Following an extensive review and evaluation of previous studies, the IARC, first in 1979 and then in 1987 [3, 4], provided sound evidence for a causal association between VC-PVC exposure and liver cancer, as well as tumors of the brain, lung and hemolymphopoietic system. Despite such an authoritative stance on the issue, a good share of epidemiological literature continues to consider liver angiosarcoma as the only proven tumor caused by working in this petrochemical sector, mainly because RRs for this rare tumor have been found to be statistically elevated in almost all published studies [5, 8, 15–18]. Excesses for hepatic tumors other than liver angiosarcoma, when detected, have been considered as misclassifications of angiosarcoma [15, 16]. Risks for other neoplastic and non-neoplastic diseases have been often ignored, with the exception of some findings for brain  and hemolymphopoietic system cancer . Nevertheless, excesses for lung cancer have recently been re-detected in specific subgroups of workers exposed to PVC dust employed in the same Italian plant [8, 19], and our previous studies  found excesses of liver tumors and liver cirrhosis among autoclave workers and of lung cancer among PVC baggers.
In an attempt to clarify these contradictory results, in which the healthy worker effect (HWE) likely played an important role, the same cohort of VC-PVC workers was reanalyzed using an internal comparison group constituted by unexposed (or less exposed) workers, instead of an external population based on general regional or national figures. External comparison is probably one of the major causes of biased results, mainly due to the evaluation of very different populations (likely very healthy workers vs. the mix of healthy and unhealthy people in the general population). Consequently, the HWE may lead to a relative underestimation of the true mortality risks among exposed workers.
Our reanalysis has revealed a significantly elevated risk for all causes of death among exposed blue collar workers compared to unexposed technicians and clerks. Specifically, increased mortality from both liver tumors (RRpm = 9.57; p < 0.05) and liver cirrhosis (RRpm = 2.80; p < 0.10) was observed among autoclave workers, where both an elevated risk of liver angiosarcoma  and the exposure to VC and PVC dusts during reactor cleaning operations have already been documented . A case-control study nested in the same cohort, by holding the confounding factors constant in a logistic regression analysis, found that each extra increase of 1,000 ppm × years of VC cumulative exposure increased the risk of hepatocellular carcinoma by 71% (OR = 1.71; 95% CI, 1.28–2.44) and the risk of liver cirrhosis by 37% (OR = 1.37; 95% CI, 1.13–1.69) .
An increased mortality from all causes (RR = 1.72; p < 0.05) and lung cancer (RR = 3.13; p < 0.10) was clearly observable in PVC baggers. Death risk from lung cancer confirmed a recent case-control study nested in the same cohort, which found a 20% increased risk for this cause of death among PVC baggers for each extra year worked (OR = 1.20; 95% CI = 1.08–1.35; p = 0.0010) after adjustment for age and smoking habits . In addition, previous analyses revealed a statistically significant dose-response relationship (p < 0.05) between duration of employment and lung cancer mortality, and a progressive reduction in mortality after work cessation. The risk decreased from the high value observed 5 years after work cessation (SMR = 2.4) to values lower than unity after 15–20 years . This trend reflected what was observed by Doll and Peto among former smokers after smoking cessation , and also by Mastrangelo et al., who reported that "In our [PVC] baggers, recent rather than distant exposure to PVC dust had the most profound effects on lung cancer risk" .
The main task of PVC compound workers was to mix granular PVC with many other likely toxic and carcinogenic chemical agents (Tab. 1), whose characteristics differed according to the final PVC-based product . Workers performing this task should be considered as a new at risk group, since they showed an increased risk of death from all causes (RR = 1.71; p < 0.05) and from liver cancer (RRpm = 2.46; p < 0.10), and RRs for all tumors combined and lung cancer were increased too, even though increase was not statistically significant.
Other blue collar workers showed excess (not statistically significant) risks of death for nearly all causes considered. This result suggests that high health risks occurred among all workers in this category, in addition to those usually considered at risk (i.e., autoclave workers and PVC baggers).
Deaths from hemolymphopoietic system tumors (14 cases) occurred only among exposed workers (PVC baggers, PVC compound workers, other blue collar workers), preventing any estimate of RR. For this reason, SMRs were calculated and revealed significantly increased values among the total blue collar workforce and specifically among PVC baggers, while PVC compound workers and other blue collar workers showed more than two-fold increased SMRs (not statistically significant). These findings support the causal association already reported in the scientific literature between occupational exposure and hemolymphopoietic system tumors [3, 4].
Attributable number of deaths
The total number of deaths attributable to employment as a blue collar worker in a VC-PVC production plant was estimated to be 83.2 (out of 160) and 81.3 (out of 229) when the follow-up was updated to 1995 and 1999, respectively . The consistency of these values is evidence of the reliability of results.
The longer follow-up did not lead to an increase in the total number of attributable deaths. Actually, while the RR was estimated to be 2.09 after the previous update (1972–1995), it was estimated to be 0.97 for the most recent 5-year period (1995–1999), suggesting that the effect of the exposure to noxious substances – or exposure itself – may have been greater in the past and lower in more recent years. On the other hand, as expected for diseases with a long latency (i.e., tumors), attributable deaths from all tumors increased from 28.1 to 34.9 when the duration of follow-up was increased.
Limitations, strengths and remarkable results
The present epidemiological study, like many other studies on occupational cohorts, lacked information about measures of individual occupational exposures over time during the employment period. Job category and length of employment were used as surrogate indicators of exposure type and cumulative exposure, respectively. Two studies on the same cohort already cited [19, 20] revealed a drawback in the cohort database stemming from a misclassification of both exposure and disease (information bias). In any case, such a misclassification could have led to an underestimation of the risk among exposed workers. A lack of fund prevented a more recent follow-up update, nevertheless the study had a power large enough to detect significant risks. Finally, it could be prudent to bear in mind that the study suffered from some limitation concerning the control of possible confounders, even if it unlikely could have lead to a significant modification of the results, as it will be made clearer afterward.
Despite these limitations, this analysis was, in our opinion, grounded on a reasonable approach and achieved some noteworthy results. First of all, the present reanalysis sought to reduce the comparison bias by using as a reference group – instead of the general population – a working population with limited or null exposure to occupational carcinogenic agents and with hiring criteria and duration of employment similar to those of the exposed group(s) under study. In addition, we tried to avoid another possible source of underestimation of the true risk, i.e. the inclusion of unexposed (or less exposed) workers in the exposed group (misclassification of exposure). In this way, the HWE and the related underestimation of the health risks should have been eliminated or at least controlled. Even if it was not possible to assess whether and how technicians and clerks might differ from the exposed workers other then the exposures of interest, the comparison seemed appropriate, and the socio-economic status of the exposed and unexposed workers should be fairly comparable. For this reason and as it was found to be at low (or null) exposure to toxic and carcinogenic agents , this group of workers (i.e., technicians and clerks) was the best available comparison group, while other blue collar workers included workers employed in different tasks not specialized and/or not confined in a specific workplace, such maintenance staff, cleaning operators, and other workers that handled, or were exposed to, most of the toxic substances listed in table 1. A recent study tried to quantify the possible amount of the bias due to the joint effect of the dilution effect (DE) and the comparison bias (CB) in occupational cohort studies. DE and CB respectively occur when exposed and unexposed workers in a cohort are pooled together and an internal referent group is not used. The study confirmed that "results from occupational cohort studies without internal referent groups may be unreliable" . Then, internal comparison and separating blue collar workers into subgroups with homogenous exposure reduced the possible DE and resulting estimates were likely not biased by confounding due to smoking or to other factors. As suggested by "good epidemiological practice" guidelines , RR estimates obtained using an internal reference are more reliable than those based upon both national and local reference, and, as it was observed, "internal analyses of "dose-response" in cohort studies are unlikely to be seriously confounded by smoking habits" . Within the same cohort analyzed in the present study, Mastrangelo et al.  found a lung cancer risk among baggers comparable to our estimates, but using a case-control approach, that by definition takes smoking (as other confounders) into account. Moreover, a clear dose-response relationship between length of exposure and lung cancer was detected among PVC bagger workers. In fact, not exposed workers and PVC bagger workers with a length of employment – used as a proxy of length of exposure – of 0–5, 6–10 and 10+ years, showed the following SMRs: 64.79, 108.35, 216.45 and 355.86, respectively. As this trend (p = 0.054) was observed among workers belonging to the same job category, it was likely unaffected by confounding effects, including those generated by smoking status. Finally, applying the Axelson approach to indirect adjustment for a confounder, it was clear that smoking unlikely played a major role when lung cancer RR was greater than 1.66 [27, 28].
The two procedures used in this study (i.e. internal comparison and separating blue collar workers into subgroups with homogenous exposure) revealed the pattern of diseases, likely due to exposures to specific occupational risk factors, typical of each subgroup of workers.