Increased Risk of Hepatocellular Carcinoma and Liver Cirrhosis in Vinyl Chloride Workers: Synergistic Effect of Occupational Exposure with Alcohol Intake
Mastrangelo, Giuseppe, Fedeli, Ugo, Fadda, Emanuela, Valentini, Flavio, Agnesi, Roberto, Magarotto, Giancarlo, Marchi, Teresio, Buda, Andrea, Pinzani, Massimo, Martines, Diego, Environmental Health Perspectives
Hepatocellular carcinoma (HCC) and liver cirrhosis (LC) are not well-established vinyl chloride monomer (VCM)-induced diseases. Our aim was to appraise the role of VCM, alcohol intake, and viral hepatitis infection, and their interactions, in the etiology of HCC and LC. Thirteen cases of HCC and 40 cases of LC were separately compared with 139 referents without chronic liver diseases or cancer in a case-referent study nested in a cohort of 1,658 VCM workers. The odds ratios (ORs) and the 95% confidence intervals (CIs) were estimated by common methods and by fitting models of logistic regression. We used Rothman's synergy index (S) to evaluate interactions. By holding the confounding factors constant at logistic regression analysis, each extra increase of 1,000 ppm x years of VCM cumulative exposure was found to increase the risk of HCC by 71% (OR = 1.71; 95% CI, 1.28-2.44) and the risk of LC by 37% (OR = 1.37; 95% CI, 1.13-1.69). The joint effect of VCM exposure above 2,500 ppm x years and alcohol intake above 60 g/day resulted in ORs of 409 (95% CI, 19.6-8,553) for HCC and 752 (95% CI, 55.3-10,248) for LC; both S indexes suggested a synergistic effect. The joint effect of VCM exposure above 2,500 ppm x years and viral hepatitis infection was 210 (95% CI, 7.13-6,203) for HCC and 80.5 (95% CI, 3.67-1,763) for LC; both S indexes suggested an additive effect. In conclusion, according to our findings, VCM exposure appears to be an independent risk factor for HCC and LC interacting synergistically with alcohol consumption and additively with viral hepatitis infection. Key words." alcohol, case-referent studies, cirrhosis, hepatocellular carcinoma, occupational diseases, vinyl chloride. Environ Health Perspect 112:1188-1192 (2004). doi:10.1289/ehp.6972 available via http://dx.doi.org/[Online 27 May 2004]
Although a large body of evidence from experimental and epidemiologic studies has demonstrated the relationship between exposure to vinyl chloride monomer (VCM) and angiosarcoma [International Agency for Research on Cancer (IARC) 1987; Lee et al. 1996], there is little evidence of a causal association between VCM and hepatocellular carcinoma (HCC) and liver cirrhosis (LC).
In their study on the U.S. cohort of VCM-exposed workers, Mundt et al. (2000) found an increased risk of liver cancer, mainly liver angiosarcomas. In the study, however, they distinguished HCC from angiosarcoma on the basis of information on the cause of death reported in death certificates. In the European cohort of VCM workers, Ward et al. (2001) searched for the best evidence of liver cancer by reviewing all available documentation and found a marked exposure-response relationship for all liver cancers (71 cases), angiosarcoma (37 cases), and HCC (10 cases). This evidence is also inconclusive because the number of HCC cases was small, there was a disproportionate excess of liver cancers with "other and unknown histology," and the risk estimates were not adjusted for the influence of well-known risk factors for HCC: alcohol consumption and viral infection. Recently Wong et al. (2003) suggested an interaction between occupational VCM exposure and hepatitis B virus (HBV) infection in the development of liver cancer.
Data on an association between VCM and LC are even scarcer and are inconclusive. Du and Wang (1998) reported a significantly increased number of hospital admissions among Taiwanese VCM workers due to primary liver cancer and cirrhosis of the liver. In the European cohort of vinyl chloride workers, Ward et al. (2001) reported that overall mortality from cirrhosis was decreased, although there was a trend toward an increase in cirrhosis mortality proportionate to an increase in cumulative exposure. In this case, risk estimates were not adjusted for the confounding influence of alcohol consumption and HBV infection.
Pirastu et al. (2003) reported on a cohort of 1,658 workers employed in a VCM manufacturing plant, in which the standardized mortality ratio (SMR) for primary liver cancer of 2. …