Int. J. lmmunopharmac., Vol. 2, pp. 269-279 © 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 collected often does not consider the entire immune response 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 compounds. Finally, many immunoassays have a relatively 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 techniques which determine the effect of the compounds on the function of B and T lymphocytes, macrophages, 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 involvement, since T cells, such as helper, suppressor, or cytotoxic functional subclasses, may be affected individually 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. Knowledge recently acquired for some of the heavy metals will be discussed in the following sections.
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 characterized, alteration of the reticuloendothelial system and hepatic function has been predicted (Trejo et al., 1972). Further, there is substantial evidence to suggest 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 immunization 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 pseudorabies virus (Koller, 1973). Further, lead impairs antibody synthesis in both rats (Luster, Faith & 269
LOREN D. KOLLER
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 transformation of normal lymphocytes. Concanavalin A Table 1.
Immune parameters of lead
Susceptibility to E. coli endotoxin Susceptibility to S. t y p h i m u r i u m endotoxin Susceptibility to S. enteriditis endotoxin Susceptibility to S. t y p h i m u r i u m Susceptibility to E. coli Susceptibility to EMC virus Susceptibility to Langet virus Susceptibility to EMC virus Clearance of Serratia marcescens Antibody titer to virus Antibody synthesis--SRBC Antibody synthesis--SRBC Antibody synthesis--SRBC Antibody titers; synthesis--SRBC EAC--C 3 receptor, B cell Memory Mitogen PHA Mitogen Con A, LPS Mitogen PHA, Con A Mitogen LPS?
Rats Mouse Rats Mouse Mouse Mouse Mouse Rabbit Mouse Mouse Rats Mouse Mouse Mouse Mouse Mouse Rat Mouse
(Con A) and phytohemagglutinin ( P H A ) activate T lymphocytes whereas lipopolysaccharide (LPS) stimulates 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 cellmediated immune responses, while interference of LPS blastogenesis may indicate humoral involvement. 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
Selye et al., 1966
Rippe & Berry, 1973
I I I I 1 I
Cook et al., 1974 Hemphill et al., 1971 Cook et al., 1975 Gainer, 1977 Thind et al., 1977 Exon et al., 1979
D D D D D D D D N D
D D N D D D I D
Koller, 1973 Koller & Kovacic, 1974 Koller et al., 1976 Luster et al., 1978 Blakley et al., 1980 Koller & Brauner, 1977 Koller & Roan, in press, b Gaworski & Sharma, 1978 Koller et al., 1979b Faith et al., 1979 Shenker et al., 1977; Gallagher et al., 1979 MOiler et al., 1977 Faith et al., 1979 Koller & Roan, in press Cook et al., 1974 Trejo et al., 1972 Filkins & Buchanan, 1973 Koller & Roan, 1977 Kaminski et al., 1977
I I I I
Gainer, 1973 Hinton et al., 1979 Kerkvliet et al., in press Kerkvliet, personal communication
Mouse Rat Mouse Rats Mouse Rats Mouse Rat Mouse Rat Mouse Rat
Delayed-type hypersensitivity Delayed-type hypersensitivity Mixed lymphocyte culture Vascular clearance lipids In vivo phagocytosis In vivo phagocytosis In vitro phagocytosis Macrophage viability Tumor growth--Rauscher leukemia virus Tumor growth--FBPA Tumor growth--MSB sarcoma Tumor incidence--ENU
* 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 impaired in mice (MUller, Gillert, Krause, Gross, AgeShehr & 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 intravascular 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 macrophages 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 communications) 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 subclinical dosages and, therefore, may be detrimental to the health of animals and perhaps of man by
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 cocarcinogenicity. CADMIUM
The immunosuppressive properties of cadmium are rather ambiguous compared to those of lead (Table 2). Cadmium has produced a profound increase 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 reduced mortality compared to non-cadmium inoculated 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 injected 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, Burkholder & Chang, 1978; Graham, Miller, Daniels, Payne & Gardner, 1978). Recently, the memory response 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 exposure 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).
LOREN D. KOLLER Table 2.
Immune parameters of cadmium
Susceptibility to S. enteriditis endotoxin Susceptibility to E. coil Susceptibility to EMC virus Susceptibility to EMC virus Susceptibility to EMC virus Susceptibility to H e x a m i t a muris Susceptibility to S. gallinarum Antibody titer to gammaglobulin Antibody titer to virus Antibody synthesis--SRBC Antibody synthesis--SRBC Antibody synthesis--SRBC Antibody synthesis--SRBC EAC-C 3 receptor, B cell Memory Lymphocyte concentration cadmium Vascular clearance lipids Macrophage phagocytosis Macrophage phagocytosis Macrophage cytotoxicity EA-Fc receptor, macrophage Mitogen--PHA, PWM Mitogen--Con A Mitogen--LPS Mixed lymphocyte culture Tumor growth--MSB sarcoma Cytotoxic T lymphocytes
Rats Mouse Mouse Mouse Mouse Chick Rats Rabbits Mouse Mouse Mouse Mouse Mouse Mouse Human Rats Mouse Mouse Mouse Rabbit Mouse Mouse Mouse Mouse Mouse Mouse
1 I I D D I I-D I-D D D I-D D D D I 1 1 I D I D D N I N D I
Cook et al., 1974 Cook et al., 1975 Gainer, 1977 Exon et al., 1979 Exon et al., in press Exon et al., 1975 Hill, 1979 Jones et al., 1971 Koller, 1973 Koller et al., 1975 Koller et al., 1976 Bozelka et al., 1978 Graham et al., 1978 Koller & Brauner, 1977 Koller & Roan, in press, a Hildebrand & Cram, 1979 Cook et al., 1974 Koller & Roan, 1977 Loose et al., 1978a Loose et al., 1978b Hadley et al., 1977 Gaworski & Sharma, 1978 Koller et al., 1979b Koller et al., 1979b Koller & Roan, in press, a Kerkvliet et al., 1979 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 obtained 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 , cellmediated cytotoxicity of tumor cells in v i t r o is enhanced by exposure of the animals to cadmium (Kerkvliet et al., 1979). These data, as viewed in the context of current information, indicate that cadmium 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 (methylmercury) 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 mercuric 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 methylmercury 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 exposed to methylmercury during embryonic development and up to 9 weeks of age (Ohi, Fukuda, Seto & Yagyu, 1976). When methylmercury is fed to weanling mice, the primary immune response is significantly 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
Table 3. Immune parameters of mercury Species
Mouser Mouse:~ Rabbits~ Rabbits* Mouse:~ Mouse:~ Mouse* Mouse* Mouser
Susceptibility to EMC virus Susceptibility to EMC virus Antibody titer to virus Antibody titer to virus Antibody synthesis--SRBC Antibody synthesis--SRBC Antibody titers; synthesis--SRBC Memory response--SRBC Mitogen transformation--PHA, PWM In vitro phagocytosis EA-B cell, Fc receptor EAC-B ceils, C3 receptor Mixed lymphocyte reaction Tumor growth, Rauscher leukemia virus Tumor latency--ENU
Mouse:~ Mouse* Mouse:~ Mouse* Mouse* Rat:~
1 I D D D D D D
Gainer, 1977 Koller, 1975 Koller, 1973 Koller et al., 1977a Ohi et al., 1976 Koller et al., 1977b Blakley et al., 1980 Koller & Roan, in press, b
D N N I N
Gaworski & Sharma, 1979 Koller et aL, in press Koller et al., in press Koller et al., in press Koller & Roan, in press, b
Koller, 1975 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 inhibits stimulation of lymphocytes with PHA and PWM (Garworski & Sharma, 1978). Other studies recently completed indicate that methylmercury does not alter phagocytic properties of peritoneal macrophages 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 methylmercury 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 information 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 vaccinated with a canine distemper infectious hepatitis vaccine have lower antibody titers than do nondeficient 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 response but also abrogated the depressed antibody response 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 toxicological studies have, therefore, dealt with the effect of zinc deficiency on the immune response.
LOREN D. KOLLER Table 4.
Immune parameters of selenium
Mouse Dog Mouse Mouse Mouse
Vaccine--canine distemper Antibody titer to SRBC Antibody synthesis SRBC Antibody synthesis SRBC
I 1 I I
Desowitz & Barnwell, 1980 Sheffy & Schultz, 1979 Spallholz et al., 1973a, b Spallholz et al., 1975 Koller et al., 1979a
* I = Increase.
Immune parameters of zinc
Mouser Chickt Mousei Mouser
Susceptibility to Susceptibility to Susceptibility to Susceptibility to
Macrophage phagocytosis Thymus--atrophy
Mouse$ Mouse$ Mouse? $ Mouser $
Helper T cell A rosettes Mitogens--PHA, Con A, LPS, SEA Mixed lymphocyte culture
D 1 N N
Cytotoxic T lymphocytes Cytotoxic T lymphocytes
Natural killer lymphocytes Tumor growth--PYB6
S. gallinarium S. typhimurium F. tulerensis and
Gainer, 1977 Hill, 1979 Sobocinski et al., 1977 Sobocinski et al., 1977 Karl et al., 1973 Fraker et al., 1978 Fernandes et al., 1979 Luecke et al., 1978 Fraker et al., 1978 Fernandes et al., 1979 Fraker et al., 1978 Nash et al., 1979 Mulhern, 1980 Mulhern & Vessey, personal communication Fernandes et aL, 1979 Mulhern & Vessey, personal communication Fernandes et al., 1979 Mulhern, 1980
* I = Increase; D = Decrease; N = None. ? Zinc excess. Zinc deficient. Few studies have been conducted using diets containing 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 intraperitoneally 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 , enhanced 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 macrophages (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 suggested 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 alteration 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 cultures and cell-mediated lymphocyte cytotoxicity (Chr 51) assays (Mulhern & Vessey, personal communication). However, high levels of zinc (300 ppm) decreases tumor incidence and increases the latent period of PYB6-induced neoplasms in mice (Mulhern, 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 neoplasia can be fully assessed. MISCELLANEOUS METALS A recent report reviewed the effect of iron excess and deficiency on infection and immune responses
(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, complement 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 concentration 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
Mouse Mouse Mouse
Arsenic Arsenic Arsenic
Mouse Mouse Mouse Mouse Rat Rabbit Mouse Rat Mouse Mouse Rat Mouse Mouse
Cobalt Nickel Nickel Nickel Nickel Nickel Nickel Nickel Silica Silica Chromium Platinum Magnesiumt
* I = Increase; D = Decrease. 1"Magnesium deficiency.
Susceptibility to EMC virus Tumor growth Antibody titers--synthesis-SRBC Susceptibility to EMC virus Susceptibility to EMC virus Susceptibility to EMC virus Susceptibility to S. pyogenes Antibody titer to Tl phage In vitro phagocytosis In vitro phagocytosis In vitro phagocytosis Antibody synthesis Mitogen transformation--LPS Antibody titer to Tl phage Antibody titer to SRBC Antibody synthesis--SRBC
Gainer & Pry, 1972 Kerkvliet et al., in press
D I I I
Blakley et al., 1980 Gainer, 1972 Gainer, 1977 Exon, personal communication Adkins et al., 1979 Figoni & Treagan, 1975 Graham et al., 1975 Karl et al., 1973 Chvapil et al., 1977 Miller & Zarkower, 1974 Miller & Zarkower, 1976 Figoni & Treagan, 1975 Berenbaum, 1971 Elin, 1975
D D D D D D D D D
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 Streptococcus pyogenes (Adkins, Richards & Gardner, 1979) in mice. Other studies report that nickel acetate depresses circulating antibody titers (Figoni & Treagan, 1975) to T-phages and inhibits the interferon response 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 antibody 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 deficiency also appears to have profound immunosuppressive capabilities (Elin, 1975). CONCLUSIONS It has been well documented that many of the metals compromise the immune system of experimental 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 antigen. 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 combinations 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 segments 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 compiled considerable data to document the adverse effects of metals on the immune response of experimental 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.
ADKINS, B., RICHARDS, J. H. & GARDNER, D. E. (1979). Enhancement of experimental respiratory infection following nickel inhalation. Envir. Res., 20, 33--42. BERENBAUM, M. C. (1971). Immunosuppression by platinum diamines. Br. J. Cancer, 25, 208. BLAKLEY,B. R., SISODIA,C. S. & MUKKUR,T. K. (1980). The effect of methylmercury, tetraethyl lead and sodium arsenite on the humoral immune response in mice. Toxic. appl. Pharmac., 52,245-254. BOZELKA, B. E., BURKHOLDER,P. M. & CHANG, L. W. (1978). Cadmium, a metallic inhibitor of antibody-mediated immunity in mice. Envir. Res., 17, 390. CHVAPIL, M., STANKOVA,L., BERNHARD,D. S., WEEDY,P. L., CARLSON,E. C. & CAMPBELL,J. B. (1977). Effect of Zinc on peritoneal macrophages in vitro. Infec. Imm., 16, 367-373. CooK, J. A., HOFFMAN,E. O. & DILUZtO, N. R. (1975). Influence of lead and cadmium on the susceptibility of rats to bacterial challenge. Proc. soc. exp. Biol. Med., 150, 741. CooK, J. A., MARCONI,E. A. & DILuzIo, N. R. (1974). Lead, cadmium, endotoxin interaction: Effect on mortality and hepatic function. Toxic. appl. Pharmac., 28, 292. DEBRUIN, A. (1971). Certain biological effects of lead upon the animal organisms. Archs. envir. Hlth., 23, 249. DERKACH, V. V. & BURMAKINA,L. 1. (1970). The influence of cobalt on precipitin formation and development of the Arthus phenomenon. Zh. MikrobioL Epidem. Immunobiol., 47, 59--62.
Immunotoxicology of Heavy Metals
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