Sheffield University Academics Publish In-Depth Review of Occupational Bladder Cancer and its Associated Carcinogens

At the University of Sheffield, researchers have been collating and analysing occupational histories of patients newly diagnosed with bladder cancer.[1]

Tracing backwards, they were able to identify or confirm specific injurious substances, employment sectors, job titles and work tasks associated with the fatal disease. What is more, they also investigated the level of health risk posed by each type of exposure.

Results were published last month, in the Public Library of Science (PLoS) One journal.[2]

In the introduction to the scientific paper, the authors remarked that bladder cancer is one of the most expensive malignancies to manage, affecting predominantly older men in the Western World.

According to Cancer Research UK, bladder cancer is the 11th most common cancer in Great Britain, accounting for 3% of new cases each year (around 10,200). It is also the 9th most common cause of cancer mortality, accounting for 3% of annual deaths (around 5,400). On average, 3 in 4 people diagnosed with bladder cancer (England only) have a projected survival of 1-year or more, whilst approximately 1 in 2 will go on to live in excess of 10-years or more.[3]

The most common bladder cancer sub-type is urothelial cell carcinoma (UCC), which is caused by exposure to carcinogens excreted in urine.

Typically, exposure to bladder cancer carcinogens occurs via inhalation of tobacco smoke and in the course of employment. Up to 10% of bladder cancers are understood to arise following occupational exposures.[4]

Bladder cancer carcinogens are broadly classified as either aromatic amines, polycyclic aromatic hydrocarbons (PAHs), heavy metals, or mixed compounds. Exposure levels have been limited, to a large extent, by the Carcinogens and Mutagens Directive (CMD) 2004/37/EC, the Chemical Agents Directive (CAD) 98/24/EC and the Control of Substances Hazardous to Health Regulations 2002. Changes made to manufacturing processes over time have also had a positive impact on work-related health.

Nonetheless, it is suspected that some high risk urothelial carcinogens have not yet been identified and, since those who suffer from this latent condition have been regularly exposed to a cocktail of commonplace carcinogens in diesel exhaust and tobacco cigarette plumes, isolating those unknown sources is fraught with complications.

This latest UK study sought to build on prior work, which attempted, albeit ineffectively, to explore the hypothesis that patterns of occupational exposure would be linked to particular bladder cancer phenotypes (observable characteristics).[5]

Where previously, a large Scandinavian dataset had been used, the present cohort included 454 patients who had been treated at the Royal Hallamshire Hospital, in Sheffield, UK, with a male to female ratio of 7:2 (352 men to 102 women).

These 454 participants constituted 85% of respondents to a structured questionnaire detailing employment, work tasks, known exposures, smoking habits, lifestyle and family history. All of them had been diagnosed with primary urothelial bladder cancers and held complete histopathological records.

Following treatment, 1 in 2 suffered with recurrent disease, 1 in 4 experienced disease progression and 1 in 3 died (average of 8 years post-diagnosis). Fewer than expected deaths were seen in healthcare workers, whereas garage workers exposed to diesel fuels/fumes, workers who undertook plumbing/gas-fitting/ventilation tasks, workers making/handling rubber products, workers making/using cement, workers involved in smelting and welders were all associated with faster rates of disease progression and/or more radical treatment methods.

Survey responses revealed that 282 (62%) participants had been in contact with up to 14 potential occupational carcinogens (average of 3 carcinogens-per-worker), the most common exposures including diesel fumes/fuels, coal/oil/gas by-products [combustion products, including polycyclic aromatic hydrocarbons (PAHs)] and solvents. Out of a list of 33 tasks, the most common tasks undertaken by bladder cancer patients were welding, making cement, use of lubricating/coolant oils, soldering/brazing, degreasing and work involving forging/cooling operations. There were discernible differences between the sexes too. Males with bladder cancer were generally employed in engineering, steel, mining, metalworking and building professions. By contrast, female test subjects largely occupied roles in service industries, such as hairdressing, laundry and healthcare.

Bladder cancers were distinguished by stage at diagnosis, separating premature ‘non-muscle invasive’ tumours (normally 70% of all cases) in the bladder lining or connective tissue, from more advanced ‘muscle invasive’ tumours (normally 30% of all cases) in the muscle wall of the bladder). They were also stratified by grade, either being categorised as ‘low-grade tumours’ [characterised by papillary (finger-like) growth patterns, few genetic alterations and indolent behaviour], ‘moderate-grade tumours’, or ‘high-grade tumours’ (characterised by aggressive disease, genetic/epigenetic instability and multiple mutations).

Substances

For workers exposed to chromium, coal products and diesel exhaust fumes/fuels, higher stage bladder cancer was more frequently described.

Evidence dictated that higher grade bladder cancer affected those who had recalled exposure to crack detection dyes, chromium, coal/oil/gas by-products, diesel fumes/fuel and aircraft fuel and solvents (e.g. trichloroethylene). 

Sectors

As regards to higher stage bladder cancer, this predominantly affected workers in engineering and metal industries.

Higher grade bladder cancer was more prevalent in workers who recounted employment in steel, foundry, metal, engineering and transport industries.

Occupations and Occupational Tasks

Both higher staging and higher grading of bladder cancer was associated with welding, the use of mineral oil, lubricants and protective resins, as well as specific jobs that exposed workers to diesel fumes/fuels.

Aggressive bladder cancer was also especially common among electrical workers performing welding and soldering tasks, which give rise to lead oxide, heavy metal (e.g. arsenic, cadmium, chromium, nickel, etc.) and colophony (rosin-based flux, consisting of acetone and carbon monoxide) exposure.

Confining analysis to females only, high grading and high staging of bladder cancer was shown to impact workers undertaking electroplating processes, cutlery manufacture, degreasing and painting – evidence of a juxtaposition brought about by sex and occupational demographics. Females also inhaled more passive cigarette smoke than their male counterparts and were more likely to use hair dye.

Conclusions

Besides coming to terms with the fact that certain phenotypic patterns of bladder cancer had been instigated by a range of work-related factors, the research team made a number of other observations, principally labouring on the theme of diesel exposure.

The article’s authors cited the International Agency for Research on Cancer’s (IARC) classification of diesel fumes as a Group 1 carcinogen, in 2012,[6] and made direct reference to the fact that there was ‘limited evidence’ of bladder cancer risk at that time. The fact that this latest study showed that contact with diesel fuels/fumes was associated with high grading and staging of cancer, as well as greater risks of disease progression, was said to bolster support for the carcinogenicity of diesel fumes on the urothelium.

Diesel exposure primarily occurred in male-dominated welding, soldering, agriculture, building, transport and engine repair sectors and there was some evidence of a dose interaction with cigarette smoking. It was also accepted that non-occupational diesel exposure (e.g. related to hobbies) could have impacted on their findings.

As regards to other possible study limitations, the authors eluded to the fact that the sample size was small (especially when compared against the earlier Scandinavian model), that follow-up time was immature (median 8.4 years) and could therefore have missed prospective cancer outcomes, that the questionnaires were self-completed and thus prone to bias (exaggerated exposures)/mistake (missed key exposures) and finally that the broad range of duration times reported could have disproportionately brought attention to the impact of dose-response relationships.

A knock-on effect of the small sample size and male-heavy bias was the likely underestimation of bladder cancers tied to aromatic amines, including 2-naphythylamine, benzidine, 4-aminobiphenyl and o-toluidine. These exposures are common in dyestuff manufacture, rubber, printing, painting and textile industries and were associated with some of the highest bladder cancer incidence rates in an earlier faculty investigation involving over 700,000 people.[7]

 

[1] ‘Bladder cancer patients report work exposures to multiple carcinogens’ (6 November 2020 Workers Health & Safety Centre) <https://www.whsc.on.ca/What-s-new/News-Archive/Bladder-cancer-patients-report-work-exposures-to-multiple-carcinogens> accessed 26 November 2020.

[2] Reed O et al., Occupational bladder cancer: A cross section survey of previous employments, tasks and exposures matched to cancer phenotypes. PLoS One. 2020; 15(10): e0239338.<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577448/pdf/pone.0239338.pdf> accessed 26 November 2020.

[3] ‘Bladder Cancer Statistics’ (Cancer Research UK) <https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer> accessed 26 November 2020.

[4] Rushton L et al., Occupation and cancer in Britain. Br J Cancer. 2010 Apr 27; 102(9): 1428–1437. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865752/pdf/6605637a.pdf > accessed 26 November 2020.

[5] Noon AP et al., Occupation and Bladder Cancer Phenotype: Identification of Workplace Patterns That Increase the Risk of Advanced Disease Beyond Overall Incidence. Eur Urol Focus. 2018 Sep;4(5):725-730. <https://www.eu-focus.europeanurology.com/article/S2405-4569(16)30093-1/fulltext> accessed 26 November 2020.

[6] ‘IARC: DIESEL ENGINE EXHAUST CARCINOGENIC’ (12 June 2012 IARC) <https://www.iarc.fr/wp-content/uploads/2018/07/pr213_E.pdf> accessed 29 November 2020.

[7] Cumberbatch MG et al., The contemporary landscape of occupational bladder cancer within the United Kingdom: a meta‐analysis of risks over the last 80 years. BJU Int. 2017 Jan;119(1):100-109. <https://bjui-journals.onlinelibrary.wiley.com/doi/epdf/10.1111/bju.13561> accessed 30 November 2020.