Int. J. lmmunopharmac., Vol. 2, pp. 269-279
00/0
© Pergamon Press Ltd. 1980. Printed in Great Britain.
REVIEW/COMMENTARY
IMMUNOTOXICOLOGY OF HEAVY METALS
LOREN D. KOLLER
Veterinary Medicine, University of Idaho, Moscow, Idaho 83843, U.S.A.
(Received 24 March 1980)
The field of immunotoxicology is in its infancy, but
in the past few years considerable knowledge has
been acquired on many chemicals in several species
of animals by utilizing a variety of immunoassays.
These investigations have only scratched the surface
of what could be serious implications for human
health. However, much of the data that has been col-
lected often does not consider the entire immune res-
ponse nor reactions by other body systems which
may influence those responses. Further, baseline data
concerning mechanisms by which these compounds
compromise the immune system of a host are either
inconclusive or lacking for most groups of com-
pounds. Finally, many immunoassays have a rela-
tively low sensitivity index and, therefore, require
considerable suppression or enhancement to detect
significant differences.
Ideally, it would be advantageous to determine
that a chemical renders animals more susceptible to
infectious agents or impedes antibody titers and
thereby is amenable to immunologic investigation.
These studies should be followed by detailed tech-
niques which determine the effect of the compounds
on the function of B and T lymphocytes, macro-
phages, their soluble factors and the interrelationship
of these cells. The investigations should be carried
out both in vivo and in vitro. Suppression of humoral
immunity does not necessarily assure B cell involve-
ment, since T cells, such as helper, suppressor, or
cytotoxic functional subclasses, may be affected indi-
vidually or collectively. Lymphokines and soluble
factors from lymphocytes and macrophages also
have a role in the regulation of immunity. Therefore,
once it has been established that a chemical interferes
with the immune response of a host, every effort
should be made to determine the actual mechanism
by which that compound alters the response, whether
it is cellular or subcellular and if it involves a single or
several components of the immune system. Know-
ledge recently acquired for some of the heavy metals
will be discussed in the following sections.
269
0192-0561/80/1201-0269 $05.
LEAD
There is considerable evidence that lead exerts
adverse effects on the resistance of the body to
disease (Table 1). The ability of lead salts to induce a
profound sensitization to endotoxicosis in rats, mice
(Selye, Tuchweber & Bertok, 1966; Schumer & Erve,
1973: Rippe & Berry, 1973; Cook, Marconi &
DiLuzio, 1974) and chickens (Truscott, 1970) is well
documented. Lead has also been shown to increase
the susceptibility of rats to bacterial (E. colt) disease
(Cook, Hoffman & DiLuzio, 1975) and of mice to
Salmonella typhimurium (Hemphill, Kaeberle &
Buck, 1971), encephalomyocarditus virus (Gainer,
1977; Exon, Koller & Kerkvliet, in press), langet virus
(Thind, Thind & Louria, 1977) and Hexamita muris
(Exon, Patton & Koller, 1975). Further, inhalation of
lead chloride impairs elimination of bacteria (Serratia
marcescens) from the lungs (Schlipkoter & Frieler,
1979).
Although the exact mechanism by which lead alters
the host response has not been completely charac-
terized, alteration of the reticuloendothelial system
and hepatic function has been predicted (Trejo et al.,
1972). Further, there is substantial evidence to sug-
gest that the enhanced mortality in metal-exposed
animals may be due to an immunosuppressive effect
exerted by the metal (Koller, 1979).
Lead-treated animals subjected to active immuni-
zation develop lesser quantities of serum globulin,
complement and anti-typhoid antibody (DeBruin,
1971). Interference with the phagocytic activity of
polymorphonuclear leukocytes (Ward, Goldschmidt,
& Greene, 1975) and a reduction in lysozyme activity
(DeBruin, 1971) also occurs following lead exposure.
In most laboratories, lead consistently suppresses
the immune system of experimental animals. In fact,
lead acetate results in as much as a nine-fold decrease
in antibody titer in rabbits challenged with pseudo-
rabies virus (Koller, 1973). Further, lead impairs
antibody synthesis in both rats (Luster, Faith &
270
Kimmel, 1978) and mice (Koller & Kovacic, 1974) as
well as the memory response in mice (Koller & Roan,
in press, a). Lead also interferes with complement
receptors on B lymphocytes (Koller & Brauner,
1977). Finally, tetraethyl lead suppresses antibody
titers and impairs antibody synthesis in mice
(Blakley, Sisodia & Mukkur, 1980). Therefore, lead
definitely appears to impede the humoral immune
response o f experimental animals.
Several studies which examined the response of
lymphocytes to mitogens after exposure to lead were
recently completed. Mitogens can induce blast trans-
formation of normal lymphocytes. Concanavalin A
LOREN D. KOLLER
(Con A) and phytohemagglutinin ( P H A ) activate T
lymphocytes whereas lipopolysaccharide (LPS) stim-
ulates B lymphocytes in certain species. Pokeweed
mitogen (PWM) activates both T and B lymphocytes.
Interference o f mitogen proliferation after treatment
with Con A and P H A suggests alteration of cell-
mediated immune responses, while interference of
LPS blastogenesis may indicate humoral involve-
ment. In one study (Gaworski & Sharma, 1978) lead
inhibited the P H A and P W M induced proliferation
of lymphocytes while in another study (Koller, Roan
& Kerkvliet, 1979), lead did not alter the lymphocyte
transformation due to Con A and LPS. In another

Table 1. Immune parameters of lead

Species Parameter Effect* References

Rat Susceptibility to E. coli endotoxin I Selye et al., 1966

Mice Susceptibility to S. t y p h i m u r i u m
endotoxin I Rippe & Berry, 1973
Rats Susceptibility to S. enteriditis
endotoxin I Cook et al., 1974
Mouse Susceptibility to S. t y p h i m u r i u m I Hemphill et al., 1971
Rats Susceptibility to E. coli I Cook et al., 1975
Mouse Susceptibility to EMC virus I Gainer, 1977
Mouse Susceptibility to Langet virus 1 Thind et al., 1977
Mouse Susceptibility to EMC virus I Exon et al., 1979
Mouse Clearance of Serratia marcescens
Rabbit Antibody titer to virus D Koller, 1973
Mouse Antibody synthesis--SRBC D Koller & Kovacic, 1974
Mouse Antibody synthesis--SRBC D Koller et al., 1976
Rats Antibody synthesis--SRBC D Luster et al., 1978
Mouse Antibody titers; synthesis--SRBC D Blakley et al., 1980
Mouse EAC--C 3 receptor, B cell D Koller & Brauner, 1977
Mouse Memory D Koller & Roan, in press, b
Mouse Mitogen PHA D Gaworski & Sharma, 1978
Mouse Mitogen Con A, LPS N Koller et al., 1979b
Rat Mitogen PHA, Con A D Faith et al., 1979
Mouse Mitogen LPS? Shenker et al., 1977; Gallagher
I et al., 1979
Mouse Delayed-type hypersensitivity D MOiler et al., 1977
Rat Delayed-type hypersensitivity D Faith et al., 1979
Mouse Mixed lymphocyte culture N Koller & Roan, in press
Rats Vascular clearance lipids D Cook et al., 1974
Mouse In vivo phagocytosis D Trejo et al., 1972
Rats In vivo phagocytosis D Filkins & Buchanan, 1973
Mouse In vitro phagocytosis I Koller & Roan, 1977
Rat Macrophage viability D Kaminski et al., 1977
Mouse Tumor growth--Rauscher leukemia
virus I Gainer, 1973
Rat Tumor growth--FBPA I Hinton et al., 1979
Mouse Tumor growth--MSB sarcoma I Kerkvliet et al., in press
Rat Tumor incidence--ENU I Kerkvliet, personal communication

* I = Increase; D = Decrease; N = None.

? In vitro exposure to lead.
 Immunotoxicology of Heavy Metals
study (Faith, Luster & Kimmel, 1979) in which rats
were exposed to lead pre- and postnatally, both
PHA- and Con A-induced lymphocyte responses
were diminished. Further, in vitro studies have
shown lead to possess mitogenic properties as well as
decreasing the viability of cultured lymphocytes
(Shenker, Matarazzo, Hirsch & Gray, 1977;
Gallagher, Mattarazzo & Gray, 1979). Finally,
lymphocytes co-cultured with lead and LPS showed
greater proliferation than those cultured in LPS
alone (Shenker et al., 1977).
Cell-mediated immunity (CMI) is also affected by
lead. Delayed-type hypersensitive reactions were im-
paired in mice (MUller, Gillert, Krause, Gross, Age-
Shehr & Diamantstein, 1977) and rats (Faith et al.,
1979). However, lead did not significantly alter
lymphocyte stimulation of responder cells in mixed
lymphocyte cultures (Koller & Roan, in press, b).
Specific CMI investigations must be conducted by
the use of a variety of techniques to determine if
other segments of the cellular immune system are
compromised.
Since the macrophage has an important role as an
accessory cell by cooperating with T cells in the
enhancement of the B cell response to antigens, the
effect of lead on macrophages has been investigated.
A single intravenous injection of lead depresses intra-
vascular clearance of lipids (Cook et al., 1974) and
colloidal carbon (Filkins & Buchanan, 1973) and
impairs the phagocytic ability of Kupffer cells in the
liver (Trejo et al., 1972). However, when lead was fed
to mice for 10 weeks, macrophages were actually
activated as enumerated by stimulated phagocytosis
and increased acid phosphatase levels (Koller &
Roan, 1977). The viability of pulmonary macro-
phages is reduced after lead exposure (Kaminski,
Fischer, Kennedy & Calandra, 1977).
Lead appears to promote the growth of viral and
chemical induced neoplasms. Lead enhances the
development of Rauscher leukemia virus (Gainer,
1973), MSB sarcoma (Kerkvliet, Beacher, Exon &
Koller, in press), N-(4'-fluoro-4-biphenyl) acetamide
(Hinton, Lipsky, Heatfield & Trump, 1979) and
ethylnitrosourea-induced (Kerkvliet, personal com-
munications) tumors. It is not currently known if this
phenomenon is due to immunosuppressive effects of
lead or is caused by some other mechanism.
However, the phagocytic activity of peritoneal
macrophages in the MSB sarcoma-inoculated
animals is impaired (Kerkvliet et al., in press).
In summary, lead suppresses the immune system,
particularly the humoral response in animals (Table
1). This suppression often occurs at very low sub-
clinical dosages and, therefore, may be detrimental
to the health of animals and perhaps of man by
271
mechanisms other than the typical well-documented
toxicity which occurs at larger dosages. Future
investigations are warranted further to elucidate
effects of lead on cell-mediated immunity and co-
carcinogenicity.
CADMIUM
The immunosuppressive properties of cadmium
are rather ambiguous compared to those of lead
(Table 2). Cadmium has produced a profound in-
crease in susceptibility of rats to bacterial endotoxins
(Cook et aL, 1974; Cook et al., 1975) and of mice to
infection with en~ephalomyocarditis virus (EMCV)
(Gainer, 1977) and Hexamita muris (Exon et al.,
1975). However, in two other studies (Exon, Koller &
Kerkvliet, 1979; Exon et al., in press), mice which
were exposed to cadmium acetate in drinking water
and subsequently inoculated with EMCV had re-
duced mortality compared to non-cadmium inocu-
lated mice. Cadmium also increases the resistance of
chicks to Salmonella gallinarium (Hill, 1979). These
conflicting reports could partially be accounted for
by differences in species, dosages, length of
exposure, virulence of virus, etc.
The effects of cadmium on the immune system of
laboratory animals is controversial. Cadmium in-
jected into rats seven days after an antigen will
suppress serum antibody, but when injected 14 days
prior to antigen, it will enhance antibody titer (Jones,
Williams & Jones, 1971). Chronic exposure to
cadmium produces a significant decrease in antibody
titer in rabbits (Koller, 1973) and antibody synthesis
in mice (Koller, Exon & Roan, 1975; Bozelka, Burk-
holder & Chang, 1978; Graham, Miller, Daniels,
Payne & Gardner, 1978). Recently, the memory res-
ponse was reported (Koller & Roan, in press, b) to be
actually augmented, rather than impeded, in
cadmium-exposed animals. Cadmium also inhibits
EAC rosette formation of B cells, an assessment of
the complement receptor activity (Koller & Brauner,
1977). Finally, human lymphocytes exposed in vitro
to cadmium accumulate cellular concentrations of
cadmium at a level that is 3000-fold greater than the
culture medium (Hildebrand & Cram, 1979),
Cadmium also affects macrophages. Cadmium ex-
posure promotes intravascular clearance of lipids
(Cook et al., 1974) and stimulates phagocytosis by
macrophages (Koller & Roan, 1977). Conversely,
cadmium impairs EA rosette formation of alveolar
macrophages, a measure of the Fc receptor activity
(Hadley, Gardner, Coffin & Menzel, 1977). Further,
cadmium has been demonstrated to be directly toxic
to macrophages (Loose, Silkworth & Warrington,
1978b) and depresses their phagocytic capacity
(Loose, Silkworth & Simpson, 1978a).
272 LOREN D. KOLLER
Table 2. Immune parameters of cadmium

Species Parameter Effect* References

Rat Susceptibility to S. enteriditis

endotoxin 1 Cook et al., 1974
Rats Susceptibility to E. coil I Cook et al., 1975
Mouse Susceptibility to EMC virus I Gainer, 1977
Mouse Susceptibility to EMC virus D Exon et al., 1979
Mouse Susceptibility to EMC virus D Exon et al., in press
Mouse Susceptibility to H e x a m i t a muris I Exon et al., 1975
Chick Susceptibility to S. gallinarum I-D Hill, 1979
Rats Antibody titer to gammaglobulin I-D Jones et al., 1971
Rabbits Antibody titer to virus D Koller, 1973
Mouse Antibody synthesis--SRBC D Koller et al., 1975
Mouse Antibody synthesis--SRBC I-D Koller et al., 1976
Mouse Antibody synthesis--SRBC D Bozelka et al., 1978
Mouse Antibody synthesis--SRBC D Graham et al., 1978
Mouse EAC-C 3 receptor, B cell D Koller & Brauner, 1977
Mouse Memory I Koller & Roan, in press, a
Human Lymphocyte concentration cadmium 1 Hildebrand & Cram, 1979
Rats Vascular clearance lipids 1 Cook et al., 1974
Mouse Macrophage phagocytosis I Koller & Roan, 1977
Mouse Macrophage phagocytosis D Loose et al., 1978a
Mouse Macrophage cytotoxicity I Loose et al., 1978b
Rabbit EA-Fc receptor, macrophage D Hadley et al., 1977
Mouse Mitogen--PHA, PWM D Gaworski & Sharma, 1978
Mouse Mitogen--Con A N Koller et al., 1979b
Mouse Mitogen--LPS I Koller et al., 1979b
Mouse Mixed lymphocyte culture N Koller & Roan, in press, a
Mouse Tumor growth--MSB sarcoma D Kerkvliet et al., 1979
Mouse Cytotoxic T lymphocytes I Kerkvliet et al., 1979

* I = Increase; D = Decrease; N= None.

Cell-mediated responses after cadmium exposure

vary considerably. C a d m i u m inhibits lymphocyte
transformation by mitogens P H A and P W M
(Garworski & Sharma, 1978) while having no effect
on the response to Con A and actually stimulating
the blastogenesis produced by LPS, a B cell mitogen.
To further confuse the issue, when lymphocytes ob-
tained from cadmium exposed animals are tested in
mixed lymphocyte cultures, there is no appreciable
effect (Koller & Roan, in press). Finally, cadmium
impairs growth of transplanted tumors as well as
promotes regression of those which do develop
(Kerkvliet, Koller, Beacher & Brauner, 1979). In
agreement with decreased tumor growth in v i v o , cell-
mediated cytotoxicity of tumor cells in v i t r o is en-
hanced by exposure of the animals to cadmium
(Kerkvliet et al., 1979). These data, as viewed in the
context of current information, indicate that cad-
mium can deter certain segments of the immune
system but augment others. The mechanism by which
cadmium compromises the immune system needs
further study.
MERCURY
This section will deal with both organic (methyl-
mercury) and inorganic forms of mercury. Both
inorganic (Gainer, 1977) and organic mercury
(KoUer, 1975) enhance mortality o f mice challenged
with E M C V (Table 3). Rabbits administered mer-
curic chloride in drinking water and inoculated with
pseudorabies virus have lower neutralizing antibody
titers than do controls (Koller, 1973). Similar results
were found when rabbits were exposed to methyl-
mercury and then challenge-inoculated with A / P R 8
influenza virus (Koller, Exon & Arbogast, 1977a).
Methylmercury suppresses both primary and
secondary immune responses in mice which are ex-
posed to methylmercury during embryonic develop-
ment and up to 9 weeks of age (Ohi, Fukuda, Seto &
Yagyu, 1976). When methylmercury is fed to
weanling mice, the primary immune response is signi-
ficantly decreased and the secondary response is also
somewhat impaired (Koller, Exon & Brauner, 1977b;
Blakley et al., 1980). These studies suggest that the
 Immunotoxicology of Heavy Metals 273
Table 3. Immune parameters of mercury

Species Parameter Effect* References

Mouser Susceptibility to EMC virus 1 Gainer, 1977

Mouse:~ Susceptibility to EMC virus I Koller, 1975
Rabbits~ Antibody titer to virus D Koller, 1973
Rabbits* Antibody titer to virus D Koller et al., 1977a
Mouse:~ Antibody synthesis--SRBC D Ohi et al., 1976
Mouse:~ Antibody synthesis--SRBC D Koller et al., 1977b
Mouse* Antibody titers; synthesis--SRBC D Blakley et al., 1980
Mouse* Memory response--SRBC D Koller & Roan, in press, b
Mouser Mitogen transformation--PHA,
PWM D Gaworski & Sharma, 1979
Mouse:~ In vitro phagocytosis N Koller et aL, in press
Mouse* EA-B cell, Fc receptor N Koller et al., in press
Mouse:~ EAC-B ceils, C3 receptor I Koller et al., in press
Mouse* Mixed lymphocyte reaction N Koller & Roan, in press, b
Mouse* Tumor growth, Rauscher leukemia
virus N Koller, 1975
Rat:~ Tumor latency--ENU D Nixon et al., 1979

* I = Increase, D = Decrease; N = None.

t Exposure to mercuric chloride.
* Exposure to methylmercury.

embryo or neonate may be especially susceptible to
mercury, since exposure occurs during critical
periods of development of the immune system.
Methylmercury also inhibits the antibody memory
response of lymphocytes (Koller & Roan, in press).
Mitogen studies reveal that mercuric chloride in-
hibits stimulation of lymphocytes with PHA and
PWM (Garworski & Sharma, 1978). Other studies
recently completed indicate that methylmercury does
not alter phagocytic properties of peritoneal macro-
phages or the Fc receptors on B lymphocytes (Koller,
Roan & Brauner, in press). Further, methylmercury
fails to alter the response of lymphocytes in the
mixed lymphocyte reaction (Koller & Roan, in press).
Methylmercury markedly reduces the mean latent
period for induction of ethylnitrosourea-induced
neoplasms and the mean survival time in rats (Nixon,
Koller & Exon, 1979). However, when methyl-
mercury is fed to mice which are inoculated with
Rauscher leukemia virus, the course of neoplasia is
unaltered (Koller, 1975).
The effect of methylmercury on the immune
system needs further investigation. Little informa-
tion is available concerning possible effects on T
lymphocytes and macrophages.
SELENIUM
Not all metals suppress the immune response.
Selenium is " u n i q u e " among the metals in that it
generally potentiates the immune response rather
than suppressing it (Table 4). Selenium potentiates
the protective effect of a killed P l a s m o d i u m b e r g h e i
vaccine in Swiss-Webster mice (Desowitz & Barnwell,
1980). Vitamin E and selenium deficient dogs vac-
cinated with a canine distemper infectious hepatitis
vaccine have lower antibody titers than do non-
deficient dogs (Sheffy & Schultz, 1978). Since the
interaction of vitamin E and selenium are often
necessary for maximum biological action, a recent
report (Sheffy & Schultz, 1979) of vitamin E's role on
immune response mechanisms should be reviewed by
those interested in investigating this metal.
Selenium enhances the primary immune response
and hemagglutinating titers of mice immunized with
sheep red blood cells (Spallholz, Martin, Gerlach &
Heinzerling, 1973a, b, 1975). In another study
(Koller, Kerkvliet & Exon, 1979a), selenium not only
stimulated the primary and secondary immune res-
ponse but also abrogated the depressed antibody res-
ponse produced by methylmercury when the two
chemicals were fed simultaneously to mice. Perhaps
selenium could be of therapeutic value when animals
or man are intoxicated by other chemicals.
ZINC
Zinc is an essential metal for maximum activity of
many enzymes and contributes to the development
and maintenance of the thymus. Much of the toxi-
cological studies have, therefore, dealt with the effect
of zinc deficiency on the immune response.
 274 LOREN D. KOLLER
Table 4. Immune parameters of selenium

Species Parameter Effect* References

Mouse Vaccine--Plasmodium berghei I Desowitz & Barnwell, 1980

Dog Vaccine--canine distemper I Sheffy & Schultz, 1979
Mouse Antibody titer to SRBC 1 Spallholz et al., 1973a, b
Mouse Antibody synthesis SRBC I Spallholz et al., 1975
Mouse Antibody synthesis SRBC I Koller et al., 1979a

* I = Increase.

Table 5. Immune parameters of zinc

Species Parameter Effect* References

Mouser Susceptibility to EMCV N Gainer, 1977

Chickt Susceptibility to S. gallinarium N Hill, 1979
Mousei Susceptibility to S. typhimurium I Sobocinski et al., 1977
Mouser Susceptibility to F. tulerensis and
S. pneumoniae D Sobocinski et al., 1977
Mouser Macrophage phagocytosis D Karl et al., 1973
Mouse:[: Thymus--atrophy Fraker et al., 1978
Fernandes et al., 1979
Mouse++ Antibody synthesis--SRBC D Luecke et al., 1978
Fraker et al., 1978
Fernandes et al., 1979
Mouse$ Helper T cell D Fraker et al., 1978
Mouse$ A rosettes 1 Nash et al., 1979
Mouse? $ Mitogens--PHA, Con A, LPS, SEA N Mulhern, 1980
Mouser $ Mixed lymphocyte culture N Mulhern & Vessey, personal
communication
Mouse$ Cytotoxic T lymphocytes D Fernandes et aL, 1979
Mouser Cytotoxic T lymphocytes N Mulhern & Vessey, personal
communication
Mouse$ Natural killer lymphocytes D Fernandes et al., 1979
Mouser Tumor growth--PYB6 D Mulhern, 1980

* I = Increase; D = Decrease; N = None.

? Zinc excess.
Zinc deficient.

Few studies have been conducted using diets con-
taining zinc in excess. When excessive levels of zinc
are fed to mice (Gainer, 1977) and chicks (Hill,
1979), their resistance to disease is unaltered (Table
5). However, when mice were injected intraperi-
toneally with zinc and then inoculated with S.
t y p h i m u r i u m , F. tulerensis or S. p n e u m o n i a e , en-
hanced mortality occurred in S. t y p h i m u r i u m -
challenged animals, while mortality was actually
diminished in animals inoculated with F. tulerensis or
S. p n e u m o n i a e (Sobocinski, Cantebury & Powanda,
1977). Both low and high dosages of zinc inhibit the
phagocytic capacity of mouse peritoneal macro-
phages (Karl, Chvapil & Zukoski, 1973).
Zinc deficiency results in marked atrophy of the
thymus and reduced antibody synthesis provoked by
interference of the T lymphocyte helper function
(Fraker, Haas & Luecke, 1977; Luecke, Simonel &
Fraker, 1978; Fernandes, Nair, Onoe, Tanaka, Floyd
& Good, 1979). However, nutritional repletion of
zinc in zinc-restricted animals restores thymus and T
cell-dependent antibody mediated responses (Fraker,
 Immunotoxicology of Heavy Metals
Jarkieu, Zwickl & Luecke, 1978). It has been sug-
gested that diminished levels of serum corticosterone
are responsible for the loss of immune responsiveness
in zinc deficient animals (Jardieu & Fraker, 1979).
Further, zinc deficient mice exhibit increased A
rosette formation which may be attributable to alter-
ation of thymic function (Nash, Iwata, Fernandes,
Good & Incefy, 1979). Therefore, adequate levels of
zinc must be maintained to insure proper immune
function.
Response of lymphocytes to mitogens PHA, Con
A, LPS, and SEA are essentially unaltered when
animals are fed zinc-depleted or zinc-supplemented
diets (Mulhern, 1980). Further, similar diets fail to
alter lymphocyte responses in mixed lymphocyte cul-
tures and cell-mediated lymphocyte cytotoxicity
(Chr 51) assays (Mulhern & Vessey, personal com-
munication). However, high levels of zinc (300 ppm)
decreases tumor incidence and increases the latent
period of PYB6-induced neoplasms in mice (Mul-
hern, 1980). Conversely, zinc deficient diets depress
T killer cell activity against EL-4 tumor cells and
impair natural killer cell activity in mice (Fernandes
et al., 19797. These reports indicate that considerably
more knowledge needs to be accumulated concerning
zinc-deficiency and excess before its effect on neo-
plasia can be fully assessed.
MISCELLANEOUS METALS
A recent report reviewed the effect of iron excess
and deficiency on infection and immune responses
275
(Weinberg, 1978). Briefly, to summarize from that
report, iron excess has been observed to inhibit
chemotaxis and bacterial action of leukocytes but
does not alter neutrophil ingestion of bacteria,
opsonization of bacteria by serum factors, comple-
ment fixation nor immunoglobulin synthesis. Two
other studies (Holbein, Jericho & Likes, 1979; Payne
& Finkelstein, 1978) since that review concur that
excess iron enhances disease produced by various
pathogens. However, when chicks are fed high levels
of iron, an increase in resistance to infection by S.
gallinarium occurs (Hill, 1979).
Iron deficiency in some instances may impair the
bactericidal activity of neutrophils and depresses
immunoglobulin synthesis, migratory inhibition
factor and T lymphocyte transformation (Weinberg,
1978). However, data are often conflicting; several
reports state that iron deficiency does not alter these
specific immune parameters. Nevertheless, the con-
centration of iron in body tissues does appear to
effect the pathogenesis of infectious disease.
Arsenicals (Gainer & Pry, 1972) and cobalt sulfate
(Gainer, 1972) render experimental animals more
susceptible to infectious agents (Table 6). Arsenic
also inhibits antibody titers and antibody synthesis in
mice (Blakley et al., 1980). However, when mice are
exposed to arsenic for 10 weeks and then challenged
with MSB sarcoma cells, the latent period for
development of tumors is increased and the tumor
incidence is decreased (Kerkvliet et al., in press).
Cell-mediated tumor immunity is either unaffected
or enhanced by exposure to arsenic. Therefore,

Table 6, Immune parameters of arsenic, nickel, cobalt, silica, chromium, platinum and magnesium
i

Species Metal Parameter Effect* References

i f

Mouse Arsenic Susceptibility to EMC virus I Gainer & Pry, 1972

Mouse Arsenic Tumor growth D Kerkvliet et al., in press
Mouse Arsenic Antibody titers--synthesis--
SRBC D Blakley et al., 1980
Mouse Cobalt Susceptibility to EMC virus I Gainer, 1972
Mouse Nickel Susceptibility to EMC virus I Gainer, 1977
Mouse Nickel Susceptibility to EMC virus I Exon, personal communication
Mouse Nickel Susceptibility to S. pyogenes 1 Adkins et al., 1979
Rat Nickel Antibody titer to Tl phage D Figoni & Treagan, 1975
Rabbit Nickel In vitro phagocytosis D Graham et al., 1975
Mouse Nickel In vitro phagocytosis D Karl et al., 1973
Rat Nickel In vitro phagocytosis D Chvapil et al., 1977
Mouse Silica Antibody synthesis D Miller & Zarkower, 1974
Mouse Silica Mitogen transformation--LPS D Miller & Zarkower, 1976
Rat Chromium Antibody titer to Tl phage D Figoni & Treagan, 1975
Mouse Platinum Antibody titer to SRBC D Berenbaum, 1971
Mouse Magnesiumt Antibody synthesis--SRBC D Elin, 1975

* I = Increase; D = Decrease.
1"Magnesium deficiency.
276 LOREND. KOLLER
arsenic does not appear to be detrimental to mice in
terms of tumor growth and suppression of cytotoxic
activity.
Nickel enhances infectivity of EMC virus (Gainer,
1977; Exon, personal communication) and Strepto-
coccus pyogenes (Adkins, Richards & Gardner, 1979)
in mice. Other studies report that nickel acetate de-
presses circulating antibody titers (Figoni & Treagan,
1975) to T-phages and inhibits the interferon res-
ponse of metal treated cells (Treagan & Furst, 1970).
Nickel also inhibits the phagocytic ability and other
properties of macrophages (Graham, Gardner,
Waters & Coffin, 1975). Delay in the development of
delayed hypersensitivity reactions occur in guinea
pigs that are exposed to nickel (Parker & Turk,
1978).
One of the lighter metals, silica dioxide (Miller &
Zarkower, 1974) has been reported to depress anti-
body synthesis (Zarkower & Morges, 1972) and to
impair T lymphocyte stimulation by Con A. Silica
dioxide also inhibits the response of B lymphocytes
to LPS (Miller & Zarkower, 1976), and impairs the
phagocytic ability of macrophages. Some other
metals, including cobalt (Derkach & Burmakina,
1970), chromium (Figoni & Treagan, 1975) and
platinum (Berenbaum, 1971) have been reported to
suppress the immune response. Magnesium defi-
ciency also appears to have profound immuno-
suppressive capabilities (Elin, 1975).
CONCLUSIONS
It has been well documented that many of the
metals compromise the immune system of experi-
mental animals. Damage may occur to a particular
cell (B, T, or macrophage) or may involve more than
one cell which regulates the proliferation and differ-
entiation of other cells responsible for normal
function of the immune system. Preliminary studies
are often necessary to ascertain if the chemicals
actually alter antibody response to a particular anti-
gen. Once that fact is established, then the B and T
lymphocyte, as well as the macrophage, must be
examined individually and collectively to determine
the mechanism by which the suppression occurs.
Many of the metals, and particularly various com-
binations of metals, need to be investigated in greater
detail due to their abundance in the environment.
From data which has been accumulated, lead
appears to consistently suppress most of the segments
of the immune system while cadmium has produced
mixed reactions. Mercury suppresses the primary
humorai immune response while selenium enhances
humoral immunity. Zinc deficiency results in atrophy
of the thymus with subsequent reduction in the
humoral immune capacity. Nickel deters many seg-
ments of the immune response. Many of the other
metals also compromise various parts of the immune
system.
This review is certainly not complete but has com-
piled considerable data to document the adverse
effects of metals on the immune response of experi-
mental animals. Many of these immunosuppressive
features are unaccompanied by clinical signs of
disease. Therefore, it is apparent that many metals
are detrimental to health by mechanisms other than
direct toxicity. A chemical that impairs or destroys
any portion of the immune system usually limits the
defense mechanism of a host to infectious agents,
thereby potentiating pathogenicity of that organism.
A host that is rendered increasingly susceptible to an
infectious agent is likely to develop complications or
succumb to what normally would be a nonfatal
condition.

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