An industrial risk: Beryllium
Year 2012,
, 141 - 148, 01.03.2012
Emrah Çaylak
Metin Aytekin
Abstract
Beryllium is a vocational disease factor and beryllium exposure can potentially lead to Chronic Beryllium Disease (CBD) in 2-6 % of workers. While acute lymphocytic pneumonia occurred in individuals who were exposed to high doses of beryllium, low dose exposure to beryllium followed by a long subclinical period can cause CBD characterized with chronic granulomatosis. It has been observed that varying amounts of beryllium exposure are necessary to produce symptoms of CBD or beryllium sensitization (BeS). Genetic differences between patients may be the underlying cause of these dose-effects and further study of the differences in patients exposed to beryllium may lead to earlier diagnosis and the identification of biomarkers of CBD. In this review, it is summarized the general properties of beryllium exposure, the immunopathogenesis and genetic differences of beryllium-induced diseases, genotoxicity and the carcinogenic effects of beryllium.
References
- Van Ordstarnd HS, Hughes R, Carmody MG. Chemi- cal pneumonia in workers extracting beryllium oxide. Report of three cases. Cleve Clin Q 1984;51(2):431-9.
- Hardy HL, Tabershaw IR. Delayed chemical pneumo- nitis occurring in workers exposed to beryllium com- pounds. J Ind Hyg Toxicol 1946;28(2):197-211.
- Hardy HL. Delayed chemical pneumonitis in workers exposed to beryllium compounds. Am Rev Tuberc 1948; 57(6):547-56.
- McCanlies EC, Kreiss K, Andrew M, Weston A. HLA- DPB1 and chronic beryllium disease: a HuGE review. Am J Epidemiol 2003;157(5):388-98.
- Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 micrograms/m3. Am J Ind Med 1996;30(1):16-25.
- Kelleher PC, Martyny JW, Mroz MM, et al. Beryl- lium particulate exposure and disease relations in a beryllium machining plant. J Occup Environ Med 2001;43(3):238-49.
- Schuler CR, Kent MS, Deubner DC, et al. Process- related risk of beryllium sensitization and disease in a copper-beryllium alloy facility. Am J Ind Med 2005;47(3):195-205.
- Newman LS, Maier LA, Martyny JW, Mroz MM, Van- Dyke M, Sackett HM. Beryllium workers’ health risks. J Occup Environ Hyg 2005;2(6):D48-50.
- Saltini C, Winestock K, Kirby M, Pinkston P, Crystal RG. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells. N Engl J Med 1989;320(17):1103-9.
- Sprince NL, Kanarek DJ, Weber AL, Chamberlin RI, Kazemi H. Reversible respiratory disease in beryllium workers. Am Rev Respir Dis 1978;117(6):1011-7.
- Stoeckle JD, Hardy HL, Weber AL. Chronic beryl- lium disease: Long-term follow-up of sixty cases and selective review of the literature. Am J Med 1969; 46(4):545-61.
- Newman LS, Kreiss K. Nonoccupational beryllium dis- ease masquerading as sarcoidosis: identification by blood lymphocyte proliferative response to beryllium. Am Rev Respir Dis 1992;145(5):1212-4.
- Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of dis- ease definition and natural history. Am Rev Respir Dis 1989;139(6):1479-86.
- Newman LS, Mroz MM, Maier LA, Daniloff EM, Balkis- soon R. Efficacy of serial medical surveillance for chronic beryllium disease in a beryllium machining plant. J Occup Environ Med 2001;43(3):231-7.
- Freiman DG, Hardy HL. Beryllium disease. The re- lation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the U.S. beryllium case registry. Hum Pathol 1970;1(1): 25-44.
- Sterner JH, Eisenbud M. Epidemiology of beryl- lium intoxication. AMA Arch Ind Hyg Occup Med 1951;4(2):123-51.
- Curtis GH. The diagnosis of beryllium disease, with special reference to the patch test. AMA Arch Ind Health 1959;19(2):150-3.
- Curtis GH. Cutaneous hypersensitivity due to beryl- lium; a study of thirteen cases. AMA Arch Derm Syphi- lol 1951;64(4):470-82.
- Tinkle SS, Antonini JM, Rich BA, et al. Skin as a route of exposure and sensitization in chronic beryllium dis- ease. Environ Health Perspect 2003;111(9):1202-8.
- Hanifin JM, Epstein WL, Cline MJ. In vitro studies on granulomatous hypersensitivity to beryllium. J Invest Dermatol 1970;55(4):284-8.
- Deodhar SD, Barna BP. Immune mechanisms in beryl- lium lung disease. Cleve Clin J Med 1991;58(2):157- 60.
- Sawyer RT, Day BJ, Fadok VA, et al. Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease. Am J Respir Cell Mol Biol 2004; 31(4):470-7.
- Epstein PE, Dauber JH, Rossman MD, Daniele RP. Bronchoalveolar lavage in a patient with chronic beryl- liosis: evidence for hypersensitivity pneumonitis. Ann Intern Med 1982;97(2):213-6.
- Rossman MD, Kern JA, Elias JA, et al. Proliferative response of bronchoalveolar lymphocytes to beryl- lium. A test for chronic beryllium disease. Ann Intern Med 1988; 108(5):687-93.
- Newman LS, Bobka C, Schumacher B. Compart- mentalized immune response reflects clinical sever- ity of beryllium disease. Am J Respir Crit Care Med 1994;150(1):135-42.
- Eisenbud M, Lisson J. Epidemiological aspects of be- ryllium-induced nonmalignant lung disease: a 30-year update. J Occup Med 1983;25(3):196-202.
- Denardi JM, Van Ordstrand HS, Curtis GH, Zielinski J. Berylliosis; summary and survey of all clinical types observed in a twelve-year period. AMA Arch Ind Hyg Occup Med 1953;8(1):1-24.
- Apostoli P, Schaller KH. Urinary beryllium-a suitable tool for assessing occupational and environmental beryllium exposure? Int Arch Occup Environ Health 2001;74(3):162-6.
- Stefaniak AB, Hoover MD, Dickerson RM, et al. Sur- face area of respirable beryllium metal, oxide, and copper alloy aerosols and implications for assess- ment of exposure risk of chronic beryllium disease. AIHA J (Fairfax, Va) 2003;64(3):297-305.
- Gregory L, Finch JAM, Eidson AF, Hoover MD, Rothenberg SJ. In vitro dissolution characteristics of beryllium oxide and beryllium metal aerosols. J Aeros Sci 1998;19(3):333-42.
- Eidson AF, Taya A, Finch GL, Hoover MD, Cook C. Dosimetry of beryllium in cultured canine pulmonary alveolar macrophages. J Toxicol Environ Health 1991;34(4):433-48.
- Stefaniak AB, Guilmette RA, Day GA, Hoover MD, Breysse PN, Scripsick RC. Characterization of pha- golysosomal simulant fluid for study of beryllium aero- sol particle dissolution. Toxicol In Vitro 2005;19(1):123- 34.
- Day GA, Hoover MD, Stefaniak AB, et al. Bioavail- ability of beryllium oxide particles: an in vitro study in the murine J774A.1 macrophage cell line model. Exp Lung Res 2005;31(3):341-60.
- Abbas AK, Lichtman AH, Pober JS. Cellular and Mo- lecular Immunology. WB Saunders Co: Philadelphia, 2000.
- Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383(6603):787- 93.
- O’Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Im- munity 1998;8(3):275-83.
- Fontenot AP, Maier LA. Genetic susceptibility and immune-mediated destruction in beryllium-induced disease. Trends Immunol 2005;26(10):543-9.
- Saltini C, Kirby M, Trapnell BC, Tamura N, Crystal RG. Biased accumulation of T lymphocytes with “memory”- type CD45 leukocyte common antigen gene expres- sion on the epithelial surface of the human lung. J Exp Med 1990;171(4):1123-40.
- Fontenot AP, Canavera SJ, Gharavi L, Newman LS, Kotzin BL. Target organ localization of memory CD4(+) T cells in patients with chronic beryllium dis- ease. J Clin Invest 2002;110(10):1473-82.
- Fontenot AP, Palmer BE, Sullivan AK, et al. Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response. J Clin Invest 2005;115(10):2886-93.
- Fontenot AP, Kotzin BL. Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity. Tissue Antigens 2003;62(6):449-58.
- Fontenot AP, Newman LS, Kotzin BL. Chronic beryl- lium disease: T cell recognition of a metal presented by HLA-DP. Clin Immunol 2001;100(1):4-14.
- Tinkle SS, Kittle LA, Schumacher BA, Newman LS. Beryllium induces IL-2 and IFN-gamma in berylliosis. J Immunol 1997;158(1):518-26.
- Tinkle SS, Kittle LA, Newman LS. Partial IL-10 inhibi- tion of the cell-mediated immune response in chronic beryllium disease. J Immunol 1999;163(5):2747-53.
- Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 gluta- mate 69: a genetic marker of beryllium disease. Sci- ence 1993;262(5131):242-4.
- Wang Z, White PS, Petrovic M, et al. Differential sus- ceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles. J Immunol 1999163(3):1647-53.
- Rossman MD, Stubbs J, Lee CW, Argyris E, Magira E, Monos D. Human leukocyte antigen Class II amino acid epitopes: susceptibility and progression markers for beryllium hypersensitivity. Am J Respir Crit Care Med 2002;165(6):788-94.
- Maier LA, McGrath DS, Sato H, et al. Influence of MHC class II in susceptibility to beryllium sensiti- zation and chronic beryllium disease. J Immunol 2003;171(12):6910-8.
- Amicosante M, Berretta F, Franchi A, et al. HLA-DP- unrestricted TNF-alpha release in beryllium-stimulat- ed peripheral blood mononuclear cells. Eur Respir J 2002;20(5):1174-8.
- Galanis A, Karapetsas A, Sandaltzopoulos R. Metal- induced carcinogenesis, oxidative stress and hypoxia signalling. Mutat Res 2009;674(1-2):31-5.
- IATC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC monographs on the evaluation of carcinogenic risks to hummans. World Health Organization. Lyon, 1993.
- Henschler D. Gesundheitsschädliche Arbeitsstoffe: toxikologisch-arbeitsmedizinische von MAK-Werten (Maximale Arbeitsplazt-Konzentra- tionen). Wiley-VHC. Weinheim, 2003. Begründungen
- Zakour RA, Glickman BW. Metal-induced mutagen- esis in the lacI gene of Escherichia coli. Mutat Res 1984;126(1):9-18.
- Joseph P, Muchnok T, Ong T. Gene expression profile in BALB/c-3T3 cells transformed with beryllium sul- fate. Mol Carcinog 2001;32(1):28-35.
- Misra UK, Gawdi G, Akabani G, Pizzo SV. Cadmi- um-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. Cell Signal 2002;14(4):327-40.
- Keshava N, Zhou G, Spruill M, Ensell M, Ong TM. Carcinogenic potential and genomic instability of be- ryllium sulphate in BALB/c-3T3 cells. Mol Cell Bio- chem 2001;222(1-2):69-76.
- Belinsky SA, Snow SS, Nikula KJ, Finch GL, Tellez CS, Palmisano WA. Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens. Car- cinogenesis 2002;23(2):335-9.
- Nickell-Brady C, Hahn FF, Finch GL, Belinsky SA. Analysis of K-ras, p53 and c-raf-1 mutations in be- ryllium-induced rat lung tumors. Carcinogenesis 1994;15(2):257-62.
- Creedon FT, Delahant AB, Durkan TM, Schepers GW. The biological action of inhaled beryllium sulfate; a preliminary chronic toxicity study on rats. AMA Arch Ind Health 1957;15(1):32-58.
- Vorwald AJ, Reeves AL. Pathologic changes induced by beryllium compounds; experimental studies. AMA Arch Ind Health 1959;19(2):190-9.
- Reeves AL, Deitch D, Vorwald AJ. Beryllium carcino- genesis. I. Inhalation exposure of rats to beryllium sul- fate aerosol. Cancer Res 1967;27(3):439-45.
- Vorwald AJ. The induction of experimental pulmonary cancer in the primate (Abstract I-07-e).Springer. Ber- lin, Germany, 1967.
Endüstriyel bir risk: Berilyum
Year 2012,
, 141 - 148, 01.03.2012
Emrah Çaylak
Metin Aytekin
Abstract
Berilyum mesleki bir hastalık faktörü olup, berilyum maruz kalan işçilerin % 2-16\'sında Kronik Berilyum Hastalığı\'na (KBH) neden olmaktadır. Yüksek dozda maruziyete bağlı olarak bireylerde akut lenfositik pnömoni; düşük dozlarda maruziyette ise uzun bir subklinik periyodu takiben kronik granulomatoz karakterli KBH görülmektedir. Farklı miktarlarda berilyum maruziyetinin KBH ve berilyum hassasiyeti (BeS) belirtilerine yol açtığı gözlenmiştir. Hastalar arasındaki genetik farklılıklar bu doz-etki ilişkisine neden olmakta, berilyuma maruz kalmış hastalardaki farklılıklar hakkında yapılacak daha fazla çalışma ise erken tanıya ve KBH belirteçlerinin belirlenmesine neden olacaktır. Bu derlemede berilyum maruziyetinin genel özellikleri, berilyumla-indüklenen hastalıkların immunopatogenezi ve genetik farklılıkları ile berilyumun genotoksisitesi ve karsinojenik etkileri özetlenmiştir.
References
- Van Ordstarnd HS, Hughes R, Carmody MG. Chemi- cal pneumonia in workers extracting beryllium oxide. Report of three cases. Cleve Clin Q 1984;51(2):431-9.
- Hardy HL, Tabershaw IR. Delayed chemical pneumo- nitis occurring in workers exposed to beryllium com- pounds. J Ind Hyg Toxicol 1946;28(2):197-211.
- Hardy HL. Delayed chemical pneumonitis in workers exposed to beryllium compounds. Am Rev Tuberc 1948; 57(6):547-56.
- McCanlies EC, Kreiss K, Andrew M, Weston A. HLA- DPB1 and chronic beryllium disease: a HuGE review. Am J Epidemiol 2003;157(5):388-98.
- Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 micrograms/m3. Am J Ind Med 1996;30(1):16-25.
- Kelleher PC, Martyny JW, Mroz MM, et al. Beryl- lium particulate exposure and disease relations in a beryllium machining plant. J Occup Environ Med 2001;43(3):238-49.
- Schuler CR, Kent MS, Deubner DC, et al. Process- related risk of beryllium sensitization and disease in a copper-beryllium alloy facility. Am J Ind Med 2005;47(3):195-205.
- Newman LS, Maier LA, Martyny JW, Mroz MM, Van- Dyke M, Sackett HM. Beryllium workers’ health risks. J Occup Environ Hyg 2005;2(6):D48-50.
- Saltini C, Winestock K, Kirby M, Pinkston P, Crystal RG. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells. N Engl J Med 1989;320(17):1103-9.
- Sprince NL, Kanarek DJ, Weber AL, Chamberlin RI, Kazemi H. Reversible respiratory disease in beryllium workers. Am Rev Respir Dis 1978;117(6):1011-7.
- Stoeckle JD, Hardy HL, Weber AL. Chronic beryl- lium disease: Long-term follow-up of sixty cases and selective review of the literature. Am J Med 1969; 46(4):545-61.
- Newman LS, Kreiss K. Nonoccupational beryllium dis- ease masquerading as sarcoidosis: identification by blood lymphocyte proliferative response to beryllium. Am Rev Respir Dis 1992;145(5):1212-4.
- Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of dis- ease definition and natural history. Am Rev Respir Dis 1989;139(6):1479-86.
- Newman LS, Mroz MM, Maier LA, Daniloff EM, Balkis- soon R. Efficacy of serial medical surveillance for chronic beryllium disease in a beryllium machining plant. J Occup Environ Med 2001;43(3):231-7.
- Freiman DG, Hardy HL. Beryllium disease. The re- lation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the U.S. beryllium case registry. Hum Pathol 1970;1(1): 25-44.
- Sterner JH, Eisenbud M. Epidemiology of beryl- lium intoxication. AMA Arch Ind Hyg Occup Med 1951;4(2):123-51.
- Curtis GH. The diagnosis of beryllium disease, with special reference to the patch test. AMA Arch Ind Health 1959;19(2):150-3.
- Curtis GH. Cutaneous hypersensitivity due to beryl- lium; a study of thirteen cases. AMA Arch Derm Syphi- lol 1951;64(4):470-82.
- Tinkle SS, Antonini JM, Rich BA, et al. Skin as a route of exposure and sensitization in chronic beryllium dis- ease. Environ Health Perspect 2003;111(9):1202-8.
- Hanifin JM, Epstein WL, Cline MJ. In vitro studies on granulomatous hypersensitivity to beryllium. J Invest Dermatol 1970;55(4):284-8.
- Deodhar SD, Barna BP. Immune mechanisms in beryl- lium lung disease. Cleve Clin J Med 1991;58(2):157- 60.
- Sawyer RT, Day BJ, Fadok VA, et al. Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease. Am J Respir Cell Mol Biol 2004; 31(4):470-7.
- Epstein PE, Dauber JH, Rossman MD, Daniele RP. Bronchoalveolar lavage in a patient with chronic beryl- liosis: evidence for hypersensitivity pneumonitis. Ann Intern Med 1982;97(2):213-6.
- Rossman MD, Kern JA, Elias JA, et al. Proliferative response of bronchoalveolar lymphocytes to beryl- lium. A test for chronic beryllium disease. Ann Intern Med 1988; 108(5):687-93.
- Newman LS, Bobka C, Schumacher B. Compart- mentalized immune response reflects clinical sever- ity of beryllium disease. Am J Respir Crit Care Med 1994;150(1):135-42.
- Eisenbud M, Lisson J. Epidemiological aspects of be- ryllium-induced nonmalignant lung disease: a 30-year update. J Occup Med 1983;25(3):196-202.
- Denardi JM, Van Ordstrand HS, Curtis GH, Zielinski J. Berylliosis; summary and survey of all clinical types observed in a twelve-year period. AMA Arch Ind Hyg Occup Med 1953;8(1):1-24.
- Apostoli P, Schaller KH. Urinary beryllium-a suitable tool for assessing occupational and environmental beryllium exposure? Int Arch Occup Environ Health 2001;74(3):162-6.
- Stefaniak AB, Hoover MD, Dickerson RM, et al. Sur- face area of respirable beryllium metal, oxide, and copper alloy aerosols and implications for assess- ment of exposure risk of chronic beryllium disease. AIHA J (Fairfax, Va) 2003;64(3):297-305.
- Gregory L, Finch JAM, Eidson AF, Hoover MD, Rothenberg SJ. In vitro dissolution characteristics of beryllium oxide and beryllium metal aerosols. J Aeros Sci 1998;19(3):333-42.
- Eidson AF, Taya A, Finch GL, Hoover MD, Cook C. Dosimetry of beryllium in cultured canine pulmonary alveolar macrophages. J Toxicol Environ Health 1991;34(4):433-48.
- Stefaniak AB, Guilmette RA, Day GA, Hoover MD, Breysse PN, Scripsick RC. Characterization of pha- golysosomal simulant fluid for study of beryllium aero- sol particle dissolution. Toxicol In Vitro 2005;19(1):123- 34.
- Day GA, Hoover MD, Stefaniak AB, et al. Bioavail- ability of beryllium oxide particles: an in vitro study in the murine J774A.1 macrophage cell line model. Exp Lung Res 2005;31(3):341-60.
- Abbas AK, Lichtman AH, Pober JS. Cellular and Mo- lecular Immunology. WB Saunders Co: Philadelphia, 2000.
- Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383(6603):787- 93.
- O’Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Im- munity 1998;8(3):275-83.
- Fontenot AP, Maier LA. Genetic susceptibility and immune-mediated destruction in beryllium-induced disease. Trends Immunol 2005;26(10):543-9.
- Saltini C, Kirby M, Trapnell BC, Tamura N, Crystal RG. Biased accumulation of T lymphocytes with “memory”- type CD45 leukocyte common antigen gene expres- sion on the epithelial surface of the human lung. J Exp Med 1990;171(4):1123-40.
- Fontenot AP, Canavera SJ, Gharavi L, Newman LS, Kotzin BL. Target organ localization of memory CD4(+) T cells in patients with chronic beryllium dis- ease. J Clin Invest 2002;110(10):1473-82.
- Fontenot AP, Palmer BE, Sullivan AK, et al. Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response. J Clin Invest 2005;115(10):2886-93.
- Fontenot AP, Kotzin BL. Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity. Tissue Antigens 2003;62(6):449-58.
- Fontenot AP, Newman LS, Kotzin BL. Chronic beryl- lium disease: T cell recognition of a metal presented by HLA-DP. Clin Immunol 2001;100(1):4-14.
- Tinkle SS, Kittle LA, Schumacher BA, Newman LS. Beryllium induces IL-2 and IFN-gamma in berylliosis. J Immunol 1997;158(1):518-26.
- Tinkle SS, Kittle LA, Newman LS. Partial IL-10 inhibi- tion of the cell-mediated immune response in chronic beryllium disease. J Immunol 1999;163(5):2747-53.
- Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 gluta- mate 69: a genetic marker of beryllium disease. Sci- ence 1993;262(5131):242-4.
- Wang Z, White PS, Petrovic M, et al. Differential sus- ceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles. J Immunol 1999163(3):1647-53.
- Rossman MD, Stubbs J, Lee CW, Argyris E, Magira E, Monos D. Human leukocyte antigen Class II amino acid epitopes: susceptibility and progression markers for beryllium hypersensitivity. Am J Respir Crit Care Med 2002;165(6):788-94.
- Maier LA, McGrath DS, Sato H, et al. Influence of MHC class II in susceptibility to beryllium sensiti- zation and chronic beryllium disease. J Immunol 2003;171(12):6910-8.
- Amicosante M, Berretta F, Franchi A, et al. HLA-DP- unrestricted TNF-alpha release in beryllium-stimulat- ed peripheral blood mononuclear cells. Eur Respir J 2002;20(5):1174-8.
- Galanis A, Karapetsas A, Sandaltzopoulos R. Metal- induced carcinogenesis, oxidative stress and hypoxia signalling. Mutat Res 2009;674(1-2):31-5.
- IATC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC monographs on the evaluation of carcinogenic risks to hummans. World Health Organization. Lyon, 1993.
- Henschler D. Gesundheitsschädliche Arbeitsstoffe: toxikologisch-arbeitsmedizinische von MAK-Werten (Maximale Arbeitsplazt-Konzentra- tionen). Wiley-VHC. Weinheim, 2003. Begründungen
- Zakour RA, Glickman BW. Metal-induced mutagen- esis in the lacI gene of Escherichia coli. Mutat Res 1984;126(1):9-18.
- Joseph P, Muchnok T, Ong T. Gene expression profile in BALB/c-3T3 cells transformed with beryllium sul- fate. Mol Carcinog 2001;32(1):28-35.
- Misra UK, Gawdi G, Akabani G, Pizzo SV. Cadmi- um-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. Cell Signal 2002;14(4):327-40.
- Keshava N, Zhou G, Spruill M, Ensell M, Ong TM. Carcinogenic potential and genomic instability of be- ryllium sulphate in BALB/c-3T3 cells. Mol Cell Bio- chem 2001;222(1-2):69-76.
- Belinsky SA, Snow SS, Nikula KJ, Finch GL, Tellez CS, Palmisano WA. Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens. Car- cinogenesis 2002;23(2):335-9.
- Nickell-Brady C, Hahn FF, Finch GL, Belinsky SA. Analysis of K-ras, p53 and c-raf-1 mutations in be- ryllium-induced rat lung tumors. Carcinogenesis 1994;15(2):257-62.
- Creedon FT, Delahant AB, Durkan TM, Schepers GW. The biological action of inhaled beryllium sulfate; a preliminary chronic toxicity study on rats. AMA Arch Ind Health 1957;15(1):32-58.
- Vorwald AJ, Reeves AL. Pathologic changes induced by beryllium compounds; experimental studies. AMA Arch Ind Health 1959;19(2):190-9.
- Reeves AL, Deitch D, Vorwald AJ. Beryllium carcino- genesis. I. Inhalation exposure of rats to beryllium sul- fate aerosol. Cancer Res 1967;27(3):439-45.
- Vorwald AJ. The induction of experimental pulmonary cancer in the primate (Abstract I-07-e).Springer. Ber- lin, Germany, 1967.