Vinyl chloride and the liver: Misrepresentation of epidemiological evidence
Authors: Giuseppe Mastrangelo, Diego Martines, Ugo Fedeli
Journal: Journal of Hepatology (2010)

Vinyl chloride and the liverJournal of HepatologyVol. 51Issue 6PreviewVinyl chloride monomer is a known cause of angiosarcoma of the liver. It also has other toxic effects on the liver, and it has recently been suggested that exposure to vinyl chloride also causes hepatocellular carcinoma. However, the data on which this conclusion is based is incomplete. There is inadequate ascertainment of unequivocal diagnoses. In the largest studies lack of data meant that confounding diseases such as viral hepatitis or alcoholic liver disease could not be assessed. At best, the increase in risk is minimal, based on more than 22,000 exposed workers and more than 640,000 person years of observation. Full-Text PDF Open Access In reviewing the epidemiological literature on vinyl chloride monomer (VCM) and hepatocellular carcinoma (HCC), Sherman incurred errors and misrepresentation of the overall evidence [[1]Sherman M. Vinyl chloride and the liver.J Hepatol. 2009; 51: 1074-1081Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. First, the author provides a surprising estimate of an annual incidence of liver angiosarcoma (LAS) among US exposed workers equal to 0.014/100,000. This is probably the incidence of LAS in the US general population which was about 0.014–0.025/100,000 in 1964–1974 [[2]Falk H. Herbert J. Crowley S. Ishak K.G. Thomas L.B. Popper H. et al.Epidemiology of epatic angiosarcoma in the United States 1964–1974.Environ Health Perspect. 1981; 41: 107-113Crossref PubMed Scopus (111) Google Scholar]. Indeed, the mortality (close to incidence) rate was 15.2/100,000 (48 cases in 316,520 person-years) in the North American cohort of VCM workers [[3]Mundt K.A. Dell L.D. Austin R.P. Luippold R.S. Noess R. Bieglow C. 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. 2000; 57: 774-781Crossref PubMed Scopus (86) Google Scholar], three orders of magnitude higher than that reported by Sherman. Second, the author contradicts himself in regards to the association between VCM and HCC in the European cohort [[4]Ward E. Boffetta P. Andersen A. Colin D. Comba P. Deddens J.A. et al.Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry.Epidemiology. 2001; 12: 710-718Crossref PubMed Scopus (103) Google Scholar], affirming, on page 1077, that "this study did not suggest that there was a dose–response relationship between exposure and the development of HCC", and on page 1080 that "there seems to be a trend towards a higher HCC death rate with increasing dose". Third, our case–control study [[5]Mastrangelo G. Fedeli U. Fadda E. Valentini F. Agnesi R. Magarotto G. et al.Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake.Environ Health Perspect. 2004; 112: 1188-1192Crossref PubMed Scopus (77) Google Scholar] was presented as a "cohort study" on page 1078, while on page 1077 the study from Ward (cohort study) [[4]Ward E. Boffetta P. Andersen A. Colin D. Comba P. Deddens J.A. et al.Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry.Epidemiology. 2001; 12: 710-718Crossref PubMed Scopus (103) Google Scholar] and that from Boffetta (meta-analysis of cohort studies) [[6]Boffetta P. Matisane L. Mundt K.A. Dell L.D. Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality.Scand J Work Environ Health. 2003; 29: 220-229Crossref PubMed Scopus (79) Google Scholar] were confused with "case–control studies". In the same statement, Sherman affirms that "case–control studies" use "non-exposed workers as controls". This is similarly incorrect, since controls in a case–control study are subjects without disease and not without exposure. Fourth, he reports that case–control studies used office workers as controls, with non-comparability with cases in regards to viral hepatitis and alcohol consumption. This is not true, as the only case–control study that he cites is our study [[5]Mastrangelo G. Fedeli U. Fadda E. Valentini F. Agnesi R. Magarotto G. et al.Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake.Environ Health Perspect. 2004; 112: 1188-1192Crossref PubMed Scopus (77) Google Scholar], where cases and controls were all blue-collar workers coming from the same VCM plant. Fifth, he claims that in our analyses when examining interactions, each cell contained 10 or fewer cases, making results unreliable even if statistically significant. Nonetheless, if the reader does not like the analysis of interactions, he can rely on the full analysis of thirteen cases of HCC and 40 cases of liver cirrhosis (LC), that were separately compared to 139 referents without chronic liver diseases or cancer in a case–control study nested in a cohort of 1658 VCM workers. By holding the confounding factors (alcohol, age, markers of B/C viruses) constant at logistic regression, each extra increase of 1000 ppm × years of VCM cumulative exposure was found to increase the risk of HCC by 71% (odds ratio, OR = 1.71; 95% confidence interval, CI = 1.28–2.44) and the risk of LC by 37% (OR = 1.37; CI = 1.13–1.69) [[5]Mastrangelo G. Fedeli U. Fadda E. Valentini F. Agnesi R. Magarotto G. et al.Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake.Environ Health Perspect. 2004; 112: 1188-1192Crossref PubMed Scopus (77) Google Scholar]. Sixth, Sherman reports that results from our study are doubtful because cumulative exposure was associated with cirrhosis but is also a function of age. Indeed, our analyses were stratified for year of birth (controlling for age carried similar results). Furthermore, he states that the same objection applies to the study of Pirastu et al. [[7]Pirastu R. Baccini M. Biggeri A. Comba P. Epidemiologic study of workers exposed to vinyl chloride in Porto Marghera: mortality update.Epidemiol Prev. 2003; 27: 161-172PubMed Google Scholar]. This does not make sense, since this was a cohort study where the measure of association (standardized mortality ratio) takes into account age and calendar period. Seventh, Sherman claims that an ascertainment bias could have affected the diagnosis of HCC in the epidemiological studies reviewed since they rely upon death certificates and not "upon autopsy data, biopsy data, angiography or a diagnostic elevated AFP" (alpha-fetoprotein, a serological marker of HCC, is rarely increased in LAS). In our study [[5]Mastrangelo G. Fedeli U. Fadda E. Valentini F. Agnesi R. Magarotto G. et al.Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake.Environ Health Perspect. 2004; 112: 1188-1192Crossref PubMed Scopus (77) Google Scholar], however, out of 13 cases of HCC, eight were confirmed by histology and five based on the criteria – focal hepatic lesions at ultrasonography and alpha-fetoprotein greater than 400 μg/L – issued by the Italian Association Study of Liver and British Society of Gastroenterology [[8]Ryder S.D. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults.Gut. 2003; 52: 1-8PubMed Google Scholar]. The author declares in a footnote to be "consultant to the European Council of Vinyl Manufacturer's for the workshop on the relationship between VCM and HCC" [[1]Sherman M. Vinyl chloride and the liver.J Hepatol. 2009; 51: 1074-1081Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. Furthermore, in his conclusion Sherman cites as supporting evidence only two papers [9Dragani T.A. Zocchetti C. Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma.Cancer Causes Control. 2008; 19: 1193-1200Crossref PubMed Scopus (19) Google Scholar, 10McLaughlin J.K. Lipworth L. A critical review of the epidemiologic literature on health effects of occupational exposure to vinyl chloride.J Epidemiol Biostat. 1999; 4: 253-275PubMed Google Scholar] – two reviews both written by consultants of the vinyl chloride industry in a lawsuit against the management of a VCM plant. We think that a conflict of interests does not represent a fatal flaw for research until it does not heavily affect the quality of papers. Moreover, in such a specific matter it is difficult not to have some conflict of interest: two authors (G.M. and D.M.) of the present letter were consultants of Public Prosecutors in the above lawsuit. With his paper carrying errors and inconsistencies, Sherman concludes that the relation between VCM and HCC remains "unproven". This is a misrepresentation of the current epidemiological evidence that, according to the International Agency for Research on Cancer, there is "sufficient evidence" that exposure to vinyl chloride in humans causes both HCC and LAS [[11]Grosse Y. Baan R. Straif K. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of 1,3-butadiene, ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide.Lancet Oncol. 2007; 8: 679-680Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Two of the authors (G.M. and D.M.) were consultants of Italian Government and Public Prosecutors in a lawsuit opposing workers, local municipalities, and the Italian Government against the management of an Italian vinyl chloride plant.