- Email: [email protected]
Cadmium carcinogenesis in review
www.elsevier.nl/locate/jinorgbio Journal of Inorganic Biochemistry 79 (2000) 241–244
Cadmium carcinogenesis in review Michael P. Waalkes * Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27706, USA Received 15 July 1999; received in revised form 17 December 1999; accepted 22 December 1999
Abstract Cadmium is an inorganic toxicant of great environmental and occupational concern which was classified as a human carcinogen in 1993. Occupational cadmium exposure is associated with lung cancer in humans. Cadmium exposure has also, on occasion, been linked to human prostate cancer. The epidemiological data linking cadmium and pulmonary cancer are much stronger than for prostatic cancer. Other target sites for cadmium carcinogenesis in humans (liver, kidney, stomach) are considered equivocal. In rodents, cadmium causes tumors at several sites and by various routes. Cadmium inhalation in rats results in pulmonary adenocarcinomas, supporting a role in human lung cancer. Prostate tumors and preneoplastic proliferative lesions can be induced in rats after cadmium ingestion or injection. Prostatic carcinogenesis in rats occurs only at cadmium doses below those that induce chronic degeneration and dysfunction of the testes, a well-known effect of cadmium, confirming the androgen dependency of prostate tumors. Other targets of cadmium in rodents include the testes, adrenals, injection sites, and hematopoietic system. Various treatments can modify cadmium carcinogenesis including supplemental zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumors. Cadmium is poorly mutagenic and probably acts through indirect mechanisms, although the precise mechanisms remain unknown. q2000 Elsevier Science Inc. All rights reserved. Keywords: Cadmium; Carcinogenesis; Humans; Rodents; Zinc
1. Introduction Cadmium is a toxic transition (‘heavy’) metal of continuing occupational and environmental concern with a wide variety of adverse effects [1]. Cadmium has an extremely long biological half-life that essentially makes it a cumulative toxin [1]. To date there are no proven effective treatments for chronic cadmium intoxication [1]. Cadmium accumulates primarily in the liver and kidney where it is bound to metallothionein (MT), a low molecular weight metal binding protein thought to detoxify the metal through high affinity sequestration [1]. The toxic effects of cadmium often stem from interference with various zinc mediated metabolic processes, and zinc treatments frequently reduce or abolish the adverse effects of cadmium [1]. There are several sources of human exposure to cadmium, including employment in primary metal industries and consumption of tobacco products [2]. Cadmium has been designated a human carcinogen by the International Agency for Research on Cancer and the US National Toxicology Program [2,3] and is clearly a potent, * Tel.: q1-919-541-2328; fax: q1-919-541-3970; e-mail: waalkes@ niehs.nih.gov
multi-tissue animal carcinogen [4,5]. Occupational exposure to cadmium is associated with lung cancers in humans, while other sites, potentially including the prostate, are not definitively established [2–5]. Rodent studies have shown that chronic inhalation of cadmium causes pulmonary adenocarcinomas [4–6], in clear support of human data [2,3]. Cadmium can also cause prostatic proliferative lesions, including adenocarcinomas, after systemic or direct exposure [7–10]. Other target tissues of cadmium carcinogenesis in animals include injection sites, adrenals, testes, and the hemopoietic system [2–5,8]. Certain treatments modify cadmium carcinogenicity, including administration of zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumor formation [10]. Diets deficient in zinc increase the progression of testicular tumors [11] but reduce the progression of prostatic tumors [8]. There are definite species and strain-related differences in sensitivity to cadmium carcinogenicity. The potential mechanism or mechanisms of cadmium carcinogenesis are unknown but may well involve non-genotoxic or indirectly genotoxic events since cadmium is, in general, a poor mutagen [5]. Such events could include enhanced proliferation, depressed apoptosis, and/or altered DNA repair.
0162-0134/00/$ - see front matter q2000 Elsevier Science Inc. All rights reserved. PII S 0 1 6 2 - 0 1 3 4 ( 0 0 ) 0 0 0 0 9 - X
Friday Apr 07 11:00 AM
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
242
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
2. Cadmium metabolism Cadmium metabolism has several unique facets [1,12] and absorption of cadmium shows marked route dependency. Only about 5% of a given dose of cadmium is absorbed from the gastrointestinal tract while cadmium absorption from the lung is very high, with as much as 90% of a dose deposited in the deep lung being absorbed. Once absorbed, cadmium is rapidly cleared from the blood and concentrates in various tissues. Cadmium in the liver and kidney usually make up the bulk of the total body burden [1,12,13]. Hepatic and renal accumulation may be due to the ability of these organs to produce large amounts of MT, a metal binding protein with high affinity for cadmium [13]. The presence of cellular MT will markedly decrease the adverse effects of cadmium [13]. However, probably as a consequence of binding to MT, cadmium is very slowly eliminated from the body. This long residence time could enhance the probability of neoplastic transformation by cadmium.
3. Cadmium carcinogenesis in humans The International Agency for Research on Cancer and the US National Toxicology Program [2,3] have both concluded that there is adequate evidence that cadmium is a human carcinogen. This designation as a human carcinogen was prompted primarily by repeated findings of an association between occupational cadmium exposure and lung cancer, as well as very strong rodent data which included the pulmonary system as a target site [2,3]. Thus, the lung is the most definitively established site of human carcinogenesis from cadmium exposure. In some studies, occupational or environmental cadmium exposure has also been associated with development of cancers of the prostate, kidney, liver, hematopoietic system and stomach [2–5]. The linkage of cadmium exposure with human neoplasia of any specific site other than the lung has, however, not been absolutely established. Clearly, further epidemiological and experimental work is necessary to determine the target sites and nature of the carcinogenic risk from cadmium exposure to humans.
4. Cadmium carcinogenesis in animals The earliest suspicion that cadmium might be carcinogenic in rodents came from the 1961 study of Haddow et al. [14] who gave either subcutaneous (sc) or intramuscular (im) injections of ferritin which had been prepared from rat liver by cadmium precipitation. They subsequently found malignant tumors at the site of injection in rats and mice [14]. It was unclear at that time if cadmium was the carcinogenic agent, but it was suspected [14]. These results prompted further investigations and cadmium now has been established as a potent rodent carcinogen for over 35 years. The carcin-
Friday Apr 07 11:00 AM
ogenic potential of cadmium was first shown at repositorytype injection sites, such as im or sc, where it forms sarcomas at high incidence [2–5]. Early studies also showed cadmium to be an effective testicular tumorigen, with a single exposure producing a high incidence of testicular interstitial cell tumors [2–5]. Several studies have established that inhaled cadmium is a potent pulmonary carcinogen in the rat, supporting its potential as a human lung carcinogen [2,3]. In the initial study, rats that were chronically exposed by inhalation to cadmium chloride aerosols showed dose-related increases in pulmonary carcinoma incidence to a maximum of over 70% [6]. Several other forms of cadmium, including cadmium oxide, have subsequently been established as pulmonary carcinogens in rats after inhalation [2,3]. In contrast to the activity in rat lung, inhaled cadmium is not an effective pulmonary carcinogen in the mouse or hamster [2–5]. Pulmonary tumors can be induced by sc cadmium exposure in at least one strain of mice [15]. Prostatic cancer is an important and deadly human malignant disease of essentially undefined etiology. Several studies in rats indicate that cadmium can induce tumors and preneoplastic lesions of the prostate in rats [1–5,7–10]. The ability of cadmium to induce prostate cancer is atypically dosedependent and depends on the effects of the metal on the testes. An analysis of the carcinogenicity of a single sc injection of cadmium in rats over two years using a wide range of doses showed that prostatic tumor incidence was elevated only at doses of cadmium below the threshold for significant testicular toxicity (;5.0 mmol Cd/kg), but the response was lost at higher doses [9]. At these lower doses, dose-related increases in prostatic tumors occurred [9]. Testicular androgen production is essential for the growth and maintenance of the prostate and prostate tumors are often testosterone dependent [16,17]. In rodents testosterone alone will increase the incidence of prostatic carcinoma [17]. The toxic effects of high dose cadmium (G5.0 mmol Cd/kg, sc) on the rodent testes can results in a drop up to 80% in circulating testosterone which, in turn, induces marked prostatic atrophy [18]. Such atrophy would likely counter any proliferative stimulus. Thus, the testicular toxicity of cadmium probably is responsible for the lack of prostatic tumorigenicity at cadmium doses resulting in overt testicular toxicity. Oral cadmium exposure can also induce proliferative lesions in the rat prostate [11] while direct injection of cadmium into the rat prostate will produce prostatic adenocarcinomas [7]. Cadmium treatment can also enhance the appearance of chemically induced prostatic tumors in rats [19]. The finding of prostatic tumors in cadmium-treated rats by a variety of routes supports, but does not establish, a possible causative role in human prostate cancer. The rat testes are also extremely sensitive to cadmiuminduced tumorigenesis. Cadmium, when given at sufficiently high parenteral doses, rapidly induces severe testicular hemorrhagic necrosis [1]. After the initial toxic lesion, a high incidence of testicular interstitial cell tumors is observed [2–
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
5]. Oral cadmium exposure can also result in interstitial cell tumors in the rat testes [8]. The development of testicular tumors in rats is thought to be related to the chronic degenerative effects of cadmium in this tissue, which results in loss of androgen production, and a subsequent overstimulation of remnant testicular cells by the pituitary [18]. Malignant tumors develop at the site of sc or im injections of cadmium in rats and mice [2–5,14] but not hamsters [21]. The tumors produced at these sites are typically fibrosarcomas [2–5,14]. Cadmium-induced injection site sarcomas appear to be strictly related to accumulated dosage at the site [2–5]. The formation of injection site sarcomas is a common occurrence with many metals [20]. The strain of rodents has a pronounced effect on the incidence of cadmium-induced injection site sarcomas, indicating a genetic basis for sensitivity to these tumors [2–5]. In rats, oral cadmium can induce dose-related increases in the incidence of leukemia [8]. Dose-related increases in lymphoma have been shown to be induced by sc injections of cadmium in certain strains of mice [15,22,23]. When cadmium is given sc concurrently with calcium, an elevated incidence of islet cell tumors of the rat pancreas has been shown [2–5]. Induction of tumors of the adrenals has been reported with sc cadmium treatment in hamsters and the incidence of proliferative lesions of the adrenal cortex approached 55% in these animals [23]. The incidence of adrenal tumors can also be increased by sc injections of cadmium in mice [24].
5. Modification of the carcinogenic response to cadmium in rodents; some mechanistic considerations Zinc can have an important impact on cadmium carcinogenesis. In several tissues, including the lung, testes, and at the injection site, zinc treatments reduce cadmium carcinogenesis [2–5]. In this regard calcium and magnesium are relatively ineffective in reducing the carcinogenic effects of cadmium compared to zinc [2–5]. This selective antagonism by zinc of the carcinogenic effects of cadmium at so many different target sites could point to a basic mechanism of cadmium carcinogenesis. Cadmium often competes with zinc for a variety of important binding sites in cells, including sites potentially important in gene regulation or enzyme activity [1]. Zinc can induce the synthesis of the metal-binding protein, MT, which reduces many of the adverse effects of cadmium [13]. Cadmium can also induce MT and thereby induces self-tolerance [13]. The induction of MT could be an important aspect of reduced cadmium carcinogenesis by zinc. This could also be a key element in differential species sensitivity to cadmium carcinogenesis. For instance, cadmium is an effective pulmonary carcinogen after inhalation only in the rat, while inhaled cadmium is not carcinogenic in the lungs of mice [2–5]. The acute toxicity of inhaled cadmium in the lung shows similar species differences, being more severe in
Friday Apr 07 11:00 AM
243
the rat compared to mice [25,26]. Both the differences in acute toxicity and chronic carcinogenicity may be due to a higher production of MT in the lungs of mice than rats [26]. In contrast to inhibition in some tissues, zinc can facilitate cadmium-induced tumor production in the prostate, probably through prevention of testicular toxicity and the consequent maintenance of androgen support [10]. Furthermore, dietary zinc deficiency diminishes the carcinogenic potential of cadmium in the prostate probably because zinc deficiency induces atrophy of the prostate secondary to a reduction in testicular androgen secretion [8]. A diet deficient in zinc will, however, enhance the progression of testicular proliferative lesions and increase the incidence of injection site sarcomas induced by cadmium [11]. Thus, zinc can either facilitate or inhibit cadmium carcinogenesis depending on the tissue and circumstances.
6. Possible mechanisms in cadmium carcinogenesis Although cadmium can produce genotoxic and mutagenic events, these generally require high doses [4,5,27]. Cadmium will not form stable DNA adducts and, since cadmium is not a redox active metal, indirect oxidative DNA damage is unlikely as a primary carcinogenic mechanism. Thus, epigenetic non-genotoxic or indirect genotoxic mechanisms may apply. Such mechanisms could include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Both these potential mechanisms could result in carcinogenic transformation in the absence of cadmiuminduced genetic damage. Alternatively, cadmium can inhibit repair of DNA [28] which could be an indirect source of mutational events. Together with upregulation of mitogenic signaling, perturbed DNA repair and the resulting indirect genotoxicity could be key events in carcinogenesis [29]. Cadmium can clearly activate transcription factors that normally require zinc, such as with the MT gene [1,13]. Furthermore, cadmium can activate some proto-oncogenes or genes associated with cell proliferation, such as c-myc or c-jun, in cells and in animals [30,31]. This activation could enhance proliferation in a cell population and, assuming a basal level of cells with chemically or spontaneously damaged DNA, this could enhance the colonal expansion of such damaged cells. The suppression of DNA repair by cadmium [28] would potentially add to the population of cells with damaged DNA. Thus, enhanced cellular proliferation rates could help fix in place genetic errors that would otherwise be recognized and repaired or cause cellular elimination. Similarly, apoptotic cell death is an ongoing, normal event in the control of cell populations and will cause elimination of cells with damaged genetic material. In this regard chemically induced apoptosis can be very effectively blocked by cadmium [32]. This hindered apoptosis could presumably facilitate aberrant cell accumulation, allowing cells to survive that would otherwise not pass apoptotic checkpoints. This may be a critical step in the pathogenesis of cadmium-induced
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
244
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
malignancies. Thus for cadmium, disorders of cell accumulation, including enhanced proliferation and disrupted apoptosis, may be crucial events in carcinogenesis.
7. Summary and conclusions The carcinogenic potential of cadmium is clearly established in humans and experimental animals. Further efforts are warranted in the epidemiology of cadmium in order to determine more precisely the risks and target sites in humans. The mechanisms of cadmium carcinogenesis remain unknown. However, the mechanisms appear to be related in some undefined way to zinc metabolism because of the pronounced effects that zinc can have on cadmium carcinogenesis in many experimental systems. As yet there is no consensus on the molecular events associated with cadmiuminduced malignant transformation but, since this metal is not strongly genotoxic, non-genotoxic and or indirectly genotoxic mechanisms may apply. Such mechanisms could include altered cell proliferation or blocked apoptosis, which could result in cell transformation in the absence of cadmiuminduced genetic damage. Thus, with cadmium, disruption of cell accumulation, perhaps due to enhanced proliferation and blocked apoptosis, may be a crucial event in carcinogenesis. Alternatively, cadmium-induced disruption of DNA repair, in combination with enhanced proliferation, could lead to tumor formation. Further research is required to define the mechanism of cadmium carcinogenesis.
8. Abbreviations MT sc im
metallothionein subcutaneous intramuscular
References [1] P.L. Goering, M.P. Waalkes, C.D. Klaassen, in: R.A. Goyer, M.G. Cherian (Eds.), Handbook of Experimental Pharmacology, vol. 115, Toxicology of Metals, Biochemical Effects, Springer, New York, 1994, pp. 189–214. [2] International Agency for Research on Cancer Monographs, vol. 58, Cadmium, IARC Press, Lyon, 1993, pp. 119–238.
Friday Apr 07 11:00 AM
[3] Ninth Report on Carcinogens, National Toxicology Program, Research Triangle Park, NC, in press. [4] M.P. Waalkes, in: G. Berthan (Ed.), Handbook on Metal–Ligand Interactions of Biological Fluids, vol. 2, Marcel Dekker, New York, 1995, pp. 471–482. [5] M.P. Waalkes, R.R. Misra, in: L.W. Chang (Ed.), Toxicology of Metals, CRC Press, Boca Raton, FL, 1996, pp. 231–244. ¨ ¨ [6] S. Takenaka, H. Oldiges, H. Konig, D. Hochrainer, G. Oberdorster, J. Natl. Cancer Inst. 70 (1983) 367. ¨ P. Gase, C. [7] L. Hoffmann, H.P. Putzke, H.J. Kampehl, R. Russbult, Simonn, T. Erdmann, C. Huckstorf, J. Cancer Res. Clin. Oncol. 109 (1985) 193. [8] M.P. Waalkes, S. Rehm, Fundam. Appl. Toxicol. 19 (1992) 512. [9] M.P. Waalkes, S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, J.R. Henneman, M.S. Balaschak, Cancer Res. 48 (1988) 4656. [10] M.P. Waalkes, S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, J.R. Henneman, Cancer Res. 49 (1989) 4282. [11] M.P. Waalkes, R. Kovatch, S. Rehm, Toxicol. Appl. Pharmacol. 108 (1991) 448. [12] C.D. Klaassen, Fundam. Appl. Toxicol. 1 (1981) 353. [13] C.D. Klaassen, J. Liu, S. Choudhuri, Annu. Rev. Pharmacol. Toxicol. 39 (1999) 267. [14] A. Haddow, C.E. Dukes, B.C.V. Mitchley, Annu. Rep. Br. Empire Cancer Campaign 37 (1961) 74. [15] M.P. Waalkes, S. Rehm, Fundam. Appl. Toxicol. 23 (1994) 21. [16] D.S. Coffey, J.T. Isaacs, Urology 3 (1981) 17. [17] R.L. Nobel, Cancer Res. 37 (1977) 1929. [18] M.P. Waalkes, S. Rehm, D.E. Devor, Toxicol. Appl. Pharmacol. 142 (1997) 50. [19] T. Shirai, S. Iwasaki, T. Masui, T. Mori, T. Kato, N. Ito, Jpn. J. Cancer Res. 84 (1993) 1023. [20] M.P. Waalkes, in: R.A. Goyer, C.D. Klaassen, M.P. Waalkes (Eds.), Metal Toxicology, Academic Press, San Diego, 1995, p. 47. [21] M.P. Waalkes, S. Rehm, Toxicology 126 (1998) 173. [22] M.P. Waalkes, S. Rehm, Toxic Subst. J. 13 (1994) 97. [23] M.P. Waalkes, S. Rehm, B. Sass, R. Kovatch, J.M. Ward, Toxic. Subst. J. 13 (1994) 15. [24] M.P. Waalkes, S. Rehm, Toxic Subst. Mech. 14 (1995) 79. [25] I.M. McKenna, M.P. Waalkes, L.C. Chen, T. Gordon, Toxicol. Appl. Pharmacol. 146 (1997) 196. [26] I.M. McKenna, T. Gordon, L.C. Chen, M.R. Anver, M.P. Waalkes, Toxicol. Appl. Pharmacol. 153 (1998) 169. [27] R.R. Misra, G.T. Smith, M.P. Waalkes, Toxicology 126 (1998) 103. [28] A. Hartwig, Toxicol. Lett. 102–103 (1998) 235. [29] D. Beyersman, S. Hechtenberg, Toxicol. Appl. Pharmacol. 144 (1997) 247. [30] M.K. Abshire, G.S. Buzard, N. Shiraishi, M.P. Waalkes, J. Toxicol. Environ. Health 48 (1996) 359. [31] H. Zheng, J. Liu, K.H. Choo, A.E. Michalska, C.D. Klaassen, Toxicol. Appl. Pharmacol. 136 (1996) 229. [32] H. Shimada, Y.-H. Shiao, M.A. Shibata, M.P. Waalkes, J. Toxicol. Environ. Health 54 (1998) 159.
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
Cadmium carcinogenesis in review Michael P. Waalkes * Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27706, USA Received 15 July 1999; received in revised form 17 December 1999; accepted 22 December 1999
Abstract Cadmium is an inorganic toxicant of great environmental and occupational concern which was classified as a human carcinogen in 1993. Occupational cadmium exposure is associated with lung cancer in humans. Cadmium exposure has also, on occasion, been linked to human prostate cancer. The epidemiological data linking cadmium and pulmonary cancer are much stronger than for prostatic cancer. Other target sites for cadmium carcinogenesis in humans (liver, kidney, stomach) are considered equivocal. In rodents, cadmium causes tumors at several sites and by various routes. Cadmium inhalation in rats results in pulmonary adenocarcinomas, supporting a role in human lung cancer. Prostate tumors and preneoplastic proliferative lesions can be induced in rats after cadmium ingestion or injection. Prostatic carcinogenesis in rats occurs only at cadmium doses below those that induce chronic degeneration and dysfunction of the testes, a well-known effect of cadmium, confirming the androgen dependency of prostate tumors. Other targets of cadmium in rodents include the testes, adrenals, injection sites, and hematopoietic system. Various treatments can modify cadmium carcinogenesis including supplemental zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumors. Cadmium is poorly mutagenic and probably acts through indirect mechanisms, although the precise mechanisms remain unknown. q2000 Elsevier Science Inc. All rights reserved. Keywords: Cadmium; Carcinogenesis; Humans; Rodents; Zinc
1. Introduction Cadmium is a toxic transition (‘heavy’) metal of continuing occupational and environmental concern with a wide variety of adverse effects [1]. Cadmium has an extremely long biological half-life that essentially makes it a cumulative toxin [1]. To date there are no proven effective treatments for chronic cadmium intoxication [1]. Cadmium accumulates primarily in the liver and kidney where it is bound to metallothionein (MT), a low molecular weight metal binding protein thought to detoxify the metal through high affinity sequestration [1]. The toxic effects of cadmium often stem from interference with various zinc mediated metabolic processes, and zinc treatments frequently reduce or abolish the adverse effects of cadmium [1]. There are several sources of human exposure to cadmium, including employment in primary metal industries and consumption of tobacco products [2]. Cadmium has been designated a human carcinogen by the International Agency for Research on Cancer and the US National Toxicology Program [2,3] and is clearly a potent, * Tel.: q1-919-541-2328; fax: q1-919-541-3970; e-mail: waalkes@ niehs.nih.gov
multi-tissue animal carcinogen [4,5]. Occupational exposure to cadmium is associated with lung cancers in humans, while other sites, potentially including the prostate, are not definitively established [2–5]. Rodent studies have shown that chronic inhalation of cadmium causes pulmonary adenocarcinomas [4–6], in clear support of human data [2,3]. Cadmium can also cause prostatic proliferative lesions, including adenocarcinomas, after systemic or direct exposure [7–10]. Other target tissues of cadmium carcinogenesis in animals include injection sites, adrenals, testes, and the hemopoietic system [2–5,8]. Certain treatments modify cadmium carcinogenicity, including administration of zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumor formation [10]. Diets deficient in zinc increase the progression of testicular tumors [11] but reduce the progression of prostatic tumors [8]. There are definite species and strain-related differences in sensitivity to cadmium carcinogenicity. The potential mechanism or mechanisms of cadmium carcinogenesis are unknown but may well involve non-genotoxic or indirectly genotoxic events since cadmium is, in general, a poor mutagen [5]. Such events could include enhanced proliferation, depressed apoptosis, and/or altered DNA repair.
0162-0134/00/$ - see front matter q2000 Elsevier Science Inc. All rights reserved. PII S 0 1 6 2 - 0 1 3 4 ( 0 0 ) 0 0 0 0 9 - X
Friday Apr 07 11:00 AM
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
242
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
2. Cadmium metabolism Cadmium metabolism has several unique facets [1,12] and absorption of cadmium shows marked route dependency. Only about 5% of a given dose of cadmium is absorbed from the gastrointestinal tract while cadmium absorption from the lung is very high, with as much as 90% of a dose deposited in the deep lung being absorbed. Once absorbed, cadmium is rapidly cleared from the blood and concentrates in various tissues. Cadmium in the liver and kidney usually make up the bulk of the total body burden [1,12,13]. Hepatic and renal accumulation may be due to the ability of these organs to produce large amounts of MT, a metal binding protein with high affinity for cadmium [13]. The presence of cellular MT will markedly decrease the adverse effects of cadmium [13]. However, probably as a consequence of binding to MT, cadmium is very slowly eliminated from the body. This long residence time could enhance the probability of neoplastic transformation by cadmium.
3. Cadmium carcinogenesis in humans The International Agency for Research on Cancer and the US National Toxicology Program [2,3] have both concluded that there is adequate evidence that cadmium is a human carcinogen. This designation as a human carcinogen was prompted primarily by repeated findings of an association between occupational cadmium exposure and lung cancer, as well as very strong rodent data which included the pulmonary system as a target site [2,3]. Thus, the lung is the most definitively established site of human carcinogenesis from cadmium exposure. In some studies, occupational or environmental cadmium exposure has also been associated with development of cancers of the prostate, kidney, liver, hematopoietic system and stomach [2–5]. The linkage of cadmium exposure with human neoplasia of any specific site other than the lung has, however, not been absolutely established. Clearly, further epidemiological and experimental work is necessary to determine the target sites and nature of the carcinogenic risk from cadmium exposure to humans.
4. Cadmium carcinogenesis in animals The earliest suspicion that cadmium might be carcinogenic in rodents came from the 1961 study of Haddow et al. [14] who gave either subcutaneous (sc) or intramuscular (im) injections of ferritin which had been prepared from rat liver by cadmium precipitation. They subsequently found malignant tumors at the site of injection in rats and mice [14]. It was unclear at that time if cadmium was the carcinogenic agent, but it was suspected [14]. These results prompted further investigations and cadmium now has been established as a potent rodent carcinogen for over 35 years. The carcin-
Friday Apr 07 11:00 AM
ogenic potential of cadmium was first shown at repositorytype injection sites, such as im or sc, where it forms sarcomas at high incidence [2–5]. Early studies also showed cadmium to be an effective testicular tumorigen, with a single exposure producing a high incidence of testicular interstitial cell tumors [2–5]. Several studies have established that inhaled cadmium is a potent pulmonary carcinogen in the rat, supporting its potential as a human lung carcinogen [2,3]. In the initial study, rats that were chronically exposed by inhalation to cadmium chloride aerosols showed dose-related increases in pulmonary carcinoma incidence to a maximum of over 70% [6]. Several other forms of cadmium, including cadmium oxide, have subsequently been established as pulmonary carcinogens in rats after inhalation [2,3]. In contrast to the activity in rat lung, inhaled cadmium is not an effective pulmonary carcinogen in the mouse or hamster [2–5]. Pulmonary tumors can be induced by sc cadmium exposure in at least one strain of mice [15]. Prostatic cancer is an important and deadly human malignant disease of essentially undefined etiology. Several studies in rats indicate that cadmium can induce tumors and preneoplastic lesions of the prostate in rats [1–5,7–10]. The ability of cadmium to induce prostate cancer is atypically dosedependent and depends on the effects of the metal on the testes. An analysis of the carcinogenicity of a single sc injection of cadmium in rats over two years using a wide range of doses showed that prostatic tumor incidence was elevated only at doses of cadmium below the threshold for significant testicular toxicity (;5.0 mmol Cd/kg), but the response was lost at higher doses [9]. At these lower doses, dose-related increases in prostatic tumors occurred [9]. Testicular androgen production is essential for the growth and maintenance of the prostate and prostate tumors are often testosterone dependent [16,17]. In rodents testosterone alone will increase the incidence of prostatic carcinoma [17]. The toxic effects of high dose cadmium (G5.0 mmol Cd/kg, sc) on the rodent testes can results in a drop up to 80% in circulating testosterone which, in turn, induces marked prostatic atrophy [18]. Such atrophy would likely counter any proliferative stimulus. Thus, the testicular toxicity of cadmium probably is responsible for the lack of prostatic tumorigenicity at cadmium doses resulting in overt testicular toxicity. Oral cadmium exposure can also induce proliferative lesions in the rat prostate [11] while direct injection of cadmium into the rat prostate will produce prostatic adenocarcinomas [7]. Cadmium treatment can also enhance the appearance of chemically induced prostatic tumors in rats [19]. The finding of prostatic tumors in cadmium-treated rats by a variety of routes supports, but does not establish, a possible causative role in human prostate cancer. The rat testes are also extremely sensitive to cadmiuminduced tumorigenesis. Cadmium, when given at sufficiently high parenteral doses, rapidly induces severe testicular hemorrhagic necrosis [1]. After the initial toxic lesion, a high incidence of testicular interstitial cell tumors is observed [2–
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
5]. Oral cadmium exposure can also result in interstitial cell tumors in the rat testes [8]. The development of testicular tumors in rats is thought to be related to the chronic degenerative effects of cadmium in this tissue, which results in loss of androgen production, and a subsequent overstimulation of remnant testicular cells by the pituitary [18]. Malignant tumors develop at the site of sc or im injections of cadmium in rats and mice [2–5,14] but not hamsters [21]. The tumors produced at these sites are typically fibrosarcomas [2–5,14]. Cadmium-induced injection site sarcomas appear to be strictly related to accumulated dosage at the site [2–5]. The formation of injection site sarcomas is a common occurrence with many metals [20]. The strain of rodents has a pronounced effect on the incidence of cadmium-induced injection site sarcomas, indicating a genetic basis for sensitivity to these tumors [2–5]. In rats, oral cadmium can induce dose-related increases in the incidence of leukemia [8]. Dose-related increases in lymphoma have been shown to be induced by sc injections of cadmium in certain strains of mice [15,22,23]. When cadmium is given sc concurrently with calcium, an elevated incidence of islet cell tumors of the rat pancreas has been shown [2–5]. Induction of tumors of the adrenals has been reported with sc cadmium treatment in hamsters and the incidence of proliferative lesions of the adrenal cortex approached 55% in these animals [23]. The incidence of adrenal tumors can also be increased by sc injections of cadmium in mice [24].
5. Modification of the carcinogenic response to cadmium in rodents; some mechanistic considerations Zinc can have an important impact on cadmium carcinogenesis. In several tissues, including the lung, testes, and at the injection site, zinc treatments reduce cadmium carcinogenesis [2–5]. In this regard calcium and magnesium are relatively ineffective in reducing the carcinogenic effects of cadmium compared to zinc [2–5]. This selective antagonism by zinc of the carcinogenic effects of cadmium at so many different target sites could point to a basic mechanism of cadmium carcinogenesis. Cadmium often competes with zinc for a variety of important binding sites in cells, including sites potentially important in gene regulation or enzyme activity [1]. Zinc can induce the synthesis of the metal-binding protein, MT, which reduces many of the adverse effects of cadmium [13]. Cadmium can also induce MT and thereby induces self-tolerance [13]. The induction of MT could be an important aspect of reduced cadmium carcinogenesis by zinc. This could also be a key element in differential species sensitivity to cadmium carcinogenesis. For instance, cadmium is an effective pulmonary carcinogen after inhalation only in the rat, while inhaled cadmium is not carcinogenic in the lungs of mice [2–5]. The acute toxicity of inhaled cadmium in the lung shows similar species differences, being more severe in
Friday Apr 07 11:00 AM
243
the rat compared to mice [25,26]. Both the differences in acute toxicity and chronic carcinogenicity may be due to a higher production of MT in the lungs of mice than rats [26]. In contrast to inhibition in some tissues, zinc can facilitate cadmium-induced tumor production in the prostate, probably through prevention of testicular toxicity and the consequent maintenance of androgen support [10]. Furthermore, dietary zinc deficiency diminishes the carcinogenic potential of cadmium in the prostate probably because zinc deficiency induces atrophy of the prostate secondary to a reduction in testicular androgen secretion [8]. A diet deficient in zinc will, however, enhance the progression of testicular proliferative lesions and increase the incidence of injection site sarcomas induced by cadmium [11]. Thus, zinc can either facilitate or inhibit cadmium carcinogenesis depending on the tissue and circumstances.
6. Possible mechanisms in cadmium carcinogenesis Although cadmium can produce genotoxic and mutagenic events, these generally require high doses [4,5,27]. Cadmium will not form stable DNA adducts and, since cadmium is not a redox active metal, indirect oxidative DNA damage is unlikely as a primary carcinogenic mechanism. Thus, epigenetic non-genotoxic or indirect genotoxic mechanisms may apply. Such mechanisms could include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Both these potential mechanisms could result in carcinogenic transformation in the absence of cadmiuminduced genetic damage. Alternatively, cadmium can inhibit repair of DNA [28] which could be an indirect source of mutational events. Together with upregulation of mitogenic signaling, perturbed DNA repair and the resulting indirect genotoxicity could be key events in carcinogenesis [29]. Cadmium can clearly activate transcription factors that normally require zinc, such as with the MT gene [1,13]. Furthermore, cadmium can activate some proto-oncogenes or genes associated with cell proliferation, such as c-myc or c-jun, in cells and in animals [30,31]. This activation could enhance proliferation in a cell population and, assuming a basal level of cells with chemically or spontaneously damaged DNA, this could enhance the colonal expansion of such damaged cells. The suppression of DNA repair by cadmium [28] would potentially add to the population of cells with damaged DNA. Thus, enhanced cellular proliferation rates could help fix in place genetic errors that would otherwise be recognized and repaired or cause cellular elimination. Similarly, apoptotic cell death is an ongoing, normal event in the control of cell populations and will cause elimination of cells with damaged genetic material. In this regard chemically induced apoptosis can be very effectively blocked by cadmium [32]. This hindered apoptosis could presumably facilitate aberrant cell accumulation, allowing cells to survive that would otherwise not pass apoptotic checkpoints. This may be a critical step in the pathogenesis of cadmium-induced
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351
244
M.P. Waalkes / Journal of Inorganic Biochemistry 79 (2000) 241–244
malignancies. Thus for cadmium, disorders of cell accumulation, including enhanced proliferation and disrupted apoptosis, may be crucial events in carcinogenesis.
7. Summary and conclusions The carcinogenic potential of cadmium is clearly established in humans and experimental animals. Further efforts are warranted in the epidemiology of cadmium in order to determine more precisely the risks and target sites in humans. The mechanisms of cadmium carcinogenesis remain unknown. However, the mechanisms appear to be related in some undefined way to zinc metabolism because of the pronounced effects that zinc can have on cadmium carcinogenesis in many experimental systems. As yet there is no consensus on the molecular events associated with cadmiuminduced malignant transformation but, since this metal is not strongly genotoxic, non-genotoxic and or indirectly genotoxic mechanisms may apply. Such mechanisms could include altered cell proliferation or blocked apoptosis, which could result in cell transformation in the absence of cadmiuminduced genetic damage. Thus, with cadmium, disruption of cell accumulation, perhaps due to enhanced proliferation and blocked apoptosis, may be a crucial event in carcinogenesis. Alternatively, cadmium-induced disruption of DNA repair, in combination with enhanced proliferation, could lead to tumor formation. Further research is required to define the mechanism of cadmium carcinogenesis.
8. Abbreviations MT sc im
metallothionein subcutaneous intramuscular
References [1] P.L. Goering, M.P. Waalkes, C.D. Klaassen, in: R.A. Goyer, M.G. Cherian (Eds.), Handbook of Experimental Pharmacology, vol. 115, Toxicology of Metals, Biochemical Effects, Springer, New York, 1994, pp. 189–214. [2] International Agency for Research on Cancer Monographs, vol. 58, Cadmium, IARC Press, Lyon, 1993, pp. 119–238.
Friday Apr 07 11:00 AM
[3] Ninth Report on Carcinogens, National Toxicology Program, Research Triangle Park, NC, in press. [4] M.P. Waalkes, in: G. Berthan (Ed.), Handbook on Metal–Ligand Interactions of Biological Fluids, vol. 2, Marcel Dekker, New York, 1995, pp. 471–482. [5] M.P. Waalkes, R.R. Misra, in: L.W. Chang (Ed.), Toxicology of Metals, CRC Press, Boca Raton, FL, 1996, pp. 231–244. ¨ ¨ [6] S. Takenaka, H. Oldiges, H. Konig, D. Hochrainer, G. Oberdorster, J. Natl. Cancer Inst. 70 (1983) 367. ¨ P. Gase, C. [7] L. Hoffmann, H.P. Putzke, H.J. Kampehl, R. Russbult, Simonn, T. Erdmann, C. Huckstorf, J. Cancer Res. Clin. Oncol. 109 (1985) 193. [8] M.P. Waalkes, S. Rehm, Fundam. Appl. Toxicol. 19 (1992) 512. [9] M.P. Waalkes, S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, J.R. Henneman, M.S. Balaschak, Cancer Res. 48 (1988) 4656. [10] M.P. Waalkes, S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, J.R. Henneman, Cancer Res. 49 (1989) 4282. [11] M.P. Waalkes, R. Kovatch, S. Rehm, Toxicol. Appl. Pharmacol. 108 (1991) 448. [12] C.D. Klaassen, Fundam. Appl. Toxicol. 1 (1981) 353. [13] C.D. Klaassen, J. Liu, S. Choudhuri, Annu. Rev. Pharmacol. Toxicol. 39 (1999) 267. [14] A. Haddow, C.E. Dukes, B.C.V. Mitchley, Annu. Rep. Br. Empire Cancer Campaign 37 (1961) 74. [15] M.P. Waalkes, S. Rehm, Fundam. Appl. Toxicol. 23 (1994) 21. [16] D.S. Coffey, J.T. Isaacs, Urology 3 (1981) 17. [17] R.L. Nobel, Cancer Res. 37 (1977) 1929. [18] M.P. Waalkes, S. Rehm, D.E. Devor, Toxicol. Appl. Pharmacol. 142 (1997) 50. [19] T. Shirai, S. Iwasaki, T. Masui, T. Mori, T. Kato, N. Ito, Jpn. J. Cancer Res. 84 (1993) 1023. [20] M.P. Waalkes, in: R.A. Goyer, C.D. Klaassen, M.P. Waalkes (Eds.), Metal Toxicology, Academic Press, San Diego, 1995, p. 47. [21] M.P. Waalkes, S. Rehm, Toxicology 126 (1998) 173. [22] M.P. Waalkes, S. Rehm, Toxic Subst. J. 13 (1994) 97. [23] M.P. Waalkes, S. Rehm, B. Sass, R. Kovatch, J.M. Ward, Toxic. Subst. J. 13 (1994) 15. [24] M.P. Waalkes, S. Rehm, Toxic Subst. Mech. 14 (1995) 79. [25] I.M. McKenna, M.P. Waalkes, L.C. Chen, T. Gordon, Toxicol. Appl. Pharmacol. 146 (1997) 196. [26] I.M. McKenna, T. Gordon, L.C. Chen, M.R. Anver, M.P. Waalkes, Toxicol. Appl. Pharmacol. 153 (1998) 169. [27] R.R. Misra, G.T. Smith, M.P. Waalkes, Toxicology 126 (1998) 103. [28] A. Hartwig, Toxicol. Lett. 102–103 (1998) 235. [29] D. Beyersman, S. Hechtenberg, Toxicol. Appl. Pharmacol. 144 (1997) 247. [30] M.K. Abshire, G.S. Buzard, N. Shiraishi, M.P. Waalkes, J. Toxicol. Environ. Health 48 (1996) 359. [31] H. Zheng, J. Liu, K.H. Choo, A.E. Michalska, C.D. Klaassen, Toxicol. Appl. Pharmacol. 136 (1996) 229. [32] H. Shimada, Y.-H. Shiao, M.A. Shibata, M.P. Waalkes, J. Toxicol. Environ. Health 54 (1998) 159.
StyleTag -- Journal: JIB (Journal of Inorganic Biochemistry)
Article: 6351