If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Increased cancer risk has been reported among workers in the rubber manufacturing industry employed before the 1960s. It is unclear whether risk remains increased among workers hired subsequently. The present study focused on risk of cancer mortality for rubber workers first employed since 1975 in 64 factories.
Patients and methods
Anonymized data from cohorts of rubber workers employed for at least 1 year from Germany, Italy, Poland, Sweden, and the UK were pooled. Standardized mortality ratios (SMRs), based on country-specific death rates, were reported for bladder and lung cancer (primary outcomes of interest), for other selected cancer sites, and for cancer sites with a minimum of 10 deaths in men or women. Analyses stratified by type of industry, period, and duration of employment were carried out.
A total of 38 457 individuals (29 768 men; 8689 women) contributed to 949 370 person-years. No increased risk of bladder cancer was observed [SMR = 0.80, 95% confidence interval (CI) 0.46; 1.38]. The risk of lung cancer death was reduced (SMR = 0.81, 95% CI 0.70; 0.94). No statistically significant increased risk was observed for any other cause of death. A reduced risk was evident for total cancer mortality (SMR = 0.81, 95% CI 0.76; 0.87). Risks were lower for workers in the tyre industry compared with workers in the general rubber goods sector. Analysis by employment duration showed a negative trend with SMRs decreasing with increasing duration of employment. In an analysis of secondary end points, when stratified by type of industry and period of first employment, excess risks of myeloma and gastric cancer were observed each due, essentially, to results from one centre.
No consistent increased risk of cancer death was observed among rubber workers first employed since 1975, no overall analysis of the pooled cohort produced significantly increased risk. Continued surveillance of the present cohorts is required to confirm the absence of long-term risk.
Epidemiological studies have reported increased risk of bladder cancer and leukaemia among workers in the rubber manufacturing industry, mainly among those employed before the 1960s: these excess risks have been associated with exposure to aromatic amines, and solvents, respectively [
]. A narrative (qualitative) review of epidemiological studies published up to 1997 concluded that bladder, laryngeal, lung cancer, and leukaemia were the cancers with an increased risk among rubber workers, with evidence of substantial heterogeneity of results [
]. However, a meta-analysis based on cohort studies published through 2003 showed no excess risk for any of the cancer sites, although there was not differentiation made between natural rubber and synthetic rubber (styrene butadiene) [
]. Recently, the IARC has re-evaluated the rubber industry, and has classified rubber production as a group 1 carcinogen for cancers of the stomach, the lung, and lymphoma in addition to bladder cancer and leukaemia [
], has undergone radical technological changes since the 1950s, entailing major reductions in rubber dust and fume exposure or the removal of known carcinogenic agents, although the changes in technology were gradual and took place at variable pace in different countries. Data collected by the EU-ExAsRub consortium in the rubber manufacturing industry showed a general reduction in the exposure of workers to inhalable dust from the 1970s to 2003, however with marked differences between countries [
] showed no excess risk of overall cancer mortality, as well as bladder, stomach, and lung cancers. The present study reports data on risk of death from cancer and major causes of death from a large-scale epidemiologic study of workers first employed since 1975 in the rubber manufacturing industry from five European countries. This study provides therefore a direct evaluation of risk of cancer in the modern rubber manufacturing industry.
materials and methods
A protocol specifying inclusion criteria and a detailed statistical analysis plan was prepared between local principal investigators of the present study before data analysis (available upon request from the corresponding author). The cohort consisted of rubber workers employed in Germany, Italy, Poland, Sweden, and the UK. Workers were included if they (i) were employed for at least 1 year in one of the cohorts, and (ii) had a first employment in the rubber manufacturing industry at 1 January 1975 or later. This first employment period varied from country to country, being 1981 for the German cohort, 1982 for the UK, and 1975 for all other countries. Factories were distributed throughout all regions in Poland, Sweden, and the UK. For Italy, workers were employed in factories of the north of Italy: in the region of Piemonte (Italy). For Germany, workers were employed in factories located in western Germany in the Federal States of Lower Saxony and North Rhine-Westphalia.
For all countries but Germany, follow-up data were complete until a right censoring date (Table 1). For Germany, the follow-up data and vital status were complete until 2000, and from 2001 to 2003, cause of death and migration status was missing for the majority of workers. The period 2001–2003 was therefore excluded from the analysis for Germany. From 2004 to 2012, vital status became partially available and enabled evaluating vital status and causes of death. In order to avoid underestimation of mortality rates, correction factors, depending on migration and risk of deaths from all causes, were applied to person-years from 2001 onward. These correction factors were estimated from the 2042 workers in Hannover city for which complete information on vital status and migration was available. Sensitivity analyses were conducted to evaluate the influence of these correction factors.
Table 1Characteristics of the five European cohorts of workers first employed in the rubber manufacturing industry since 1975
The primary outcomes of interest were mortality from bladder cancer and lung cancer. Secondary outcomes were mortality from all cancers combined, stomach cancer, leukaemia, multiple myeloma. and non-Hodgkin's lymphoma (NHL). Exploratory outcomes included all other neoplasms with more than 10 observed deaths in men or women in the combined analysis and mortality from cardiovascular diseases, respiratory diseases (without pneumonia), and all-causes. If an exploratory outcome was considered for a particular site, the SMR for the other gender group was reported only if the number of deaths was >5. The list of ICD-9 codes used in the present article is reported in supplementary Table S1, available at Annals of Oncology online.
The observed numbers of deaths for each cause of death considered were compared with the expected number calculated on the basis of national or regional (Italy) gender, age-, and period-specific mortality rates. Five-year age groups were used for age and time period. National reference rates were obtained from the WHO Mortality Database (Revision of November 2014). For Italy, reference rates could be obtained from the region of Piedmont. Data from the Central Statistical Office of Poland were used when data from the WHO mortality database were not available (earlier years for a few cancer sites). For each country, standardized mortality ratios (SMRs, i.e. the ratio of observed to expected deaths) were calculated together with their confidence intervals (CIs) based on the Poisson distribution of observed deaths [
], which take into account potential heterogeneity among cohorts. Forest plots were reported for bladder and lung cancer mortality (primary outcomes) to evaluate the relative contribution of each country in the overall risk estimate.
Measures of heterogeneity was reported using I2 statistics [
As a sensitivity analysis, several stratified analyses were conducted. To evaluate whether the risk differed by type of industry, workers were separated between tyre production, general rubber goods, and a mixed category for factories that manufactured both tyres and general rubber goods. The role of the period of first employment on the risk of death was also investigated separating workers employed before 1985 to those employed from 1985 onwards.
The role of the duration of employment on the risk of death was investigated in a Poisson model with gender and a gender-specific smooth function of duration of employment as explanatory variables, and the logarithm of the expected number of deaths as ‘offset’. Duration of employment was modelled with cubic natural splines and three degrees of freedom. Cut-points (knots) of duration of employment were built from duration of employment of deceased subjects, such as at least eight deaths occurred between two points. The knots for the spline were built in a way that the knots divide duration of employment in intervals that contain the duration of employment of eight deceased workers each. This enables a stable estimation of SMR while keeping enough points for modelling the splines for the parameter of duration.
All data were anonymized before statistical analysis. P-values below 5% were considered as statistically significant.
In the five European countries, a total of 38 457 workers (29 768 men and 8689 women) were included in the present study. Each country contributed rather homogeneously to the number of workers with Poland and the UK providing the greatest number of workers (Table 1). The average follow-up was 26 years and ranged from 18.7 years in Germany to 29.4 years in Poland, contributing to a total of 949 370 person-years of observation. The majority of workers (77.4%) were men. More women were recruited in Poland and Sweden. No major difference was observed between the cohorts assembled by each country. Overall, 2725 deaths were observed during the follow-up.
Table 2 shows observed deaths and SMRs for primary, secondary, and exploratory outcomes for men, women, and both genders combined. In men, there were significantly reduced SMRs for lung cancer, colorectal cancer, all cancers combined, all causes combined, and cardiovascular diseases. In women, there were significantly reduced SMRs for all cancers combined, all causes combined, and cardiovascular diseases. In the total study population (both genders combined), there were significantly reduced SMRs for lung cancer, colorectal cancer, all cancers combined, all causes combined, and cardiovascular diseases.
Table 2Observed deaths and standardized mortality ratios (SMRs) among 38 457 workers first employed in the European rubber manufacturing industry since 1975, by gender
Table 3 shows observed deaths and SMRs for primary and secondary outcomes for men, women, and both genders combined, by industry sector. In the tyre sector, there were significantly reduced SMRs for lung cancer in men and in both genders combined, and for all cancers combined in men, women, and both genders combined. There were no significant excesses. In the general rubber goods sector, there were significantly elevated SMRs for stomach cancer in men and in both genders combined, and for multiple myeloma in men and both genders combined. There were no significant deficits. In the mixed sector, there were significantly reduced SMRs for all cancers combined in men and both genders combined. There were no significant excesses.
Table 3Observed deaths and standardized mortality ratios by type of industry among 38 457 workers first employed in the European rubber manufacturing industry since 1975, by industry sector
Based on 17 deaths observed during the follow-up, the risk of death from bladder cancer was SMR = 0.80 (95% CI 0.46–1.38) with no evidence of heterogeneity between countries (Figure 1). This absence of increased risk for bladder cancer remained when stratified by gender (Table 2), employment period (supplementary Table S2, available at Annals of Oncology online), and type of industry (Table 3). The risk of death from lung cancer was significantly decreased in rubber workers when compared with the general population with an SMR of 0.81 (95% CI 0.70–0.94) with no heterogeneity between countries (Figure 2).
For all other cancer sites as well as all-cause mortality, cardiovascular and respiratory mortality, the risk of death was not significantly increased for neither men nor women (Table 2). On the contrary, a statistically significant decrease was observed for mortality from all causes of cancer (SMR = 0.81, 95% CI 0.76–0.87), all causes of death (SMR = 0.81, 95% CI 0.73–0.89), cardiovascular diseases (SMR = 0.79, 95% CI 0.70–0.89), and for risk of death from colorectal cancer (SMR = 0.72, 95% CI 0.55–0.94). Even if only eight deaths in men were observed for mesothelioma, the SMR was estimated for this cancer site and was 1.32 (95% CI 0.72–2.43). The overall results were not affected by the correction factors applied to person-years in Germany to account for migration and risk of death in the 2001–2003 period with no follow-up information.
Workers in the tyre industry were hired at around the same age as workers in the general rubber goods industry (median age of hire being 23 and 25 years, respectively), and they were followed for about the same duration (25 and 23.5 years, respectively). However, workers in the tyre industry were more frequently men (80% men) than in the general rubber goods industry (74% men). The greatest difference was the duration of employment which was a median of 10.5 years in the tyre industry, while it was 4.2 years in the general rubber good industry. When stratifying workers by type of industry, a clear difference could be observed between these two populations with lower SMR in the tyre industry when compared with general rubber goods (Table 3). For total cancer mortality, the risk of death was SMR = 0.68 (95% CI 0.60–0.76) among workers in the tyre industry while it was close to 1 in workers in the general rubber goods industry with an SMR of 1.03 (95% CI 0.91–1.18) (Figure 3). In this stratified analysis, workers in the general rubber goods industries had a significant increased risk of stomach cancer (SMR = 1.83, 95% CI 1.23–2.72) and multiple myeloma (SMR = 3.18, 95% CI 1.61–6.27). Elevated SMRs were observed only among workers employed before 1985 (supplementary Table S2, available at Annals of Oncology online). These results were not consistent between countries and primarily driven by a majority of deaths in Poland for stomach cancer and a majority of deaths in the UK for multiple myeloma.
Workers employed from 1985 onwards had an apparently, though not significantly lower risk of total cancer mortality with an SMR of 0.74 (95% CI 0.65–0.84) when compared with workers employed before 1985 for which the SMR was 0.86 (95% CI 0.79–0.94). Such a decreased risk in more recently employed workers was also observed for other primary and secondary outcomes (supplementary Table S2, available at Annals of Oncology online).
The risk of death from any cause was further investigated in a Poisson regression with a spline function applied to the duration of employment. With a risk initially above the general population, especially among men and women in general rubber goods production, a marked decline of the risk of death was observed with increasing years of employment (Figure 4, supplementary Figure S2, available at Annals of Oncology online). This trend seemed slightly stronger in men but went in the same direction for women. A similar trend was observed when limiting the analysis to total cancer mortality (supplementary Figure S1, available at Annals of Oncology online). Although difficult to interpret because of small numbers, a similar trend was observed for lung cancer mortality.
In this cohort of workers in the rubber manufacturing industry first employed since 1975 in five European countries, there was no consistent indication of an increased risk of cancer mortality among the cancer sites pre-identified as primary or secondary outcomes of interest, i.e. total cancer mortality, and site-specific mortality for bladder, lung, stomach, leukaemia, myeloma, and NHL. In addition, none of the exploratory outcomes had their risk significantly increased.
There are a number of noticeable issues among a number of stratified analyses showing inconsistencies in the outcomes. In an analysis of secondary end points, when stratified by type of industry and period of first employment, excess risks of myeloma and gastric cancer were observed due, essentially, to results from the UK and Poland, respectively. Increases in risk of multiple myeloma and stomach cancer were observed mainly for the workers first employed before 1985, but not workers employed more recently. It is possible that these increased risks, which are further decreasing in more recently exposed workers, are the result of decrease in exposure to carcinogens. However, these results should be interpreted with caution as they were not consistent across countries, gender, and type of industry, and mainly driven by a few excess deaths observed in the UK for multiple myeloma and a few excess deaths observed in Poland for stomach cancer.
Lung cancer, one of the primary hypotheses of the study, showed decreased risks in most countries. Secondary outcomes such as colorectal cancer, total cancer mortality, all-cause mortality, and cardiovascular diseases also showed decreased risks. The reduction in risks for causes of death was lower for workers in the tyre industries than for the general rubber goods industries. Several factors could be responsible for such a reduced risk. Such a pattern of decreased risk could be the sign of a ‘healthy worker effect’ [
], in particular because the observed numbers of deaths from any cause and for total cancer mortality were systematically lower than expected. The healthy worker effect is a classical bias in epidemiology of occupational mortality and results in biased estimation of SMR when mortality of workers is compared with mortality of the general population. Its impact could play at the inception of cohort of workers with a ‘healthy population selection effect’ and during follow-up with a ‘survivor population effect’ [
In the cohorts of European rubber workers, a decreased risk of all-cause mortality is consistent with a healthy population selection effect, in particular because the follow-up started at recruitment in each cohort [
]. This would be in contradiction with the decreasing trend in SMR for longer duration of employment in rubber workers. However, staying active in the industry could be a secondary effect of selection with less healthy workers being more likely to be removed from hazardous exposure than healthier workers [
]. In the present study, SMRs were significantly decreased for several cancer sites with values even lower than the total mortality.
The difference between tyre industry and general rubber goods could be an artefact with workers in the general rubber goods industry were employed for a shorter duration. However, the effect of type of industry and duration of employment seemed independent when conducting the spline regression separately by type on industry (supplementary Figure S2, available at Annals of Oncology online). This indicates that both working in the tyre industry and for a long duration were actually associated with a decreased risk of overall mortality. In contrast, in the general rubber goods industry, a similar healthy worker effect was not evident for total mortality: elevated SMRs were evident up to 15 years duration of employment.
Rubber production is an occupation classified as group 1 carcinogen by IARC, without clear indication of what the responsible agent might be [
]. A particular focus has been made on tyre production, in particular the tyre curing process during which high temperatures are reached to stimulate reaction between different chemical compounds of the tyre. Measurements conducted with the European project ExAsRub [
] where the results can be consulted online (http://exasrub.iras.uu.nl/) revealed higher exposure to several agents in workers working in the general rubber goods when compared with workers in the tyre industry. For example, in the period 1989–1993 in the UK, personal representative measurement of rubber dust was 2.82 mg/m3 (geometric mean) in the general rubber goods and 1.18 mg/m3 in the tyre industry. The differences in the overall SMRs between tyre and general rubber goods sectors might also be due to differences in smoking habits; however, no clear data were identified to confirm this hypothesis.
Major industries in Europe have experienced major changes in occupational hygiene through increased surveillance and actions to protect workers. In the rubber manufacturing industry, these changes seemed to have started earlier as the analysis of the data collected within the EU-ExAsRub consortium showed a continuous decreasing time trends of inhalable dust from 1975 to 2005, although there was national variation [
]. The results stratified by period of employment showed that decreased risks of lung cancer and total cancer mortality were even stronger after 1985 than before 1985 which is in line with data showing a progressive decline in exposure to inhalable dust measured in rubber industries in Europe. Caution must be expressed in interpreting these findings. Comparison with mortality data in the prospective cohort, whether overall or by subgroup (such as type of manufacturing), and the dust levels are on an ecological basis, a weak type of study design compared with the prospective cohort study reported here.
The findings from this study are reassuring. However, it is recommended that these cohorts continue to be monitored regularly to ensure that the absence of increased risk is maintained for longer follow-up, and the long-term positive effects of the continual implementation of technology innovations to reduce exposures to workers can be maintained. Longer follow-up will also allow examination of cohorts employed in more recent years (after 1985). In addition, it will allow more detailed evaluation of the healthy worker effect.
The study was partially funded by an unrestricted research grant from the European Tyre and Rubber Manufacturers’ Association1 (ETRMA) and was conducted and reported in full independence from the sponsor. The German study was partially funded and supported by the BG RCI2 (formerly Berufsgenossenschaft der Chemischen Industrie, Heidelberg) and the Wirtschaftsverband der deutschen Kautschukindustrie e V, Frankfurt/M. No grant numbers apply.
European Tyre and Rubber Manufacturers’ Association
The authors have declared no conflicts of interest.
The study Working Group comprised iPRI staff (Mathieu Boniol and Peter Boyle) and each national Principal Investigator [Beata Świątkowska (Poland), Tom Sorahan (UK), Jürgen Wellmann (Germany), Kristina Jakobsson (Sweden), Enrico Pira (Italy)]. AK and CP were iPRI staff working on the project. DT was the co-principal investigator with Jürgen Wellmann working on the German cohort. CLV and PB were co-principal investigators with Enrico Pira working on the Italian cohorts. The authors would like to thank Faustine Valentini and Kim Coppens (iPRI) for the editorial support during the preparation of this manuscript, and Maria Bota (iPRI) for help in literature scoping. Prof. Neonila Szeszenia-Dąbrowska and Urszula Wilczyńska, PhD, provided background information on the rubber industry workers and allowed the follow-up of the already existing rubber manufacturing cohorts in Poland. Zoli Mikoczy, and Ulf Bergendorf were responsible for the assembly of the Swedish database.