Occupational Medicine Advance Access originally published online on August 25, 2008
Occupational Medicine 2008 58(7):496-501; doi:10.1093/occmed/kqn104
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Bladder cancer risks in workers manufacturing chemicals for the rubber industry
Institute of Occupational and Environmental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Correspondence to: Tom Sorahan, Institute of Occupational and Environmental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel: +44 121 414 3644; fax: +44 121 414 6217; e-mail: t.m.sorahan{at}bham.ac.uk
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Abstract |
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Aim To investigate bladder cancer risks in workers from a factory manufacturing chemicals for the rubber industry.
Methods The mortality (1955–2005) and cancer morbidity experience (1971–2005) of a cohort of 2160 male production workers from a chemical factory in north Wales were investigated. Exposure estimates (or surrogates) were developed for four chemicals: 2-mercaptobenzothiazole (MBT), aniline, phenyl-β-naphthylamine (PBN) and ortho-toluidine. Two analytical approaches were used, indirect standardization and Poisson regression.
Results Based on mortality rates for the general population, there was a statistically significant (P < 0.01) excess mortality from bladder cancer in the 611 study subjects potentially exposed to one or more of the four chemicals being investigated (observed 11, standardized mortality ratio 278, 95% confidence interval 139–497). There was no excess bladder cancer mortality in the remaining 1555 workers. A similar contrast was also shown for bladder cancer incidence. There were 56 study subjects who had suffered from bladder cancer (malignant or benign). In simultaneous analyses of the four exposure history variables, Poisson regression showed a significant positive trend for bladder cancer risk in relation to cumulative duration of employment in the ortho-toluidine department (P < 0.05) and non-significant positive trends in relation to cumulative duration of employment in the PBN department and to cumulative exposure to MBT.
Conclusions Some members of this cohort have suffered from occupational bladder cancer. Exposure to ortho-toluidine appears to be responsible for part of this excess and the manufacture of PBN and exposure to MBT may also have been involved.
Keywords Aniline; cohort study; 2-mercaptobenzothiazole; occupational cancer; ortho-toluidine; phenyl-β-naphthylamine
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Introduction |
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Previous investigations have studied the mortality of workers employed at a chemicals production factory in north Wales, which manufactures and uses vulcanization inhibitors and accelerators, antioxidants and many other proprietary products for the rubber industry [1,2]. The study cohort comprised 2160 male production workers and mortality and cancer morbidity were investigated to the end of 1996 and 1992, respectively. The latest update concluded that cases of occupational bladder cancer had probably occurred at the plant in workers exposed to ortho-toluidine, phenyl-β-naphthylamine (PBN), aniline or 2-mercaptobenzothiazole (MBT) and that priority should be given to studying bladder cancer risks in relation to exposure to ortho-toluidine or PBN [2]. More recently, ortho-toluidine has been reclassified by an International Agency for Research on Cancer Working Group as a (Group 1) human bladder carcinogen [3,4]. There are now an additional 9 years of mortality follow-up data and 13 years of cancer incidence data available for analysis. The purpose of the new analysis was to discover whether the bladder cancer excess had persisted in those workers exposed in previous years to ortho-toluidine, PBN, aniline or MBT and to determine whether exposure to ortho-toluidine could be solely responsible for the excess.
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Methods |
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Earlier reports [1,2] had identified all 2160 male production employees (hourly paid personnel) with at least 6-month employment at the factory and some employment in the period 1955–84. This cohort had been assembled with the agreement of company management and workforce representatives. The Office for National Statistics (ONS) has, with the earlier approval of the British Medical Association Ethics Committee, continued to supply copies of death certificates with the underlying cause of death coded to contemporaneous revisions of the International Classification of Diseases (ICD) together with details of cancer registrations as recorded in regional cancer registries. At the closing date of the survey (31 December 2005), 1458 subjects had died, 656 were traced alive, 14 had emigrated and the remaining 32 subjects were untraced. Of the 320 deaths occurring in the period 1974–2005, there were 35 for which no cancer registration particulars had been received. A review of these cases by ONS produced registration details for a further 25 subjects. A corresponding search was not attempted for any of the remaining study subjects.
Job histories for the period 1930–1988 were available in terms of some 300 unique job–department titles, and the approach used to estimate cumulative exposure to MBT and its derivatives has been described previously [2]. Equivalent job exposure matrices for PBN, ortho-toluidine and aniline are not available but cumulative durations of employment in departments involving potential exposure to these chemicals were derived as three time-dependent variables. Process descriptions at the plant were re-reviewed for the purpose of this update and six departments were found to have used aniline (including the single department that manufactured PBN); the earlier analysis only considered four departments to involve exposure to aniline [2]. Ortho-toluidine was only used in a single department (the ‘Sopanox’ department) from 1936 to 1979 where it was reacted with dicyanamide in the presence of hydrochloric acid; aniline, PBN and MBT were not used in this department. PBN was manufactured at the plant from 1945 to 1972; aniline was used in this department. For the current analysis, memberships of the ortho-toluidine-exposed subcohort (n = 53) and PBN-exposed subcohort (n = 94) were unchanged, membership of the MBT-exposed subcohort was marginally increased to 363 workers and the aniline-exposed subcohort was increased to 442 workers. There was considerable overlap in the membership of these four subcohorts; 266 workers were members of more than one of the four subcohorts and eight workers were members of all four subcohorts.
Expected numbers of deaths were calculated from serial mortality rates for England and Wales applied to similarly defined arrays of person-years at risk (pyr) generated by the data. Workers entered the pyr at the end of the 6-month minimum period of employment or 1 January 1955, whichever was the later date. They left the pyr on the closing date of the study (31 December 2005), the date of death, the date of emigration or date last known alive, whichever was the earliest date. For the occupationally exposed subcohorts, subjects entered the pyr at the end of the 6-month minimum period of employment or 1 January 1955 or the date first employed in an exposed job, whichever was the later date. Standardized mortality ratios (SMRs) were calculated as the ratio of observed deaths to expected deaths, expressed as a percentage (both numerator and denominator refer to underlying causes of death). These procedures were accomplished with the PERSONYEARS software [5]. Significance tests were two tailed and no contributions were made to observed or expected numbers past the age of 85. This censoring at 85 was applied for three reasons. First, published mortality rates are only available for the open-ended age group 
85 and the distribution of the cohort pyr by single years of age might be very different from that of the general population; second, the reliability of cause of death particulars is probably poorer at later ages and third, any study subjects incorrectly classified as traced alive at the end of the study would have a disproportionate effect on the expected numbers for the open-ended age group. Follow-up for 173 workers was censored at age 85 years.
Equivalent analyses were also carried out for cancer registration (incidence) data. National cancer registration data are not available before 1971, and the calculation of standardized registration ratios (SRRs) was limited to the period 1971–2005. These analyses were limited to malignant bladder tumours (ICD-9: 188) as national cancer incidence rates are not available for benign bladder tumours.
The SMR analysis had to be limited to an analysis of underlying causes of death and the SRR analysis had to be limited to registrations of malignant tumours. For the internal analysis, greater flexibility was available and cases of bladder cancer were selected as those deaths for which primary cancer of the bladder was mentioned on any part of the death certificate or those cancer registrations recording a diagnosis of a malignant or benign bladder tumour (ICD-8: 188, 223.3, 237.6; ICD-9: 188, 223.3, 233.7, 236.7, 239.4; ICD-10: C67, D09.0, D30.3, D41.4). For subjects with more than one notification of a bladder cancer (death certificate and cancer registration or multiple cancer registrations), the earliest date of notification was taken as ‘date of diagnosis’. Subjects with bladder tumours (before age 85 years) were notified by death certificate only (3 cases), by cancer registration particulars only (27 cases) or by both sources (26 cases); case subjects leave the pyr on the date of the first notification.
Variables considered to have the potential for influencing bladder cancer risks within the cohort were age, calendar period, cumulative exposure to MBT and duration of employment in the aniline, PBN or ortho-toluidine-exposed departments. Variables were not treated as continuous variables, but rather each variable was categorized into several levels. In constructing the models, it was necessary to ensure that there was at least one death observed at each level of each variable. Any adjustments were made before any statistical modelling was carried out. The analysis allowed subjects to contribute pyr to contemporaneous categories of these six time-dependent variables. There were no cases of bladder cancer at younger ages; all analyses were limited, therefore, to the age range 40–84 years.
The EPICURE computer program was used to provide pyr and numbers of deaths for all combinations of all levels of the selected variables [6]. The EPICURE program was also used to carry out statistical modelling by Poisson regression [7]. The purpose of the modelling was to calculate point estimates of relative risk (rate ratios) for each level of the four occupational exposure variables, with and without adjustment for the three remaining occupational exposure variables. The significance of any trend in risk across the four cumulative MBT exposure categories was assessed by repeating the analysis while treating cumulative exposure as a continuous measure, coded 1, 2, 3 or 4 for the four levels of exposure (the cut-off values for cumulative exposure were those used previously [2]). Trends in risk across categories of duration of employment were evaluated in a similar manner.
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Results |
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Mortality from all causes combined in the overall cohort was close to expectation (observed 1334, expected 1302.3, SMR 102, 95% confidence interval (CI) 97–108) as was mortality from lung cancer (observed 120, expected 131.9, SMR 91, 95% CI 75–109). Mortality from bladder cancer in the overall cohort was (non-significantly) elevated (observed 22, expected 14.43, SMR 152, 95% CI 96–231). There was a marked contrast in bladder cancer mortality (ICD-9: 188) between the combined subcohort (n = 611) with potential exposure to one or more of MBT, aniline, ortho-toluidine or PBN (observed 11, expected 3.96, SMR 278, 95% CI 139–497) and the remainder of the cohort (observed 11, expected 10.47, SMR 105, 95% CI 52–188). There was a similar marked contrast in bladder cancer incidence (ICD-9: 188) between the same combined subcohort (observed 18, expected 8.43, SRR 214, 95% CI 127–337) and the remainder of the cohort (observed 21, expected 19.87, SMR 106, 95% CI 65–162).
Observed and expected numbers of deaths from bladder cancer and all causes are shown for the combined exposed subcohort by successive periods from commencing exposed employment and by successive periods of ceasing exposed employment in Table 1. There was a significant positive trend in SMRs for bladder cancer (P < 0.05) with period from commencing exposure but no indication of risks decreasing with period from ceasing exposure.
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Observed and expected numbers of deaths and registrations (incidence data) from bladder cancer are shown for the four individual exposure subcohorts in Table 2; study subjects can be members of more than one of these subcohorts. Significantly, elevated bladder cancer mortality and cancer incidence are shown for each of the four subcohorts; the largest SMR and SRR are shown for ortho-toluidine exposure.
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A consideration of all subjects with at least one notification of bladder cancer (malignant or benign and death certificates or cancer registrations) before the age of 85 years provided a total of 56 cases for analysis. Table 3 shows relative risks for bladder cancer by categories of cumulative exposure to MBT and its derivatives and by cumulative duration of employment in the PBN, aniline and ortho-toluidine departments. Risks are all shown relative to a baseline risk of unity for workers (person-years) in the lowest exposure category for each variable. The first set of columns summarize the results of four separate analyses in which each exposure is considered in turn. The largest relative risks are shown for exposure to ortho-toluidine, although significant positive trends are shown for all four occupational exposure variables. The second set of columns summarize the results of a single analysis in which all four variables are considered simultaneously; a significant positive trend is shown only for ortho-toluidine. When the simultaneous analysis was limited to three exposures (ortho-toluidine, MBT and PBN) (not shown in Table), a significant trend was shown for ortho-toluidine (P < 0.05) and non-significant monotonic positive trends were shown for MBT and PBN.
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Discussion |
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The study found a marked excess of bladder cancer mortality and incidence in workers exposed to one or more of MBT, PBN, ortho-toluidine or aniline, and it seems certain that some members of this cohort have suffered from occupational bladder cancer. The current update found a significant positive trend of bladder cancer risk with cumulative duration of exposure to ortho-toluidine with and without adjustment for the other three chemicals of interest.
Confident evaluation of the role of all four agents under investigation in this excess of bladder cancer is difficult because of the relatively small numbers of cases in the exposed subcohorts, the crude measures of exposure assessment for the four chemicals under study and the possible presence of unconsidered potential chemical confounders. Information on cigarette smoking was not available but cigarette smoking can probably be excluded as an important confounding factor on the basis of the unexceptional SMR findings for lung cancer in the overall cohort. It seems likely that a small number of cancer registrations has been missed, given that the ancillary search carried out for cancer deaths without cancer registrations produced additional registrations. If a similar proportion of under-ascertainment is assumed for other registrations, then some eight registrations remain untraced in the total cohort. The advantages of using mortality data and cancer registration data in a single analysis and the possibility that some members of the PBN subcohort were exposed to β-naphthylamine have been discussed previously [2].
The new findings for ortho-toluidine are consistent with those of three other published studies of chemical production workers that reported highly elevated bladder cancer risks in ortho-toluidine-exposed workers. Rubino et al. [8] reported elevated bladder cancer mortality in 53 men exposed to ortho-toluidine in the course of dyestuffs production (observed 5, SMR 6250, 95% CI 2029–14585). Stasik [9] reported elevated bladder cancer incidence in 116 men exposed to ortho-toluidine in the course of the production of 4-chloro-ortho-toluidine (observed 8, SRR 7273, 95% CI 3140–14330). Ward et al. [10] reported elevated bladder cancer incidence in 708 men exposed to ortho-toluidine in the course of rubber chemicals production (observed 7, SRR 648, 95% CI 261–1335).
It seems likely that ortho-toluidine was not the only bladder carcinogen present in the factory under study because the elevated SMR and SRR for the ortho-toluidine-exposed subcohort cannot explain the whole of the bladder cancer excess, and some evidence has been provided that exposure to MBT and the manufacture of PBN may both have had some role. It is also possible that the available work histories do not capture all department changes at the plant and that residual confounding from ortho-toluidine is present in the other occupational exposure variables. Veys [11,12] has argued persuasively that the use of PBN in the UK rubber industry has not led to increased bladder cancer risks, although use and manufacture may pose quite different risks to the workforces involved. Two reports have been published relating to elevated bladder cancer risks in a cohort of US workers exposed to MBT but this excess was attributed to confounding from the potent human bladder carcinogen 4-aminobiphenyl [13,14]. This US study should, as a matter of urgency, be revisited in an attempt to investigate formally any independent effect of MBT exposure. Three variables need to be considered: cumulative exposure to MBT, cumulative duration of employment in the departments using 4-aminobiphenyl and cumulative duration of employment at the plant in the period 1935–55 (to represent any plant-wide exposures to 4-aminobiphenyl). Such investigations may lead to a more confident evaluation of the potential for MBT to cause bladder cancer in humans.
In conclusion, ortho-toluidine would appear to be a potent human bladder carcinogen and regulatory authorities will need to review their standards for this chemical to be sure that current workforces are being given adequate protection.
Key points
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Acknowledgements |
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The author is grateful to Dr Linda Nichols, Dr John Jackson and Mr David Williams for their earlier assistance with this work, to the ONS for supplying follow-up data and to company management and workforce representatives for setting up this survey.
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