Loading...
 

April - June 2008: 
Volume 21, Issue 2

Click on the image to download the Issue in PDF format.

ARCHIVE

Cadmium (Cd) as a carcinogenetic factor andits participation in the induction of lung cancer
Abstract
Cadmium (Cd) is a widely spread environmental contaminant that exerts varied toxicity, including established carcinogenetic activity. Due to its long biological half-life (more than 10 years), chronic exposure and accumulation of Cd can give rise to a variety of toxic phenomena in the bones, the urogenital system and in the lungs. This short review focuses on the data that document the carcinogenic properties of Cd correlated with the induction of lung cancer. Smoking and exposure to Cd compounds at work are the main sources of Cd inhalation. The mechanisms involved have not been completely elucidated, but the oxidative and deregulating actions of Cd on certain proteins and enzymes of the exposed lung cells are thought to play a major role. Pneumon 2008; 21(2):172–177
Full text

INTRODUCTION

Cadmium (Cd) is a group IIB element of the periodic table that can be detected in all tissues of any organism, without being essential for life1,2. The main pathways of human exposure to Cd and its compounds are summarized in Figure 1. The physicochemical properties of Cd (Table 1) are similar to those of elements essential for life, such as zinc (Zn) and calcium (Ca)2-4. On the cellular level, divalent Cd (Cd2+) is characterized by a high affinity for various molecules, inducing: a) structural and functional changes, b) oxidative phenomena, and c) stimulation of metal-binding reactions3,5,6. In these ways, Cd exerts toxicity on the cells of various systems and tissues, such as the respiratory tract7, the urinary8, cardiovascular9, gastrointestinal10 and nervous11 systems and the bones12, by affecting their function either directly or indirectly. These toxic effects induce degeneration or even transmutation of the cells2,13,14.

Figure 1. The main pathways of human exposure to cadmium (Cd) and its compounds.
Table 1. Synopsis of the main physicochemical properties of cadmium (Cd).
Characteristics: metal, malleable and ductile
Colour: grey-white, blue-white
Crystal structure: modified hexagon
Atomic weight: 112.411
Atomic number: 48
Atomic radius: 1.48 A
Ionic radius: 0.97 A (for Cd2+)
Oxidation numbers: +2, +1
Density: 8.65 g/cm3
Melting point: 321 οC
Boiling point: 778 οC
Main compounds: cadmium oxide (CdO),     cadmium sulphide
(CdS), cadmium chloride (CdCl2),
cadmium bromide (CdBr2), cadmium
sulphate (CdSO4)

The literature provides clear evidence of the ability of Cd to provoke indirect oxidative damage on the DNA, leading to: a) induction of cellular proliferation, b) inhibition of the apoptotic mechanisms, and c) blocking of the DNA repair mechanisms (i.e., DNA-repair inhibition)8,15,16.However, the precise mechanisms of these indirect effects of Cd remain unclear. Cd appears to provoke the activation of certain proto-oncogenes (c-myc, c-jun)17, but the mechanisms involved are not well understood. Metallothionein (MT), a metal-binding protein, appears to play an important role in limiting the toxic and carcinogenetic effects of Cd, by assisting in its excretion6,17. Cd and its compounds have been extensively studied by the International Agency for Research on Cancer (IARC) Study Groups, and Cd has been characterized as a \"class I carcinogenic\" on the IARC scale18, which, along with other scientific findings, has led to the identification of Cd as a  major environmental contaminant and an occupational health hazard14,19. This review aims to provide a synopsis of the data concerning the carcinogenetic effects of Cd in the lung following environmental and occupational exposure.

 

THE EPIDEMIOLOGICAL ASSOCIATION OF Cd WITH LUNG CANCER

The association of Cd with lung cancer has been the subject of numerous epidemiological studies20-30. Although the most frequent causal factor in lung cancer is known to be smoking31,32, it was also necessary to investigate other risk factors, such as the working environment, dietary habits, familial environment, socioeconomic background, etc. It was within investigation of these factors that occupational exposure to Cd (Table 2) was found to be correlated with lung cancer development, with a relative risk of approximately 3.7, in the majority of epidemiological studies24-26,28-30, although the data from some older studies were in disagreement20,21. Most studies concerned workers in battery-production facilities, examined in comparison with the general population33. Some studies have proposed the possibility of combined Cd toxicity with toxicity from other heavy metals that are found along with Cd in the working environments examined, including arsenic (As), nickel (Ni), beryllium (Be) and chromium (Cr)22,23,27. Stayner et al. have suggested a dose-dependent increase in the carcinogenetic effect of Cd on the lung29, and their  findings were confirmed in patients who had also been exposed to low levels of As34.

Table 2. The main industrial uses of cadmium (Cd).
 1. Production of nickel-cd batteries
2. Part of plastic materials
3. Pvc stabilizing
4. The war and aerospace industry
5. Part of industrial alloys
6. Jewel-manufacturing
7. Cable production
8. Dental materials
9. Nuclear energy production
10.Production of semiconductors
11.Production of photochemical apparatus
12.Production of organic materials for industrial purposes
13.Other applications

The toxicological investigation of substances such as Cd is not an easy task through epidemiological research, for a variety of reasons: a) groups suitable for investigation are not easy to find, since to be eligible for study these people should be sufficiently and mainly exposed to Cd, and when identified, such a group is usually small in number33, b) the determination of the Cd compound that interacts with the organism of the workers is difficult to identify and not always stable35, and c) in occupational exposure to Cd, as with exposure of the general population, certain other factors are involved, such as the socioeconomic background and smoking behaviour32 (smoke contains high levels of Cd, and tobacco-derived Cd is deposited in the airways more easily than that from other sources, thus, smokers accumulate blood Cd in levels 4-5 times higher than non-smokers; each cigarette contains 1-2 μg Cd and 40-60% of the inhaled Cd is deposited in the lungs)36,37. These difficulties were addressed by the researchers by careful experimental design (in-vivo and in-vitro), resulting in studies that led to the definite establishment of Cd as a carcinogen for the lungs, and shed some light on the mechanisms involved.

 

EXPERIMENTAL CORRELATION TO LUNG CANCER

 Experimental studies on animals have indicated a correlation between Cd levels in the inhaled air and those found within the organism13. Cadmium is easily absorbed through the respiratory tract, in percentages varying between 7% and 40%38-40 depending on the air concentration of Cd and the specific compound of Cd available13. Exposure of experimental animals to Cdchloride vapour led to the development of emphysema and fibrosis41, while chronic exposure to this vapour can cause dose-dependent development of lung cancer, at a frequency that may reach 70%42. The development of lung cancer appears to be assisted by a cascade of pathophysiological phenomena that take place after long-term exposure to Cd. Chronic exposure to Cd-containing vapour causes accumulation and activation of leukocytes in experimental animals, with release of various inflammation mediators, which in turn activate mechanisms leading to the development of inflammation and fibrosis in the exposed lung tissues43-45. Moreover, Cd appears to affect the vascular epithelium in the lung and other organs by increasing small vessel permeability and causing accumulation of water, protein  and blood cells in the intermediate space46. This increase in small vessel permeability, regardless of the mechanisms involved, takes place through the effect of Cd on cadherin function47. Cadherin is a Ca-dependent molecule of cellular attachment that plays a significant role in keeping epithelial cells together47. By deregulation of the function of this molecule, Cd sets off a cascade of biochemical phenomena that complicate the toxic effects of Cd and develop conditions favourable for the development of malignancies46.

 

MECHANISMS OF CADMIUM-INDUCED CARCINOGENESIS IN THE LUNG

Cd induces MT synthesis6, causes indirect oxidative damage to DNA14 and free radical production11. Inadequate MT synthesis, combined with insufficient antioxidant capacity, could lead to the development of an environment suitable for the induction of mutations and the development of cancer48 (Figure 2). In rat lung epithelial cells, Cd activates the oxidative- stress related genes (glutathione-S-transferase-α, γ-glutamylcysteine synthetase and MT-1), along with the apoptotic response49. However, Cd concentrations that are high enough to activate these genes can also lead 50% of the exposed cell population to apoptosis49. The cells that are not driven to apoptosis may be subject to Cd-induced oxidative effects that inhibit DNA repair15, stimulate mitotic signalling50 and cause indirect damage to genes, although Cd has not been correlated with any direct toxic effect on the DNA molecule14 (Figure 2). The inflammation that develops due to Cd inhalation7 and the cumulative damage to DNA play a significant role in the development of lung cancer, since: a) exposure to Cd is usually chronic (i.e., occupational exposure, smoking), b) due to inflammation and apoptotic phenomena, resistant cells carrying DNA damage multiply selectively and develop an environment favourable to mutation and cellular proliferation, and c) Cd causes overexpression of the proto-oncogenes c-myc and c-jun17 and deregulation of the mechanisms inhibitory to proliferation14.

Figure 2. The usual and carcinogenetic response of a lung cell exposed to cadmium (Cd). MT: metallothionein.

 

In addition, the ability of Cd to inhibit proteoglycan and procollagen production by fibroblasts51,52 causes difficulties in the limitation of inflammation, thus developing an environment of deregulated connective tissue that is more vulnerable to the occurrence of metastases14,46. Metastatic cells pass through the endothelial barrier and enter the systemic circulation, aided by damage to bonds at two sites: a) the cell-to-cell E-cadherin bonds53, and b) the vascular  VE-cadherin bonds, enhancing the Cd-induced inflammatory processes54,55 (Figure 2).

 

CONCLUSIONS

Cd is a widely spread environmental contaminant that exerts varied toxicity and its carcinogenetic properties have been established. Smoking and exposure to Cd compounds at work are the main sources of Cd inhalation,  which can lead to the development of lung cancer. Although the epidemiological correlation between exposure to Cd and lung cancer development is complicated by other factors, experimental data indicate carcinogenetic activity of Cd in the lung, with a high degree of certainty. The mechanisms involved have not been completely elucidated, but the oxidative and deregulating actions of Cd on certain proteins and enzymes in the exposed lung cells are thought to play a major role.  

 

 REFERENCES

  1.  Carageorgiou H, Liapi C, Messari I, Tyligada K, Papadopoulos G, Sitaras N. Environmental Pharmacology. National & Kapodistrian University of Athens 2004; 195-206. 
  2. Commission of the European Communities, Industrial Health and Safety. The Toxicology of Chemicals: Carcinogenicity. Volume I. National Research Institute, Athens 1993; 45-55.
  3. Jacobson KB, Turner JE. The interaction of cadmium and certain other metal ions with proteins and nucleic acids. Toxicology 1980; 16:1-37.
  4. Sutoo D, Akiyama K, Imamiya S. A mechanism of cadmium poisoning: the cross effect of calcium and cadmium in the calmodulin-dependent system. Arch Toxicol 1990; 64:161- 164.
  5. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995; 18:321-336.
  6. Klaassen CD, Liu J, Chondhuri S. Metallothionein: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 1999; 39:267-294. 
  7. Hart BA, Potts RJ, Watkin RD. Cadmium adaptation in the lung - a double-edged sword? Toxicology 2001; 160:65-70.
  8. Zarros A, Stravodimos K. Cadmium (Cd) as a cause of transformations of the urogenital system. Medical Annals [in greek] 2006; 29:553-555.
  9. Nomiyama K, Nomiyama H. Cadmium-induced elevation of blood pressure. J Trace Elem Exp Med 2000; 13:155-163. 
  10. International Programme on Chemical Safety (IPCS). Cadmium. Environmental Health Criteria (EHC), WHO, Geneva 1992; 134.
  11.  Carageorgiou H, Tzotzes V, Pantos C, Mourouzis C, Zarros A, Tsakiris S. In vivo and in vitro effects of cadmium on adult rat brain total antioxidant status, acetylcholinesterase, (Na+, K+)- ATPase and Mg2+-ATPase activities: protection by L-cysteine. Basic Clin Pharmacol Toxicol 2004; 94:112-118.
  12. Zarros A, Karympalis V, Kalopita K, Tsakiris T, Tsakiris S. Cadmiuminduced osteoporosis and osteomalacia. Medical Annals [in greek] 2004; 27:349-353.
  13. Swiergosz-Kowalewska R. Cadmium distribution and toxicity in tissues of small rodents. Microsc Res Tech 2001; 55:208-222.
  14. Waalkes MP. Cadmium carcinogenesis. Mutat Res 2003; 533:107- 120.
  15. Hartwig A. Carcinogenicity of metal compounds: possible role of DNA repair inhibition. Toxicol Lett 1998; 102-103:235-239. 
  16. Waalkes MP. Cadmium carcinogenesis in review. J Inorg Biochem 2000; 79:241-244.
  17. Abshire MK, Buzard GS, Shiraishi N, Waalkes MP. Induction of c-myc and c-jun proto-oncogene expression in rat L6 myoblasts by cadmium is inhibited by zinc preincubation of the metallothionein gene. J Toxicol Environ Health 1996; 48:359-377.
  18. International Agency for Research on Cancer. Beryllium, Cadmium, Mercury and Exposures in the Glass Manufacturing Industry. IARC, Lyon 1993; 119-238.
  19. Satarug S, Baker JR, Urbenjapol S, et al. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol Lett 2003; 137:65-83.
  20.  Bonnell JA, Kazantzis G, King E. A follow-up study of men exposed to cadmium oxide fume. Br J Ind Med 1959; 16:135- 147.
  21. Elinder CG, Kjellstrom T, Hogstedt C, Andersson K, Spang G. Cancer mortality of cadmium workers. Br J Ind Med 1985; 42:651-655.
  22.  Kazantzis G, Blanks RG. A mortality study of cadmium exposed workers. Στο: Cook ME, Kiscock SA, Morrow H, Volpe RA (eds). Edited Proceedings of the Fourth International Cadmium Conference. Cadmium Association/Cadmium Council, New Orleans, LA 1993; 150.
  23. Kazantzis G, Blanks RG, Sullivan KR. Is cadmium a human carcinogen? In: Nordberg GF, Herber RFM, Alesio L (eds). Cadmium in the Human Environment: Toxicity and Carcinogenicity. IARC, Lyon 1992; 118:435.
  24. Kazantzis G, Lam TH, Sullivan KR. Mortality of cadmium-exposed workers. A five-year update. Scand J Work Environ Health 1988; 14:220-223.
  25. Lemen RA, Lee JS, Wagoner JK, Blejer HP. Cancer mortality among cadmium production workers. Ann NY Acad Sci 1976; 271:273-279.
  26. Sorahan T. Mortality from lung cancer among a cohort of nickel cadmium battery workers: 1946-84. Br J Ind Med 1987; 44:803-809.
  27. Sorahan T, Lister A, Gilthorpe MS, Harrington JM. Mortality of copper cadmium alloy workers with special reference to lung cancer and non-malignant diseases of the respiratory system, 1946-92. Occup Environ Med 1995; 52:804-812.
  28. Sorahan T, Watherhouse JAH. Mortality study of nickel-cadmium battery workers by the method of regression models in life tables. Br J Ind Med 1983; 40:293-300.
  29. Stayner L, Smith R, Thun M, Schnorr T, Lemen R. A dose-response analysis and quantitative assesment of lung cancer risk and occupational cadmium exposure. Ann Epidemiol 1992; 2:177- 194.
  30. Thun MJ, Schnorr TM, Smith AB, Halperin WE, Lemen RA. Mortality among a cohort of U.S. cadmium production workers - an update. J Natl Cancer Inst 1985; 74:325-333.
  31. Dragnev KH, Stover D, Dmitrovsky E, American College of Chest Physicians. Lung cancer prevention, the guidelines. Chest 2003; 123:60s-71s.
  32. Rahiotis G, Behrakis PK. Working and smoking. Pneumon 2005; 18:46-52.
  33. Silvera SAN, Rohan TE. Trace elements and cancer risk: a review of the epidemiologic evidence. Cancer Causes Control 2007; 18:7-27.
  34. Stayner L, Smith R, Schnorr T, Lemen R, Thun M. Lung cancer. Ann Epidemiol 1993; 3:114-116.
  35. Hayes RB. The carcinogenicity of metals in humans. Cancer Causes Control 1997; 8:371-385.
  36. Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of Cd exposure - a review of the literature and a risk estimate. Scand J Work Environ Health 1998; 24:s1-s51.
  37. Kazi TG, Memon AR, Afridi HI, et al. Determination of cadmium in whole blood and scalp hair samples of Pakistani male lung cancer patients by electrothermal atomic absorption spectrometer. Sci Total Environ 2008; 389:270-276.
  38. Friberg L, Nordberg GF, Vouk V. Handbook on the Toxicology of Metals. 2nd edition. Elsevier North Holland Biomedical Press, New York 1986.
  39. Friberg L, Piscator M, Nordberg GF, Kjellstrφm T. Cadmium in the Environment. 2nd edition. CRC Press Inc, Cleveland 1974. 
  40. Goyer RA. Toxic effects of metals. In: Amdur MO, Doull J, Klaassen CD (eds). Cassarett and Doull\'s Toxicology. Pergamon Press, Toronto 1991; 623-680.
  41. Snider GL, Lucey EC, Faris B, Jung-Legg Y, Stone PJ, Franzblau C. Cadmium-chloride-induced air-space enlargement with interstitial pulmonary fibrosis is not associated with destruction of lung elastin. Implications for the pathogenesis of human emphysema. Am Rev Respir Dis 1988; 137:918-923.
  42. Takenaka S, Oldiges H, Konig H, Hochrainer D, Oberdorster G. Carcinogenicity of cadmium chloride aerosols in W rats. J Natl Cancer Inst 1983; 70:367-373.
  43. Bell RR, Nonavinakere VK, Soliman MR. Intratracheal exposure of the guinea pig lung to cadmium and/or selenium: a histological evaluation. Toxicol Lett 2000; 114:101-109.
  44. Driscoll KE, Maurer JK, Poynter J, Higgins J, Asquith T, Miller NS. Stimulation of rat alveolar macrophage fibronectin release in a cadmium chloride model of lung injury and fibrosis. Toxicol Appl Pharnacol 1992; 116: 30- 37.
  45.  Hirano S, Tsukamoto N, Higo S, Suzuki KT. Toxicity of cadmium oxide instilled into the rat lung. ІІ. Inflammatory responses in broncho-alveolar lavage fluid. Toxicology 1989; 55:25-35.
  46.  Prozialeck WC, Edwards JR, Woods JM. The vascular endothelium as a target of cadmium toxicity. Life Sci 2006; 79:1493-1506.
  47. Prozialeck WC. Evidence that E-cadherin epithelium may be a target of cadmium toxicity in epithelial cells. Toxicol Appl Pharmacol 2000; 164:231-249.
  48. Kasprzak KS. Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Radic Biol Med 2002; 32:958-967.
  49. Hart BA, Lee CH, Shukla GS, et al. Characterization of cadmiuminduced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology 1999; 133:43-58.
  50.  Beyersmann D, Hechtenberg S. Cadmium, gene regulation, and cellular signaling in mammalian cells. Toxicol Appl Pharmacol 1997; 144:247-261.
  51. Chambers RC, McAnulty RJ, Shock A, Campa JS, Newman- Taylor AJ, Laurent GJ. Cadmium selectively inhibits fibroblast procollagen production and proliferation. Am J Physiol 1994; 267:L300-L308.
  52. Chambers RC, Laurent GJ, Westergren-Thorsson G. Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts. Am J Respir Cell Mol Biol 1998; 19:498- 506.
  53. Pearson CA, Prozialeck WC. E-cadherin, beta-catenin and cadmium carcinogenesis. Med Hypotheses 2001; 56:572-581.
  54.  Bazzoni G, Dejana E. Endothelium cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 2004; 84:869-901.
  55. Pearson CA, Lamar PC, Prozialeck WC. Effects of cadmium on E-cadherin and VE-cadherin in mouse lung. Life Sci 2003; 72:1303-1320.  
References