Bladder Cancer Carcinogens: Opportunities for Risk Reduction

Abstract

Bladder cancer at an individual level is likely to be the consequence of repeated, long-term exposure to one or more known bladder carcinogens, some of which are endemic or unavoidable in daily life, in addition to host factors. This Mini-Review highlights exposures that are associated with higher risk of bladder cancer, summarizes the evidence for each association, and suggests strategies to decrease risk at both individual and population levels.

Patient summary:

Tobacco smoking, exposure to certain chemicals in your diet, environment, or workplace, urinary infections, and certain medications can increase your risk of bladder cancer.

Tobacco smoking, exposure to certain chemicals in an individual’s diet, environment, or workplace, urinary infections, and certain medications can increase their risk of bladder cancer. Public policy interventions, workplace safety, and smoking cessation can reduce this risk.

1. Introduction

The primary function of the urinary bladder is prolonged storage of urine between voids, a characteristic that exposes the surface of the urothelium to contact with carcinogens present in the urine. Bladder cancer at an individual level is likely to be the consequence of repeated, long-term exposure to one or more known bladder carcinogens, some of which are endemic or unavoidable in daily life, in addition to host factors.

2. Tobacco exposure

2.1. Cigarettes and other combustible tobacco products

Smoking, the most important modifiable risk factor for bladder cancer, accounts for 30–60% of cases and increases risk in a dose-dependent fashion. Tobacco combustion produces more than 62 carcinogens known to cause bladder cancer, with modulation of risk dependent on the manner of inhalation and the type of tobacco used. Importantly, smoking cessation effectively decreases the risk of bladder cancer in former smokers compared to current smokers in as little as 1–3 yr, with risk approaching that of nonsmokers at 15 yr after cessation [1].

2.2. Electronic nicotine delivery systems

Electronic nicotine delivery systems (ENDS), colloquially known as vaping, are rapidly rising in popularity, particularly for young people, as they are marketed as a safer alternative to traditional tobacco products. However, carcinogens strongly associated with bladder cancer are found in the urine of individuals who use ENDS, suggesting that they may be at higher risk in comparison to non-users. Long-term follow-up data are required to establish a definitive association, but there is no established “safe” level of carcinogen exposure to the urinary bladder [2–4].

3. Environmental and industrial exposure

3.1. Hydrocarbon exposure

Classic hydrocarbon exposures include industrial and workplace contact with aromatic amines (textile, rubber, newspaper, and leather workers, hairdressers, and firefighters) or polycyclic aromatic hydrocarbons (mechanics, truck drivers, aluminum, electrical, and coal workers), although much of this risk has been mitigated by improvements in workplace safety practices [1]. However, recent work identified an association between airborne pollutants generated largely by vehicle emissions (hydrocarbons) and bladder cancer. Elevated ambient concentrations of non-methane hydrocarbons in the air increased the risk of bladder cancer at the population level in a dose-dependent fashion [5].

3.2. Arsenic

Arsenic is processed by the liver but excreted by the kidney. High levels of arsenic in the water supply have been linked to bladder cancer at the population level. Therefore, the risk of exposure varies by region and access to safe water, with high levels of arsenic reported in Asia, South America, and in drinking wells in more than 25 states in the USA [1,6–8].

3.3. Aristolochia

Aristolochia is a genus of herbs that cause interstitial fibrosis nephropathy and urothelial carcinoma. Aristolochia is an important component of traditional Chinese medicine and commonly grows near wheat fields in the Balkans. In these areas, it is often inadvertently incorporated in homemade bread, thereby contributing to both cultural and regional risk [1,9–11].

4. Iatrogenic exposures

4.1. Medications

Cyclophosphamide, a cytotoxic pharmaceutical used for both chemotherapy and immunosuppression indications, produces the metabolite acrolein, which is associated with hemorrhagic cystitis and mutagenesis of the urinary bladder. Cyclophosphamide is associated with a cumulative, dose-dependent increase in the risk of bladder cancer, which can be mitigated by simultaneous treatment with mesna [1,12].

Pioglitazone is a thiazolidinedione used for glycemic control in diabetes that agonizes PPAR-γ, a transcription factor associated with migration of bladder cancer cells, has a US Food and Drug Administration warning of higher bladder cancer risk [13].

Phenacetin, an anti-inflammatory drug associated with bladder cancer risk, has been withdrawn from use in the USA but remains in use globally via regulated or illicit supply [14].

While cyclophosphamide remains an important cytotoxic and immunosuppressive drug, alternatives to pioglitazone and phenacetin should be considered to avoid bladder cancer risk [1].

4.2. Radiation

Exposure to ionizing radiation at doses necessary to induce a bladder cancer most commonly occurs with radiotherapy directed at pelvic malignancy. Modern advances in radiation delivery and conformal technology that reduce unintended bladder exposure may decrease this risk [1,15].

4.3. Foreign bodies

Patients with neurogenic bladder or severe stricture disease may require chronic use of an indwelling catheter. Patients with a chronic indwelling catheter have a higher risk of bladder disease that may be compounded by the comorbid presence of bladder stones [16].

5. Infectious and comorbid exposures

5.1. Bacterial infection

Recurrent urinary tract infection is associated with a higher risk of bladder cancer. This effect is often confounded by the presence of an indwelling catheter and urinary stones in patients and could potentially be related to chronic inflammation [16]. Sexually transmitted infection with Neisseria gonorrhea is also associated with an increase in the risk of bladder cancer [1,16,17].

5.2. Viral infection

Case-control studies have found a higher prevalence of Epstein-Barr virus (a known cause of Burkitt’s lymphoma and of head and neck cancer) in the tissues of patients with urothelial bladder cancer in comparison to control subjects [1,18].

The literature on human papillomavirus (a known cause of cervical, penile, and anorectal cancers) suggests an association with higher risk of bladder cancer, although the risk is largely limited to younger patients with low-grade tumors [1,19,20].

5.3. Schistosomiasis

Schistosomiasis is a parasitic infection endemic to Africa and the Middle East that causes squamous bladder cancer induced by inflammation due to shedding of Schistosoma eggs into the urine. Public health interventions to decrease the incidence of schistosomiasis have effectively reduced the prevalence of schistosomiasis-induced bladder cancer [1,20].

6. Modulation of host factors

Urinary carcinogens do not exist in isolation and do not cause bladder cancer with perfect penetrance. Host factors contribute to bladder cancer development in patients exposed to urinary carcinogens.

6.1. Genetics

Germline or acquired genetic syndromes that affect DNA damage repair for genes such as MSH2 and BRCA1/2 place patients at higher risk of developing bladder cancer, probably because of an interplay between exposure to carcinogens and an inability to repair DNA damage. Furthermore, genetic polymorphisms in NAT2 and GSTM1 can cause slow acetylation of carcinogens, increasing risk [1,21].

6.2. Immunosuppression

The role of the immune system in protecting against the development of human cancers is well established. An intact immune system can prevent bladder infection–associated inflammation and perform immune surveillance to eliminate developing cancers. Patients treated with immunosuppressive medications (glucocorticoids or cyclophosphamide) are at higher risk of developing bladder cancer [1].

7. Conclusions

The urinary bladder is vulnerable to carcinogenesis secondary to a diverse array of exposures. However, public health and policy interventions to increase smoking cessation, reduce airborne pollutants, ensure safe drinking water, and reduce exposure to harmful herbs have the power to greatly decrease exposure to urinary carcinogens (Table 1).

Table 1 –

Overview of exposures associated with bladder cancer

Exposure	Source	Possible mechanism of action	Evidence of bladder cancer association	Potential risk reduction	Reference
Tobacco exposure
Smoking	Cigarettes, pipes, cigars	Inhaled carcinogens filtered by the kidney in contact with the urinary bladder	Dependent on dose, duration, and smoking status Current smokers: HR 4.1 (95% CI 3.7–4.5) Former smokers: HR 2.2 (95% CI 2.0–2.4)	Smoking cessation	Freedman 2011 [22]
Electronic nicotine delivery systems	E-cigarettes, vapes	Inhaled carcinogens filtered by the kidney in contact with the urinary bladder	Inferred, pending long-term exposure data	Smoking cessation	Bjurlin 2021 [3] Svendsen 2022 [2]
Environmental (inhaled, ingested, industrial)
Polycyclic aromatic hydrocarbons	Air pollutants Industrial (chimney sweeps, nurses, waiters, seamen, aluminum and oil workers)	Polyaromatic hydrocarbons: mutagenic metabolites	Dose-dependent, population level: pollutants, HR 1.8 (95% CI 1.8–1.9) per 0.13-ppm increase in tetrahydrocarbons Meta-analysis: industrial, RR for bladder cancer mortality up to 10.2 for metal workers	Limit vehicle emissions Personal protective equipment	Zhang 2022 [5] Cumberbatch 2015 [23]
Aromatic amines	Industrial (tobacco, dye, rubber, and leather workers, hairdressers, and printers)	Aromatic amines: DNA* damage	Meta-analysis: industrial, RR up to 1.7 (95% CI 1.4–2.2) for tobacco workers	Personal protective equipment	Cumberbatch 2015 [23]
Arsenic	Drinking water/soil Industrial (metal work, mining, agriculture, wood preservatives)	Urinary metabolites	Population level, epidemiological High-dose exposure (>100 μg/l drinking water), ecological	Public works Workplace safety	IARC Working Group 2012 [7] Mendez 2017 [8]
Aristolochia	Traditional Chinese medicine Home-made bread (Balkans)	Urinary metabolites	Dose-dependent Epidemiological Genomic signature	Provider-level education Regional education	Nortier 2000 [9] Yang 2014 [10] Poon 2015 [11]
Infection/inflammation
Bacterial	Recurrent UTI Neisseria gonorrhea	Inflammation	Matched cohort: recurrent UTI, HR 1.04 per UTI (95% CI 1.04–1.05) Prospective cohort: gonorrhea, RR 1.92 (95% CI 1.10–3.33), associated with higher stage disease		Hird 2021 [16] Michaud 2007 [17]
Viral	EBV, HPV	EBV-positive lymphocytes	Case-control HPV: HR 1.4 (95% CI 1.1–1.8), associated with low grade, younger age		Abe 2008 [18] Offutt-Powell 2012 [19] Shigehara 2014 [24]
Schistosomiasis	Fresh water in endemic regions	Inflammation	Population-level data demonstrate a decline in squamous bladder cancer coincident with a decline in schistosomiasis-associated disease	Public health interventions	Salem 2012 [20]
Foreign body	Catheter Bladder stone	Inflammation	Matched-cohort: chronic catheterization, HR 4.80 (95% CI 4.26–5.42)	Promote intermittent catheterization, reduce recurrent infections and stone formation	Hird 2021 [16]
Iatrogenic
Cyclophosphamide	Chemotherapy, immunosuppression	Urinary metabolites (including acrolein), immunomo dulation, oxidative stress	Case-control: RR 4.5 (95% CI 1.5–13.6)	Often unavoidable, disclose risk, give with mesna	Travis 1995 [12]
Pioglita zone	Diabetes	Unknown	Meta-analysis, dose-dependent: HR 1.27 (95% CI 1.05–1.54)	Consider alternatives	Yan 2018 [13]
Phenacetin	Pain control	p-Aminophenol	Case-control: OR 6.5 (95% CI 1.5–59.2)	Avoid use	Piper 1985 [14]
Radiation	Cancer treatment	DNA damage	Variable, dependent on the primary cancer target and radiation methodology	Minimize off-target delivery	Dracham 2018 [15]

HR = hazard ratio; RR = risk ratio; OR = odds ratio; CI = confidence interval; UTI = urinary tract infection; EBV = Epstein-Barr virus; HPV = human papillomavirus.