Approximately 49,000 people develop bladder cancer each year in the United States, with nearly half of these cases attributable to cigarette smoking. Occupational exposure to certain aromatic amines also causes bladder cancer. Many occupational groups including dye workers, rubber workers, leather workers, painters, truck drivers, and aluminum workers have increased bladder cancer risk. Less common risk factors include ionizing radiation, cyclophosphamide use, abuse of phenacetin-contain ing analgesics, and schistosomiasis infection. The roles of diet, urinary tract infections and stasis, chlorination by-products in drinking water, and genetic susceptibility need further research.

Epidemiology of bladder cancer.

Mortality from bladder cancer has shown downward trends over the last 2 decades in several western European countries (albeit 10-15 years later than similar trends in the US), but is still increasing in some eastern European countries. Tobacco smoking and occupational exposure to aromatic amines are the two major established environmental risk factors for bladder cancer. Controlling exposure to these factors has been an important contributor to the reduction in bladder cancer mortality, particularly among men. Diet could influence bladder carcinogenesis, as many compounds contained in foods--and their metabolites--are excreted through the urinary tract. Fruit and vegetable consumption was inversely related with bladder cancer in many studies, but no consistent association has emerged between intake of related micronutrients and reduced risk of bladder cancer. Other widely investigated lifestyle habits are probably not associated with risk of developing bladder cancer (e.g. coffee consumption, artificial sweetener use, hair dyes) or are difficult to assess (e.g. fluid intake). Infections and stones in the urinary tract might cause chronic irritation of the bladder epithelium, and thus increase bladder cancer risk. First-degree relatives of bladder cancer patients have a 50-100% increased relative risk of developing the disease, a risk that could be even higher when the proband is diagnosed at an early age.

Mechanisms of disease: The epidemiology of bladder cancer.

Objective To assess the association between intake of non-sugar sweeteners (NSS) and important health outcomes in generally healthy or overweight/obese adults and children. Design Systematic review following standard Cochrane review methodology. Data sources Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and reference lists of relevant publications. Eligibility criteria for selecting studies Studies including generally healthy adults or children with or without overweight or obesity were eligible. Included study designs allowed for a direct comparison of no intake or lower intake of NSS with higher NSS intake. NSSs had to be clearly named, the dose had to be within the acceptable daily intake, and the intervention duration had to be at least seven days. Main outcome measures Body weight or body mass index, glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects. Results The search resulted in 13 941 unique records. Of 56 individual studies that provided data for this review, 35 were observational studies. In adults, evidence of very low and low certainty from a limited number of small studies indicated a small beneficial effect of NSSs on body mass index (mean difference −0.6, 95% confidence interval −1.19 to −0.01; two studies, n=174) and fasting blood glucose (−0.16 mmol/L, −0.26 to −0.06; two, n=52). Lower doses of NSSs were associated with lower weight gain (−0.09 kg, −0.13 to −0.05; one, n=17 934) compared with higher doses of NSSs (very low certainty of evidence). For all other outcomes, no differences were detected between the use and non-use of NSSs, or between different doses of NSSs. No evidence of any effect of NSSs was seen on overweight or obese adults or children actively trying to lose weight (very low to moderate certainty). In children, a smaller increase in body mass index z score was observed with NSS intake compared with sugar intake (−0.15, −0.17 to −0.12; two, n=528, moderate certainty of evidence), but no significant differences were observed in body weight (−0.60 kg, −1.33 to 0.14; two, n=467, low certainty of evidence), or between different doses of NSSs (very low to moderate certainty). Conclusions Most health outcomes did not seem to have differences between the NSS exposed and unexposed groups. Of the few studies identified for each outcome, most had few participants, were of short duration, and their methodological and reporting quality was limited; therefore, confidence in the reported results is limited. Future studies should assess the effects of NSSs with an appropriate intervention duration. Detailed descriptions of interventions, comparators, and outcomes should be included in all reports. Systematic review registration Prospero CRD42017047668.

https://www.bmj.com/content/bmj/364/bmj.k4718.full.pdf

Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies

Recent incidence data from the United States indicate that transitional cell carcinoma accounts for the vast majority (95%) of bladder tumors in this country, with squamous cell carcinoma (less than 3%) and adenocarcinoma (less than 2%) comprising nearly all the remaining cases. Rates of squamous cell carcinoma and adenocarcinoma were higher in blacks compared to whites, while the reverse was true for transitional cell carcinoma. All three tumors predominated in males, especially transitional cell carcinoma. A population-based case-control study of bladder cancer conducted in 10 geographical areas of the United States identified 43 patients with squamous cell carcinoma and 32 with adenocarcinoma to permit an examination of risk factors. Cigarette smoking was significantly associated with risk of squamous cell carcinoma, with the relative risk rising to 6.1 among smokers of 40 or more cigarettes/day. Significantly elevated risks of squamous cell carcinoma were also associated with a history of 3 or more urinary tract infections (relative risk = 5.7) and with employment as welders and cooks. Risk factors were generally less conspicuous for adenocarcinoma, except for a significant trend with the amount of coffee drinking; however, this finding is based on small numbers and should be interpreted cautiously.

https://cancerres.aacrjournals.org/content/canres/48/13/3853.full.pdf

Epidemiological Characteristics of Squamous Cell Carcinoma and Adenocarcinoma of the Bladder

For guidance in decisions on how to safeguard humans from carcinogens, it is necessary to use data on carcinogenesis in animals. This paper discusses how such data, combined with human experience, may be used quantitatively in such decisions. It is demonstrated empirically that good correlations exist between different species for suitably defined carcinogenic potencies for various chemicals. This allows sufficient accuracy in extrapolating from animal data to human risk to support a logical scheme for the evaluation of such risks. Some recommendations for future research are given.

G Fodor

Papers

Artificial sweeteners and human bladder cancer