinc and zinc compounds are handled. (See the
chapter on cadmium in this series).
8. 3 Carcinogenic and teratogenic effects
Repeated intratesticular injections of zinc chloride into chickens
and rats have been reported to produce testicular sarcomas.
There is no evidence that zinc compounds are carcinogenic after
administration by any other route (Sunderman, 1976). Recently
it has been reported that additions of 150 mg Zn/kg as zinc
sulfate to the rat diet may be associated with harmful effects on
the fetus (Kumar, 1976).
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Amdur, M.O. and Corn, M. (1963). Amer. Ind. Hyg. Assoc. J.
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American Conference of Governmental Industrial Hygienists (1971).
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Ansari, M.S., Miller, W.J., Lassiter, J.W., Neathery, M.W.. and
Gentry, R.P. (1975). Proceedings of the Society for Experimental
Biology and Medicine 150, 534-536.
Athanassiadis, Y.C. (1969). Preliminary air pollution survey of
zinc and its compounds. U.S. Dept. of Health, Education and Welfare,
North Carolina.
Barrowman, J.A., Bouett, R. and Bray, P.J. (1973). Biochem.
Soc. Trans. 1, 988-989.
Batchelor, R.P., Fehnel, J.W., Thomson, R.M. and Drinker,K;R.(1926) .
J. Ind. Hyg. 8, 322-363.
Becker, W.M. and Hoekstra, W.G. (1971). In: "Intestinal Absorption
of Metal Ions, Trace Elements and Radionuclides." (S.C. Skorylla
and D. Valdron-Edward, eds.) pp 229-256, Pergamon Press, New York.
Blomfield, J., McPherson, J. and George, C.R.D. (1969) Brit. Med.
J. 2, 141-145.
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
i. REPORT NO.
EPA-600/1-77-022
2.
3. RECIPIENT'S ACCESSION>NO.
4. TITLE ANDSUBTITLE
5. REPORT DATE
Mav 1977
TOXICOLOGY OF METALS - Volume II
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Lars Friberg, Chairman
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
Subcommittee on the Toxicology of Metals
Permanent Commission and International Association of
Occupational Health
1 A/\
11. CONT
RACT/GRANT NO.
68-02-1287
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Health Effects Research Laboratory HERL.RTP
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park. N.C. 27711
14. SPONSORING AGENCY CODE
FPfl
15. SUPPLEMENTARY NOTES
Prepared in cooperation with the Swedish Environmental Protection Board, and the
Karolinska Institute
16. ABSTRACT
This report on metal toxicology contains reviews on twenty-three metals.
These have been written for inclusion in a Handbook on the Toxicology of Metals:
Environmental and Occupational Aspects which is being prepared by the Scientific
Committee on the Toxicology of Metals of the Permanent Commission and International
Association of Occupational Health. The metals covered in this volume are-
aluminum, antimony, arsenic, barium, beryllium, bismuth, cadmium, chromium^ cobalt,
copper, germanium, indium, lead, mercury, molybdenum, silver, tellurium, thallium
tin, titanium, tungsten, uranium, and zinc. '
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COS AT I Field/Group
metals
toxicology
chemical properties
chemical analysis
metabolism
excretion
permissible dosage
Environmental levels
Environmental exposure
06 T
06 T
18. DISTRIBUTION STATEMENT
RELEASE TO PUBLIC
19. SECURITY CLASS (ThisReportf
UNCLASSIFIED
21. NO. OF PAGES
491
20. SECURITY CLASS (Thispage)
UNCLASSIFIED
22. PRICE
EPA Form 2220-1 (9-73)
488
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