Abstract
Hepatocellular carcinoma (HCC) is a common form of cancer that arises from hepatocytes and whose risk may be affected by several known factors, including viruses, alcohol, cigarette smoking, and several genetic conditions. Liver angiosarcoma is a rare cancer that develops from endothelial cells and whose most relevant known risk factor is occupational exposure to vinyl chloride (VC). Since occupational exposure to high levels of VC may still occur, we reviewed the epidemiological and experimental evidence supporting the notion that inhalation exposure to VC is a risk factor for HCC. We find that available epidemiological evidence is based on a dose-risk study with 10 HCC cases and on a partially overlapping study reporting similar results: neither study provided controls for known non-occupational confounders for HCC. Carcinogenesis bioassays of VC inhalation in rodents indicate that angiosarcomas account for nearly all liver tumors induced. Thus, the role of inhalation exposure to VC in HCC risk remains unclear, awaiting further studies and the integration of results from epidemiological studies and animal models.
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References
El Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576. doi:10.1053/j.gastro.2007.04.061
Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687. doi:10.1038/nrc1934
Grosse Y, Baan R, Straif K et al (2007) Carcinogenicity of 1, 3-butadiene, ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide. Lancet Oncol 8:679–680. doi:10.1016/S1470-2045(07)70235-8
Mundt KA, Dell LD, Austin RP, Luippold RS, Noess R, Bigelow C (2000) Historical cohort study of 10 109 men in the North American vinyl chloride industry, 1942–72: update of cancer mortality to 31 December 1995. Occup Environ Med 57:774–781. doi:10.1136/oem.57.11.774
Ward E, Boffetta P, Andersen A et al (2001) Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry. Epidemiology 12:710–718. doi:10.1097/00001648-200111000-00021
Kielhorn J, Melber C, Wahnschaffe U, Aitio A, Mangelsdorf I (2000) Vinyl chloride: still a cause for concern. Environ Health Perspect 108:579–588. doi:10.2307/3434875
Ottenwalder H, Bolt HM (1980) Metabolic activation of vinyl chloride and vinyl bromide by isolated hepatocytes and hepatic sinusoidal cells. J Environ Pathol Toxicol 4:411–417
el Ghissassi F, Barbin A, Bartsch H (1998) Metabolic activation of vinyl chloride by rat liver microsomes: low-dose kinetics and involvement of cytochrome P450 2E1. Biochem Pharmacol 55:1445–1452. doi:10.1016/S0006-2952(97)00645-X
Morinello EJ, Ham AJ, Ranasinghe A, Nakamura J, Upton PB, Swenberg JA (2002) Molecular dosimetry and repair of N(2), 3-ethenoguanine in rats exposed to vinyl chloride. Cancer Res 62:5189–5195
Swenberg JA, Bogdanffy MS, Ham A et al (1999) Formation and repair of DNA adducts in vinyl chloride- and vinyl fluoride-induced carcinogenesis. In: Singer B, Bartsch H (eds) DNA Cyclic Adducts. IARC, Lyon, pp 29–43
Barbin A, Ohgaki H, Nakamura J, Kurrer M, Kleihues P, Swenberg JA (2003) Endogenous deoxyribonucleic Acid (DNA) damage in human tissues: a comparison of ethenobases with aldehydic DNA lesions. Cancer Epidemiol Biomarkers Prev 12:1241–1247
Hagenlocher T, Nair J, Becker N, Korfmann A, Bartsch H (2001) Influence of dietary fatty acid, vegetable, and vitamin intake on etheno-DNA adducts in white blood cells of healthy female volunteers: a pilot study. Cancer Epidemiol Biomarkers Prev 10:1187–1191
Bartsch H, Nair J (2000) Ultrasensitive and specific detection methods for exocylic DNA adducts: markers for lipid peroxidation and oxidative stress. Toxicology 153:105–114. doi:10.1016/S0300-483X(00)00307-3
Ottenwalder H, Kappus H, Bolt HM (1983) Covalent protein binding of vinyl chloride metabolites during co-incubation of freshly isolated hepatocytes and hepatic sinusoidal cells of rats. Arch Toxicol 6:266–270
Eckardt F, Muliawan H, de Ruiter N, Kappus H (1981) Rat hepatic vinyl chloride metabolites induce gene conversion in the yeast strain D7RAD in vitro and in vivo. Mutat Res 91:381–390. doi:10.1016/0165-7992(81)90019-1
Kuchenmeister F, Wang M, Klein RG, Schmezer P (1996) Transport of reactive metabolites of procarcinogens between different liver cell types, as demonstrated by the single cell microgel electrophoresis assay. Toxicol Lett 88:29–34. doi:10.1016/0378-4274(96)03714-9
Barbin A (1999) Role of etheno DNA adducts in carcinogenesis induced by vinyl chloride in rats. IARC Sci Publ 303–313. Lyon, France, IARC. Exocycle DNA adducts in mutagenesis and carcinogenesis.
Jones RB, Mackrodt WC (1983) Structure-genotoxicity relationship for aliphatic epoxides. Biochem Pharmacol 32:2359–2362. doi:10.1016/0006-2952(83)90189-2
Gad MZ (1994) The distribution of non-specific carboxylesterases and glutathione S-transferases in different rat liver cells. Effects of vitamin A deficiency. Biochem Pharmacol 48:139–144. doi:10.1016/0006-2952(94)90233-X
Steinberg P, Schladt L, Dienes HP, Timms C, Oesch F (1988) Microsomal and cytosolic epoxide hydrolases, the peroxisomal fatty acid beta-oxidation system and catalase. Activities, distribution and induction in rat liver parenchymal and non-parenchymal cells. Eur J Biochem 176:39–45. doi:10.1111/j.1432-1033.1988.tb14248.x
Hastings RH, Summers-Torres D, Burton D, Deftos L (1999) Growth factor control of type II cell apoptosis. Chest 116:68S. doi:10.1378/chest.116.suppl_1.68S
Holt S, Roy G, Mitra S, Upton PB, Bogdanffy MS, Swenberg JA (2000) Deficiency of N-methylpurine-DNA-glycosylase expression in nonparenchymal cells, the target cell for vinyl chloride and vinyl fluoride. Mutat Res 460:105–115
Gokel JM, Liebezeit E, Eder M (1976) Hemangiosarcoma and hepatocellular carcinoma of the liver following vinyl chloride exposure. a report of two cases. Virchows Arch Pathol Anat Histol 372:195–203. doi:10.1007/BF00433279
Evans DM, Williams WJ, Kung IT (1983) Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology 7:377–388. doi:10.1111/j.1365-2559.1983.tb02251.x
Saurin JC, Taniere P, Mion F et al (1997) Primary hepatocellular carcinoma in workers exposed to vinyl chloride: a report of two cases. Cancer 79:1671–1677. doi:10.1002/(SICI)1097-0142(19970501)79:9<1671::AID-CNCR6>3.0.CO;2-F
Infante PF (1981) Observations of the site-specific carcinogenicity of vinyl chloride to humans. Environ Health Perspect 41:89–94. doi:10.2307/3429299
Ferrell L (2000) Liver pathology: cirrhosis, hepatitis, and primary liver tumors. Update and diagnostic problems. Mod Pathol 13:679–704. doi:10.1038/modpathol.3880119
Levy AD (2002) Malignant liver tumors. Clin Liver Dis 6:147–164. doi:10.1016/S1089-3261(03)00070-9
McLaughlin JK, Lipworth L (1999) A critical review of the epidemiologic literature on health effects of occupational exposure to vinyl chloride. J Epidemiol Biostat 4:253–275
Boffetta P, Matisane L, Mundt KA, Dell LD (2003) Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality. Scand J Work Environ Health 29:220–229
Pirastu R, Baccini M, Biggeri A, Comba P (2003) Epidemiologic study of workers exposed to vinyl chloride in Porto Marghera: mortality update. Epidemiol Prev 27:161–172
Mastrangelo G, Fedeli U, Fadda E et al (2004) Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake. Environ Health Perspect 112:1188–1192
Wong RH, Chen PC, Du CL, Wang JD, Cheng TJ (2002) An increased standardised mortality ratio for liver cancer among polyvinyl chloride workers in Taiwan. Occup Environ Med 59:405–409. doi:10.1136/oem.59.6.405
Wong RH, Chen PC, Wang JD, Du CL, Cheng TJ (2003) Interaction of vinyl chloride monomer exposure and hepatitis B viral infection on liver cancer. J Occup Environ Med 45:379–383. doi:10.1097/01.jom.0000063622.37065.fd
Bosetti C, La Vecchia C, Lipworth L, McLaughlin JK (2003) Occupational exposure to vinyl chloride and cancer risk: a review of the epidemiologic literature. Eur J Cancer Prev 12:427–430. doi:10.1097/00008469-200310000-00012
Maltoni C, Lefemine G, Ciliberti A, Cotti G, Carretti D (1981) Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environ Health Perspect 41:3–29. doi:10.2307/3429291
Badzioch M, Eeles R, Leblanc G et al (2000) Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/BPG UK familial prostate cancer study coordinators and collaborators. The EU biomed collaborators. J Med Genet 37:947–949. doi:10.1136/jmg.37.12.947
Haseman JK, Huff JE, Rao GN, Arnold JE, Boorman GA, McConnell EE (1985) Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and (C57BL/6N X C3H/HeN)F1 (B6C3F1) mice. J Natl Cancer Inst 75:975–984
Tennekes H, Gembardt C, Dammann M, van Ravenzwaay B (2004) The stability of historical control data for common neoplasms in laboratory rats: adrenal gland (medulla), mammary gland, liver, endocrine pancreas, and pituitary gland. Regul Toxicol Pharmacol 40:18–27. doi:10.1016/j.yrtph.2004.04.003
Haseman JK, Winbush JS, O’Donnell MW Jr (1986) Use of dual control groups to estimate false positive rates in laboratory animal carcinogenicity studies. Fundam Appl Toxicol 7:573–584. doi:10.1016/0272-0590(86)90107-7
Pollard M, Luckert PH (1979) Spontaneous liver tumors in aged germfree Wistar rats. Lab Anim Sci 29:74–77
Reitz RH, Gargas ML, Andersen ME, Provan WM, Green TL (1996) Predicting cancer risk from vinyl chloride exposure with a physiologically based pharmacokinetic model. Toxic Appl Pharmacol 137:253–267. doi:10.1006/taap.1996.0079
Clewell HJ, Gentry PR, Gearhart JM, Allen BC, Andersen ME (2001) Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci Total Environ 274:37–66. doi:10.1016/S0048-9697(01)00730-6
Gold LS, Slone TH, Manley NB, Bernstein L (1991) Target organs in chronic bioassays of 533 chemical carcinogens. Environ Health Perspect 93:233–246. doi:10.2307/3431194
Vesselinovitch SD, Koka M, Mihailovich N, Rao KV (1984) Carcinogenicity of diethylnitrosamine in newborn, infant, and adult mice. J Cancer Res Clin Oncol 108:60–65. doi:10.1007/BF00390974
Espandiari P, Robertson LW, Srinivasan C, Glauert HP (2005) Comparison of different initiation protocols in the resistant hepatocyte model. Toxicology 206:373–381. doi:10.1016/j.tox.2004.07.014
Enomoto N, Kitamura T, Hirose M, Ikejima K, Watanabe S, Sato N (1998) Differential Ca2 +signaling in neonatal and adult rat hepatocyte doublets. J Hepatol 28:221–230. doi:10.1016/0168-8278(88)80009-6
Institute of Laboratory Animal Resources (1980) Histologic typing of liver tumors of the rat. J Natl Cancer Inst 64:177–206
Bomhard E, Karbe E, Loeser E (1986) Spontaneous tumors of 2000 Wistar TNO/W.70 rats in two-year carcinogenicity studies. J Environ Pathol Toxicol Oncol 7:35–52
Poteracki J, Walsh KM (1998) Spontaneous neoplasms in control Wistar rats: a comparison of reviews. Toxicol Sci 45:1–8. doi:10.1093/toxsci/45.1.1
King-Herbert A, Thayer K (2006) NTP workshop: animal models for the NTP rodent cancer bioassay: stocks and strains–should we switch? Toxicol Pathol 34:802–805. doi:10.1080/01926230600935938
Dragani TA, Manenti G, Della Porta G (1987) Genetic susceptibility to murine hepatocarcinogenesis is associated with high growth rate of NDEA-initiated hepatocytes. J Cancer Res Clin Oncol 113:223–229. doi:10.1007/BF00396377
Gariboldi M, Manenti G, Canzian F et al (1993) Chromosome mapping of murine susceptibility loci to liver carcinogenesis. Cancer Res 53:209–211
Drew RT, Boorman GA, Haseman JK, McConnell EE, Busey WM, Moore JA (1983) The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxic Appl Pharmacol 68:120–130. doi:10.1016/0041-008X(83)90361-7
Peto R, Gray R, Brantom P, Grasso P (1991) Dose and time relationships for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine. Cancer Res 51:6452–6469
Waddell WJ (2005) Comparisons of thresholds for carcinogenicity on linear and logarithmic dosage scales. Hum Exp Toxicol 24:325–332. doi:10.1191/0960327105ht525oa
Rozman KK (2003) Letter to the editor. Toxicol Sci 75:224–225. doi:10.1093/toxsci/kfg176
Baan R, Straif K, Grosse Y et al (2007) Carcinogenicity of alcoholic beverages. Lancet Oncol 8:292–293. doi:10.1016/S1470-2045(07)70099-2
Lee CC, Bhandari JC, Winston JM, House WB, Dixon RL, Woods JS (1978) Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 4:15–30
Hong CB, Winston JM, Thornburg LP, Lee CC, WSoods JS (1981) Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health 7:909–924
Maltoni C, Lefemine G, Ciliberti A, Cotti G, Carretti D (1984) Experimental research on vinyl chloride carcinogenesis. Princeton Scientific Publishers Inc. Arch Res Ind Carcinog
Laib RJ, Klein KP, Bolt HM (1985) The rat liver foci bioassay: I. Age-dependence of induction by vinyl chloride of ATPase-deficient foci. Carcinogenesis 6:65–68. doi:10.1093/carcin/6.1.65
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Dragani, T.A., Zocchetti, C. Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma. Cancer Causes Control 19, 1193–1200 (2008). https://doi.org/10.1007/s10552-008-9188-8
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DOI: https://doi.org/10.1007/s10552-008-9188-8