Introduction

Bladder cancer (BC) is a common human malignancy and one of the most expensive to manage [1]. Most tumours present with haematuria [2] and at diagnosis around 30% are muscle invasive and 70% non-muscle invasive cancers (NMI) [3]. NMI tumours are stratified into low and high grade lesions, to reflect different treatments and outcomes [4]. The majority of BCs are urothelial cell carcinoma (UCC) in histological sub-type and arise following exposure to carcinogens excreted in the urine [5]. The most common bladder carcinogens are found through tobacco smoke [6] or occupation task [7,8]. Risk from smoking varies with gender, duration, tobacco type and mode of inhalation [9,10]. These aetiological factors mean that BCs are most common in older patients, in men and in the Western World [1]. An individual’s risk of BC reflects their carcinogen burden and their ability to metabolise pro-carcinogens [11].

Around 10% of BCs arise following occupational exposure to carcinogens [12]. These carcinogens may be broadly classified into aromatic amines, polycyclic aromatic hydrocarbons (PAHs), heavy metals or mixed compounds [7]. The occupational exposure of workers to many carcinogens has been limited by health and safety regulations [such as the European Union directives (e.g. 90/394/EEC and 98/24/EC) and the 2002 Control of Substances Hazardous to Health Regulations in the UK] and changes in manufacturing. Whilst many high risk urothelial carcinogens have been identified, it is suspected that more are still in use. The uncertainty about and identification of further candidates reflects the long latency between exposure and cancer, variations in an individual’s risk, that many workers also smoke, and that many potential carcinogens are in widespread (such as diesel fumes) or occult use [13].

BC arises in at least two distinct phenotypes, reflecting genomic events [14,15]. Low-grade tumours are characterised by papillary growth patterns, few genetic alterations (e.g. FGFR3 or hTERT mutation) and an indolent behaviour [16]. In contrast, high-grade BC is an aggressive disease with genetic and epigenetic instability [17], and multiple mutations [18]. We hypothesised that the BC phenotypes could reflect different carcinogenic exposures and, in turn, occupational tasks. We explored this hypothesis using a large Scandinavian dataset and found various occupations with different risks for localised and invasive BCs, and higher rates of BC mortality in the building sector [19]. However, this dataset lacked granularity of occupational tasks, personal smoking exposure and classified BC by stage not grade of differentiation.

To build upon our prior work, we undertook a prospective detailed occupation survey using a consecutive cohort of patients arising in a region of high BC risk. We annotated patients with detailed histological and outcome data.

Materials and methods

Results

Patients and tumours

We collected questionnaires from 536 patients, of whom 82 (15%) were excluded as they had either non-urothelial BCs, non-primary BCs, missing follow up (e.g. in another hospital) or histopathological details were incomplete. We had sufficient data on 454 (85%) participants (Table 1), including 352 (78%) men and 102 women (22%). In total, 25% had a first degree relative with cancer and 355 (78%) participants were smokers (including 118 smoking at BC diagnosis). Women were less likely to be smokers (68% vs. 81% Chi sq. p<0.001), but more likely to inhale ETS at home (82% vs. 74% p = 0.08) and use hair dye (56%, p<0.001) than men. Hobbies varied considerably between the sexes, with more men undertaking fishing and model building (Chi sq. p<0.001). BCs were distributed evenly between low (140 (31%)), moderate (140 (31%)) and high grade (174, 38%) lesions. With regards to stage, most cancers were NMI (368 (88%)) at diagnosis, including 191 (42%) that were high risk (either pTis, pT1 or Grade 3 pTa). Following treatment, recurrence was seen in 244/447 (56%), progression in 114/448 (25%), radical treatment in 156/450 (35%) and death in 157/451 (35%) participants at median of 101 months (interquartile range 73–128).

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Table 1. Patients and tumours in this report.

https://doi.org/10.1371/journal.pone.0239338.t001

Employers and occupational class

Individual employers were documented in 393 (87%) participants, including an average of 3.2 (St dev. ± 2.7) each for men and 2.3 (± 2.1) for women (T Test p = 0.003). There were considerable differences in employment class between men and women (Table 2). The most common male occupations were in engineering, steel and metal working sectors (40%). Women most commonly worked in the service industries (25%). High grade BC was more common than low grade BC in workers from the steel, foundry, metal, engineering and transport industries (Table 2, p<0.05). With regards to stage, engineering and metal workers had higher than expected risks of high-risk NMIs BCs (pTis and pT1, chi sq. p = 0.02).

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Table 2. Occupational class compared to patient sex and tumour phenotype.

https://doi.org/10.1371/journal.pone.0239338.t002

Substance exposures

Contact with potential or confirmed bladder carcinogens was reported by 282 (62%) participants (mean 3.1 per worker (range 0–14), Table 3). There were marked differences between the genders reflecting employment patterns. The most common contacts were diesel fumes/fuel (n = 176 (39%)), coal/oil/gas by-products (151 (33%)), solvents (125 (28%)), heavy metals (50 (11%)), coking plant fumes (40 (9%)) and crack detection dyes (31 (7%)). Relatively few participants were exposed to more typical urothelial carcinogens such as textile dyes (28 (6%)), printing inks (30 (7%)), 4-aminobiphenyl/MOCA/DDM/MDA/o-toluidine (4 (1%)) reflecting the manufacturing sectors in Yorkshire. Participants often had contact with multiple, similar substances (e.g. diesel fumes (21%) and diesel fuel (18%, Pearson’s correlation r = 0.80, p<0.001), Cadmium (4%) and Chromium (8%, Pearson’s correlation r = 0.47, p<0.001)). High grade BC was more common than low grade cancer in workers exposed to crack detection dyes, chromium, coal/oil/gas by-products, diesel fumes/fuel/aircraft fuel and solvents (such as trichloroethylene). Higher staged cancers were more frequent than expected in workers exposed to Chromium, coal products and diesel exhaust fumes/fuel (p≦0.05).

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Table 3. Substance exposure compared to patient sex and tumour grade/stage.

https://doi.org/10.1371/journal.pone.0239338.t003

Occupational task

We questioned participants about their direct involvement or close proximity to (‘nearby’) 33 tasks thought to potentially reflect exposure to urothelial carcinogens (Table 4). Tasks were selected from SOHAS prior occupational cancer episodes. In total, 1,370 tasks were identified by 210 participants. The commonest tasks were welding (n = 115 (25%)), making cement (94 (21%), using lubricating/coolant oils (97 (21%)), soldering/brazing (93 (20%)), degreasing (90 (20%)) or involved inhaling fumes from quenching/forging or cooling (174 (38%)). As with substance exposures and occupational class, there were differences in tasks between the sexes and the associated BCs. Cancers of higher than expected grades were seen with welding, the use of mineral oil lubricants, the use of protective resins and with tasks that included diesel contact (all p<0.05). Tasks that included welding, mineral oil lubricants, the use of protective resins and diesel contact also had higher than expected staged cancers (all p<0.05). Conversely, higher stage cancers only were seen with the use of cement and the making of plastic foam.

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Table 4. Occupational tasks compared to patient sex and tumour phenotype.

https://doi.org/10.1371/journal.pone.0239338.t004

Clinical outcomes and occupational history

We compared the occupational histories with treatment outcomes and observed various interesting associations (Fig 1A–1D). The occupation that was performed for the longest period was the occupation that was used in the analysis when compared to clinical outcomes. For example, workers exposed to diesel fuels or fumes (Cox, HR 1.97 (95% CI 1.31–2.98) p = 0.001), or employed in a garage (HR 2.19 (95% CI 1.31–3.63) p = 0.001) were more likely to have disease progression and receive radical treatment (HR 1.75 (95% CI 1.23–2.47) p = 0.002) than others (Fig 1A and 1B). Participants undertaking plumbing/gas fitting/ventilation were also more likely to have disease progression (HR 2.15 (95% CI 1.15–4.01) p = 0.017) and receive radical treatment (HR 2.28 (95% CI 1.39–3.72) p = 0.003) than expected. Higher than expected progression (HR 2.36 (95% CI 1.19–469) p = 0.014) and radical treatment rates (HR 1.89 (95% CI 1.02–3.49) p = 0.04) were also seen in workers making/handling rubber products, whilst progression and radical treatment was more common in participants undertaking welding (HR 1.85 (95% CI 1.24–2.77) p = 0.003) and exposed to welding materials (HR 1.92 (95% CI 1.27–2.91) p = 0.002), than expected (Fig 1C). Consequently these workers (HR 1.85 (95% CI 1.24–2.77) p = 0.003), and those involved in smelting (HR 1.80 (95% CI 1.11–2.91) p = 0.016), were more likely to receive radical treatment than others. Higher than expected radical treatment rates were also seen in workers making/using cement (HR 1.85 (95% CI 1.24–2.73) p = 0.002). Finally, fewer than expected deaths were seen in healthcare workers (HR 0.17 (95% CI 0.04–0.70) p = 0.014) suggesting improved health (Fig 1D).

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Fig 1.

a. Progression free survival of bladder cancer of patients exposed and not exposed to occupational diesel fumes. b. Radical treatment free survival of bladder cancer of patients exposed and not exposed to occupational diesel fumes. c. Radical treatment free survival of bladder cancer of patients exposed and not exposed to occupational welding. d. Overall survival of bladder cancer from patients who were healthcare workers compared to any other form of work.

https://doi.org/10.1371/journal.pone.0239338.g001

Discussion

We report the outcomes from BC in consecutive patient cohort recruited in South Yorkshire, UK. We find a variety of workers with BC with high risks for aggressive disease that need radical treatment. There are several key findings that require discussion. Firstly, the occupational classes, tasks and contacts reflect local industrial patterns. Most men were employed in the steel, engineering, mining and building sectors, and few worked in industries more typical for BC (with aromatic amine contact); such as rubber, printing, painting and textile sectors. The carcinogens within our population are likely to be a mixture of PAHs, diesel fumes and combustion products. We did find some aromatic amines in occult use in the engineering and metal industries (such as crack detection dyes for non-destructive testing [13]), but these appeared uncommon. PAH exposure arises through cutaneous contact with lubricants, oils and metal working fluids, or inhalation of fumes or combustion products. Our findings contrast and complement a recent systematic review of occupational BC within the UK we conducted [8]. Within this review of 703,941 persons, we found the highest incidence of BC was in chemical process, rubber and dye workers, whilst electrical, transport and chemical process workers had the highest risks of death from BC. Our current data show that electrical workers have a high risk of developing aggressive BC and focus this risk on tasks such as welding and soldering. Fumes from these tasks contain lead oxide, heavy metals (arsenic, cadmium, chromium and nickel etc.) and colophony (rosin based flux containing acetone and carbon monoxide). Our observations may partly explain the high prevalence and mortality from BC seen in Yorkshire [8].

Secondly, our data support the carcinogenicity of diesel fumes to the urothelium. Previous reports have examined this systematically [23] and in 2012 the IARC classified diesel exhaust fumes as carcinogenic (class 1) to the lung (with ‘sufficient evidence’) and the bladder (with ‘limited evidence’) [24]. We add to these data by showing that contact with diesel fuels and fumes were associated with high grade/high stage BC and higher risks of disease progression. Reflecting employment patterns, diesel contact was more common in men than women, and there was some evidence of a dose interaction with cigarette smoking (workers with diesel exhaust exposure had higher pack years (mean: 41 ± 34) than those without (mean 30 ± 22.9, T test p = 0.008)). Workers with diesel exposure were commonly employed in the welding, soldering, agriculture, building, transport and engine repair sectors, and undertook typical task for these sectors (e.g. driving, mixing cement, welding). It is also worth noting that diesel exposure and garage work can also occur with hobbies, reflecting an additional exposure.

Thirdly, our data suggest that occupational history should be included in the BC care pathway. BC is one of the commonest human cancers and one of the most expensive to manage. Much of this expense is spent on monitoring patients with NMI cancers or in screening people with non-visible haematuria [2,25]. Better targeting of resource, with improved survival, more effective screening and lower costs, could be achieved if patient risk stratification was available [26]. Whilst current guidelines rely on age and extent of haematuria [3], our findings suggest that occupational history could guide clinicians to persons at risk of aggressive BC. For example, screening of a few very-high risk persons, e.g. those with aristolochic acid exposure [27] or employees working with aromatic amines [28] is performed, but our data suggest occupational urothelial carcinogenic exposures are common and could help triage a population (by focusing upon the risks of aggressive BCs).

Fourthly, there were differences in exposures between men and women. These included distinct patterns of employment, differences in smoking rates and patterns (direct and passive ETS), hair dye use and hobbies. Given that most participants were male; our reported findings mostly reflect risk in men. Analysis of females only, suggests associations between high grade/high stage BC and workers undertaking electroplating and cutlery manufacture, and tasks such as degreasing and painting (p<0.05).

There are limitations to our work. Most importantly, the sample size was small and so this data should be viewed as hypothesis-generating, rather than definitive. Our aim was to undertake an explorative cohort study (rather than a clinical trial) and so no formal power calculation was performed. This reflects that very little is known about occupational risks and bladder cancer phenotypes and so powering was not possible. Our findings require validation in larger cohorts enriched for engineering and metal workers. Follow up was immature (median 8.4 years) in our series, and so many progressive tumours had not led to death in the participants. As such, we used stage and grade, progression and radical treatment, as surrogate measures for BC specific mortality. With longer follow up, we would look to see if these occupational tasks were associated with mortality or whether aggressive treatment could prevent this. Finally, the questionnaires were self-completed. Workers may have missed key exposures and others appeared more prominent that their actual workload. We asked participants to estimate the duration of each task, but these dates were often missing or very broad.

Conclusions

We identified multiple occupational tasks and contacts associated with high grade and high stage BC. Workers exposed to diesel fumes, employed in a garage, undertaking plumbing/gas fitting/ventilation, welding were more likely to have disease progression and receive radical treatment than others. These findings require validation and could be used to risk stratify persons with haematuria or follow up of non-invasive BC.

Supporting information