Tumori, 93: 4-12, 2007

RISK FACTORS FOR BLADDER CANCER

Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade; 2Institute of Preventive Medicine-Zemun, Belgrade, Serbia

Aims and background: To summarize risk factors for bladder cancer, emphasizing the role of recently established associations and to present some ongoing debates on the issue. Methods: A systematic literature search was performed using MEDLINE database on bladder cancer risk factors between January 1985 and June 2006 and by detailed examination of the references of original articles, reviews and monographs retrieved. Results: Cigarette smoking is recognized as the main cause of bladder cancer and accounts for about 50% of cases in developed countries. A strong link exists between the amount and duration of cigarette smoking. A high risk of bladder carcinoma has been observed in workers exposed to some aromatic amines. Based on these and other occupational risks, it has been estimated that 5-10% of bladder carcinomas in industrialized countries were due to exposures of occupational origin. Infectious agents have a major influence on bladder cancer

risks in the areas of the world where Schistosoma haematobium infestation is endemic. Other potential risk factors for bladder cancer are other urinary tract infections and drinking tap water with chlorination by-products or arsenic. Exposure to certain drugs, like cyclophosphamide used in chemotherapy and heavy consumption of phenacetin-containing analgesics, has been shown to cause bladder cancer in humans. Total fluid intake and high consumption of fruits and vegetables are probably associated with a small decrease in risk. Conclusions: Avoidance of tobacco smoking and incriminated occupational exposures, habitual intake of fresh fruits and vegetables, and prevention and control of urinary tract infections should be recommended for bladder cancer prevention. Further studies are required to assess the role of genetic polymorphisms and their modifying effect of lifestyle risk factors for bladder cancer occurrence and to evaluate the benefit of bladder cancer screening, particularly in those at high risk.

Key words: bladder cancer, epidemiology, occupational exposure, risk factors, smoking.

Introduction

Bladder cancer is the most common malignant tumor of the urinary system. In Europe and the United States, it accounts for 5 to 10% of all malignant tumors in men. The overall public health importance of bladder cancer is increasing with the growing elderly population. In this review, some points of the well-known and potential risk factors for bladder cancer in humans are discussed. Descriptive epidemiology Internationally, the incidence of bladder cancer varies about 10-fold (Figure 1). The disease is reported most often in Europe and North America and least often in several areas of Asia. North Africa (Egypt) is also a high-risk area1. In Europe, the highest incidence rates for men were recorded in the Netherlands, Spain and Italy (about and over 30 per 100,000 men), whereas rates were high in Luxembourg and Germany, intermediate in France and United Kingdom, and the lowest in Slovenia and Bulgaria (10 per 100,000 men) 1 . In women, the highest incidence rates were in the Netherlands and Luxembourg (between 6 and 7 per 100,000 women), and the lowest in the Russian Federation (1 per 100,000 women). The diversity of the classifications, which clearly reflects the difficulty of defining bladder tumors, raises problems for descriptive epidemiology. The incidence rates recorded in various can-

cer registries may partly reflect different diagnostic criteria, but this bias could probably affect time trends rather than existing international comparisons2. In terms of mortality, 179,000 persons died of bladder cancer worldwide in 20023. The World Health Organization estimated that the burden of bladder cancer in the world in 2002 was 1,002,000 disability-adjusted life years lost in men and 476,000 in women; over 80% of this burden was attributable to mortality3. Epidemiologic data clearly indicate that bladder cancer is much more common among men, white persons, and the elderly4. In most developed countries, men are exposed to at least a three times greater risk than women5. The incidence of bladder cancer is about two times higher in whites than in blacks; however, the mortality rates are found to be similar. These findings suggest the possibility of the later stage at diagnosis of the disease among black persons, also leading to a worse prognosis of the outcome of the disease4. Incidence rates are to a certain extent lower among Asian and Hispanic groups than among blacks, and very low among American Indians6,7. There is convincing evidence that incidence and mortality rates of bladder cancer increase sharply with age starting from the age of 25 regardless of the gender. Furthermore, about two thirds of all cases occur among persons older than 651. Regarding time trends, incidence rates in developed countries have increased and remained much higher in men during the previous decades8,9. Mortality from blad-

Acknowledgments: This work was supported by the Ministry of Science and Ecology of Serbia, contract no. 145037. Correspondence to: Slavenka Jankovi c, MD, PhD, Professor of Epidemiology, Institute of Epidemiology, School of Medicine, Vis egradska 26, 11000 Belgrade, Serbia. Tel +381-361-5779; fax +381-361-5768; e-mail slavenka@eunet.yu Received February 7, 2006; accepted August 23, 2006.

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Egypt Spain Netherlands Italy Luxemburg Germany United States of America Canada France United Kingdom Australia Russian Federation Bulgaria Slovenia Japan China India 0 10 20 30 40 Males Females

and review and meta-analyses of such studies were taken into consideration for the analysis. In order to assess the level of association between potential risk factors and bladder cancer (convincing, possible or no evidence), the level of scientific evidence (hierarchy of evidence) and number of epidemiological studies showing consistent associations were taken into consideration.
Risk factors

The main recognized risk factors for bladder cancer (tobacco smoking, occupational exposure to aromatic amines and urinary shistosomiasis) and other potential risk factors for bladder cancer (occupational exposure, total fluid intake, urinary tract diseases, some drugs, genetic risk factors, etc.) are summarized in Table 1. Tobacco Cigarette smoking is an established cause of bladder cancer. The association between bladder cancer and cigarette smoking has been a subject of a number of epidemiologic studies, and nearly all of them showed an approximately 2- to 3-times higher risk of bladder cancer in ever smokers compared to nonsmokers. The risk increased with both the number of years of smoking and the number of cigarettes a person has smoked2,13. It is estimated that in some populations cigarette smoking accounts for a large percent of bladder cancer (for 50% of all male and 23% of all female bladder cancers)14. A meta-analysis comprising 16 studies on bladder cancer (73% of all participants were men and 77% were Europeans) reported an attributable risk percent for smoking of 48%15. A combined analysis of 11 case-control studies (from France, Spain, Italy, Germany, Denmark and Greece), comprising 2600 male and 685 female bladder cancer cases and their controls (5524 male and 2416 female controls), revealed that the overall risk of bladder cancer for ever-smokers compared to never-smokers was 3.6 (95% CI, 3.1-4.2) for men and 3.1 (95% CI, 2.5-3.9) for women. At the same time, the overall risk of bladder cancer for current smokers compared to never- and ex-smokers was 2.5 (95% CI, 2.2-2,7) for men and 2.9 (95% CI, 2.3-3.7) for women. From these estimates, the proportion-attributable risks (PAR) were calculated for ever smoking (66% for men and 30% for women) and for current smoking (32% for men and 18% for women). Furthermore, among men up to the age of 60, PAR of bladder cancer cases was 73% for ever-smoking and 46% for current smoking. The higher PAR among men younger than 60 would indicate that the PAR for all men is likely to increase. On the other hand, it would be possible that the reduction of exposure to workplace bladder carcinogens may have indirectly contributed to the increase in PAR for tobacco-attributable bladder cancer16. The PAR for ever smoking women varied between the studies (e.g., in women it ranged from 2% in Greece and 4-5% in Spain, up to 47% and 49% in Denmark and Italy, respectively)17. This heterogeneity in the PAR was explained by significant dif-

Figure 1 - Incidence rates (age standardized to the world population) of bladder cancer per 100,000 for selected countries, by sex for year 2002 (source: Ferlay et al., 20041).

der cancer has shown downward trends over the last two decades in several western European countries (although 10-15 years later than similar trends in the United States), but it is still increasing in some eastern European countries10,11. This pattern emphasizes the size of the tobaccorelated cancer epidemic in Eastern Europe12.
Methods

A systematic bibliographic search on potentially eligible epidemiologic studies on risk factors for bladder cancer published between January 1985 and June 2006, including reviews of such studies, was performed through the MEDLINE database. Search terms included the following keywords: bladder cancer, bladder carcinoma or bladder neoplasm and risk factors and human. A bibliographic search was carried out by two experienced medical doctors employed at the Medical library at the Military Medical Academy. Both of them independently searched the literature for the same period using the same search strategy. After that, the authors assessed the collected papers and selected all relevant items that met the criteria for the present review. Finally, the references quoted in the selected studies were searched and checked by the authors. All relevant epidemiological studies with original research data on bladder cancer as the only and clearly defined outcome

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Table 1 - Overview of potential risk and protective factors for bladder cancer occurrence Risk/protective factor Tobacco Cigarette smoking Effect Carcinogen/protective agent

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Mechanism of carcinogenesis/protection Oxidative DNA damage through endogenous enzymatic reactions; indirect (inactivation of target enzymes) and direct (strand breaks, creation of abasic sites, base adduct formation) DNA damage

Appraisal of association Convincing

Direct

Chemical carcinogens (aromatic amines, N-nitroso compounds, PAHs) reactive oxygen species (O2, OH, O2, H2O2, HOCl)

Cigar, pipe and environmental smoking Occupational exposures Direct Dyestuffs (aromatic amines), DNA damage combustion products (4-nitrobiphenyl, 4-aminobiphenyl); benzidine Mineral, cutting, lubricating oils; asphalt, some rubber-, plastic-, welding materials Reduced bladder voiding Arsenic (inorganic arsenic, high levels, Several proposed modes of action, long exposure) complex nature of arsenic-induced carcinogenesis DNA damage Chlorination by-products (trihalomethanes), nitrates Increase of voiding frequency, dilution of carcinogens N-nitroso compounds, heterocyclic amines, 4-aminobiphenyl MX [3-chloro-4-(dichloromethyl)-5hydroxy-2(5H)furanone] Antioxidant effects or other properties of vitamins and minerals Lactobacillus casei strain Shirota Chronic inflammation, altered metabolism Chronic irritation/inflammation

Possible Convincing Possible

Drinking water

Direct Direct

Convincing Possible Possible

Total fluid intake Diet Animal fats, processed meats soy (some diet products)

Inverse

Direct

Possible

Fruit and vegetable consumption Fermented milk products Urinary tract diseases Schistosoma haematobium Cystitis and other infection

Inverse Inverse Direct Direct

Possible Possible Convincing Possible

Genetic polymorphism NAT1/NAT2, GSTM1 genes involved Direct when Aromatic amines in detoxification of aromatic amines NAT2 deleted inverse when GSTM1 deleted Drugs Phenacetin Cyclophosphamide Direct Direct Phenacetin Sn-acetyl-p-aminophenol Sp-aminophenol Acrolein

Inefficient detoxification of aromatic Possible amines with consequent increased production of carcinogenic metabolites

Metabolic transformation to carcinogen Possible DNA damage by alkyl group Possible

ferences in smoking prevalence among control women, which ranged from less than 10% in Greece and Spain to over 50% in Denmark17. In terms of PAR, smoking as an independent risk factor can explain 26% of all bladder cancer among women in Italy18. These data are higher than previously estimated (PAR equaled 17%)19, likely reflecting the increase in smoking over recent decades among Italian women. A case-control study from Montreal reported that PAR due to smoking was 48% for men and 29% for women, or 53% taken as a whole20. This diversity could be a consequence of numerous factors, primarily gender, national, social and/or cultural differences in smoking habits, such as the average number of cigarettes, the depth of smoke inhalation, the age of first exposure, duration of smoking and, for former smokers, the age of smoking cessation.

There is an increasing risk of bladder cancer with increasing duration of cigarette smoking16,17,21. A dose-response relationship was observed between number of cigarettes smoked per day and incidence of bladder cancer up to a level of 15-20 cigarettes per day in both men (OR, 4.5; 95% CI, 3.8-5.3) and women (OR, 3.8; 95% CI, 2.7-5.4). However, a further increase in number of cigarettes smoked per day was not associated with the increased risk16,17. Cigarette smoking cessation and age at first exposure were not associated with risk of bladder cancer after taking into account the total duration of smoking21. For persons who gave up smoking, the risk of bladder cancer appeared to decrease by about 30-40% in the first four years after cessation. However, even after 25 years, the decrease in risk did not reach the level of the never-smokers16,17. A large case-control study from

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Los Angeles showed that the use of filtered versus unfiltered cigarettes, low-tar versus higher tar cigarettes, or the pattern of inhalation did not modify the risk. Women had a significantly higher risk of bladder cancer than men who smoked the same number of cigarettes 22. One prospective study of American men showed an increased risk for current cigar smokers who inhaled the smoke (RR, 3.6; 95% CI, 1.39-9.9)23. The case-control dataset from Canada showed a 2- to 3-fold overall increased risk for bladder cancer among smoker, and a 4- to 5-fold risk in heavy smokers24. Smokers of unfiltered, high-tar and black tobacco cigarettes are at high risk compared with smokers of filtered, low-tar or blond tobacco25. Pipe, cigar, and environmental smoking have also been reported as risk factors for bladder cancer, although the epidemiologic data on these forms of smoking in relation to bladder cancer is more equivocal2,14. Occupation It was estimated that about 20% of all male bladder cancers were caused by occupational exposure in the United States and Europe at the end of the 1980s26. More than a decade later, according to an analysis of pooled data of 11 European case-control studies, the attributable risk for men employed in any high-risk occupation was estimated to be between 4% and 7% 27. Barone-Adesi et al.28 found PARs ranging between 4% and 24% in the Italian studies investigating occupational exposure and bladder cancer risk. Aromatic amines and polycyclic aromatic hydrocarbons (PAH) were the exposures most consistently found to increase the risk 29. Most cohort and case-control studies reported an excess in risk of bladder cancer among workers professionally exposed to hair dyes, including aromatic amines30. A large population-based case-control study from Los Angeles implicated that working as a hairdresser or barber for more than 10 years was associated with an increased risk31. However, Swedish authors estimated that the incidence of bladder cancer among hairdressers has not increased in recent decades and is therefore not likely to be associated with the use of modern hair dyes32. Other occupations, except dyestuff manufacturing, have been associated with an increased risk of bladder cancer, including rubber manufacturing, painting, metal industry, leather industry, textile industry and truck driving11,33-36. An excess risk of bladder cancer was observed in some occupations entailing exposure to PAH (workers employed in the aluminum industry, coal gasification and iron and steel foundry workers)10,27,37. There is some kind of biological synergy between cigarette smoking and exposure to aromatic amines, paint components and PAH, since some of them (naphthylamine and benzo[a]pyrene) are also formed during tobacco smoking38. Concurrent cigarette smoking and permanent use of hair dyes, as potentially substantial sources of human exposure to arylamines, have additive, rather than a multiplicative effect on the development of bladder cancer39.

Exposure to carbon black in dockyard workers was associated with a two-fold increase in bladder cancer risk. This might be attributable to exposure to carbonblack dust during manual unloading of paper sacks containing carbon black40. The Lithuanian cohort study of cement-producing workers indicated that exposure to cement dust may as well increase the risk of bladder cancer41. The estimated population-attributable risk for occupational risk factors of bladder cancer in Canadian men was 10% for mineral, cutting or lubricating oil exposure, 6% for asbestos exposure, and 1% for benzidine exposure42. Control of exposure to carcinogens in the work environment has been effective in preventing a significant number of occupational bladder cancer in developed countries. Personal hair dye use Although personal use of hair dyes was suggested as a risk factor for bladder cancer in some epidemiologic studies31, recently published meta-analysis of 10 epidemiological studies did not confirm it. The pooled relative risk for ever users of hair days was 1.01 (95% CI = 0.89-1.14) for bladder cancer43. Drinking water There are three groups of compounds contained in drinking water that are generally incriminated in the occurrence of bladder cancer. Between 25 and 77 million people in Bangladesh were chronically exposed to extremely high concentrations of arsenic in drinking water, occasionally exceeding 2000 g/L44-46. During the follow-up, the lifetime mortality risk from bladder cancer in that country was doubled owing to arsenic in the drinking water47. Arsenic is not a direct-acting mutagen. Several proposed mechanisms overlap, and contribute to the complex nature of arsenic-induced carcinogenesis48. Steinmaus et al.49, showed that smokers who ingest arsenic in concentrations near 200 g/day may be at increased risk of bladder cancer. Furthermore, they suggested that the latency of arsenic-caused cancer might be even greater than 40 years. Although a number of epidemiologic studies have identified links between high concentrations of arsenic in drinking water and bladder cancer 47,49, the risks at lower exposures are largely unknown48. Epidemiological studies of the influence of disinfection by-products in drinking water have been so far focused on the carcinogenic potential of chlorination byproducts. A meta-analysis of six case-control and two cohort studies indicated a strong association of longterm consumption of chlorinated drinking water with bladder cancer, particularly in men. The relative risk was not very high, but the population-attributable risk must be taken into consideration since most of the population in industrialized countries is exposed to chlorination by-products for a long time50. Some investigators

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have reported a positive association of the risk of bladder cancer with the duration of exposure to chlorinated water, as well as with the estimated concentration of trihalomethanes. They have also supported the use of ozone in combination with chlorination, since such water treatment decreases the concentration of trihalomethanes and eliminates some mutagenic substances originating from raw water51. Nitrate contamination of drinking water, also was reported as the risk of bladder cancer. Nitrates are endogenously reduced to nitrites, which through subsequent nitrosation give rise to highly carcinogenic N-nitroso compounds. In a cohort of 21,977 Iowa women, Weyer and coauthors found positive associations for bladder cancer across all nitrate level quartiles after adjustment for a variety of cancer risk/protective factors, agents that affect nitrosation (smoking, vitamin C, and vitamin E intake), dietary nitrate intake and water source52. Total fluid intake Epidemiological findings are lagely inconsistent. The analysis of pooled data from the six case-control studies (including 2,729 cases and 5,150 controls) showed that total fluid intake was associated with an increased risk of bladder cancer in men (highest category of intake >3.5l/day, compared to those in the lowest <2l/day)53. Health Professionals Follow-up Study reported that men in the highest fluid intake category had half the risk of bladder cancer of those in the lowest fluid intake category54. Total daily fluid intake depends on many factors, but frequency of bladder voiding is directly related to the intensity and duration of urothelium flattening and is considered a more competent indicator for bladder cancer risk than total fluid intake55. Radosavljevic et al.56 found no significant difference in total daily fluid intake between cancer cases and controls (cases, 1896.2 ml; controls, 1906.4 ml), but the mean number of urinations per day was 3.49 for cancer cases versus 5.17 in controls. Coffee, alcohol and tea consumption Over 30 studies have reported a higher risk (weak to moderate) for bladder cancer in coffee drinkers than in non-drinkers, but no trend with dose or duration57. It is still unclear whether the weak association is causal or nonspecific, or due to some bias or confounding14,58. High consumption of coffee (more than four cups per day) has been observed to increase bladder cancer risk53. According to epidemiological data, the association between alcohol consumption and bladder cancer risk is not well established, with most studies reporting a nonsignificant association or no association14,59. Tea consumption is probably not associated with the occurrence of bladder cancer14. A weak inverse association between tea consumption and bladder cancer risk has been noted60,61, but it is unclear whether it could be due to total fluid intake or to some specific tea compounds.

Diet High intake of fats, particularly animal fats, could increase the risk of bladder cancer62-65. Mutagens involved in bladder cancer etiology are probably formed during the heating process66,67 from foods rich in fat or prepared in fat (fried foods). Products of protein pyrolysis (heterocyclic amines) and N-nitroso compounds could be synthesized during cooking or meat preservation68-70. Dietary intakes of grilled, salted and canned meat were associated with significantly increased risks of bladder cancer70,71. The consumption of processed meat, particularly bacon, sausage and ham, was significantly associated with an increased risk, but the authors failed to explain which component of food was the most responsible: fat, nitrite or the very fact that food was fried69. Another potentially carcinogenic substance whose residues are found in different animal tissues (liver, kidney, and muscle near the site of injection) is xylazine a tranquilizer used in veterinary medicine72. Several case-control studies65-67,70 reported a significantly increased risk with the consumption of fried eggs or eggs on the whole. In a study showing a strong positive association with cholesterol intake, it was estimated that half of the calculated cholesterol intake was derived from eggs, but the association with consumption of eggs itself was not reported73. The habitual intake of skimmed milk, yogurt (10-15 years ago)56 or other fermented milk products (containing Lactobacillus casei strain Shirota) lowered the risk for bladder cancer occurrence (OR, 0.46; 95% CI, 0.27-0.79 for consumption 1-2 times/week and OR, 0.61; 95% CI, 0.38-0.99 for consumption frequency 34 or more times/week)74. Oral intake of L. casei Shirota, in a form of drug prescribed for the control of intestinal bacteria, significantly decreased the reappearance of superficial bladder cancer after transurethral resection75,76. Most studies that investigated fruits and vegetables consumption reported an inverse relationship with bladder cancer a lower risk with bladder cancer in subjects with high consumption11. No significant association was found between total vegetable intake, vitamin A and vitamin C intake and bladder cancer and only a moderate inverse association with vitamin E intake 14,77. Most studies found a moderate inverse association between selenium status and bladder cancer risk14. A large casecontrol study provided evidence of the preventive role of carotenoids in bladder cancer, especially for individuals susceptible to DNA damage78. Two epidemiological studies79,80 have confirmed the positive association between dietary soy intake and bladder cancer risk, previously observed in animals81. To our knowledge, no study has evaluated the daily dynamics of food consumption and risk of bladder cancer. Balanced meals and habitual intake of protective foodstuffs should be investigated and recommended as prominent factors in the prevention of bladder cancer.

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Urinary tract diseases and other conditions A positive relationship between chronic cystitis or nonspecific infections of the urinary tract and the risk of bladder cancer has been consistently reported. Urinary schistosomiasis is a well-known risk factor for bladder cancer. The relation has been explained through chronic irritation of the urothelium, or alert metabolism and consequently high urinary levels of carcinogenic metabolites82. A crosssectional study in Schistosoma haematobium endemic African populations suggested an age-dependent progression of cellular abnormalities in the urinary epithelium associated with chronic S. haematobium infestation83. Similar metaplastic changes have been identified in American and European paraplegics with long-term catheter-induced bladder infection and irritation84. A large cohort study supported the hypothesis that the incidence of bladder cancer was significantly higher in patients with spinal cord injuries and those with an indwelling urinary catheter than in the general population84. The extent and pathologic stage of upper urothelial cancer were significant and independent factors for bladder cancer85. The rate of cancer recurrence in the bladder was 35% up to 5 years after resection of upper urothelial cancer85. Sadetzki et al.86 found a strong association between prostate enlargement and bladder cancer. This relation may be attributed to chronic urinary retention, which prolongs the contact between carcinogenic agents contained in urine and bladder epithelium. In a recent retrospective study, patients with prostate cancer had a higher incidence of bladder cancer87. Kravchick et al.88 showed a significant relationship between diabetes mellitus and bladder cancer. Untreated hyperlipidemia was associated with a slightly increased risk of bladder cancer89, supporting the theory that a fatty diet can be considered as a risk factor65. Drugs The increased risk of bladder cancer (OR, 6.5; 95% CI, 1.5-59.2) in young women (case-control study with 173 matched pairs) who regularly used phenacetin-containing products remained present after adjustments for all other identified risk factors90. There are highly reliable and consistent data on cyclophosphamide therapy and the risk of bladder cancer91. Results from a population-based cohort study of patients with Wegeners granulomatosis indicated a dose-response relationship between cyclophosphamide and the risk of bladder cancer, and high cumulative risks in the entire cohort91. One large case-control study of bladder cancer showed that intake of phenacetin rather than its major metabolite acetaminophen was positively related to bladder cancer risk in a dose-dependent way. Acetic acids seemed to exhibit the strongest, whereas aspirin/salicylic acids and oxicam showed the weakest protective effect92. Genetic factors N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of aromatic

and heterocyclic amines, and they exhibit wide genetic polymorphism, an important determinant of individual susceptibility to the carcinogenic effects of the mentioned amines93. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify the risk of developing bladder cancer94. The results of a case-control study with the largest sample size to date suggest that having a NAT2 slow acetylator genotype is a significant risk factor for bladder cancer, particularly in smokers and older individuals95. Overall bladder cancer risk among NAT2 slow acetylators is about 1.3- to 1.5-times higher than in rapid acetylators; the relative risk becomes higher when data are restricted to subjects exposed to arylamines. The relationship of the NAT2 slow acetylation phenotype, which is relatively common96, and bladder cancer risk differed by geographical region. The positive association was observed for studies conducted in Europe and Asia, but not for studies conducted in the United States97. The glutathione S-transferases (GST) are a family of enzymes that are important in the metabolism of environmental carcinogens. Approximately 50% of Caucasians and Asians with homozygous deletion of the GSTM1 gene lacks glutathione S-transferase M1 (GSTM1), the enzyme involved in the detoxification of a number of carcinogens (e.g., PAH found in tobacco smoke)98. Owing to their detoxification role, these enzymes and the genes encoding them may play an important role in cancer susceptibility. According to the results of a meta-analysis of 17 case-control, genotypebased studies (2,149 cases and 3,646 controls), GSTM1 null status was associated with a modest increase in the risk of bladder cancer98. In a population-based, casecontrol study of 354 bladder cancer cases and 542 controls, an increased risk of bladder cancer was associated with the GSTM1 null genotype, but only among women who smoked99. A number of studies showed an increased risk of bladder cancer in first-degree relatives and in the siblings of bladder cancer patients100,101.
Conclusions

In conclusion, all risk factors for bladder cancer taken in consideration in our review have been summarized and ranged in terms of attributable risk or populationattributable risk, whenever it has been possible. Such approach is the consequence of the fact that once the PAR is known, the potential benefits and costs of feasible preventive programs that might reduce known risk factors by a defined percentage can be considered, having in mind that PAR is place- and period-specific, as the prevalence of exposed people in the population varies in space and time. Cigarette smoking is by far the main risk factor for bladder cancer. It accounts for over 50% of all male bladder cancers, whereas in women about 25% of the disease is attributable to cigarette smoking. It should be emphasized that a major reduction of bladder cancer

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could be obtained by stopping cigarette smoking. However, the impact of a prevention policy can be predicted from the anticipated reductions in packs per day for smokers, besides the reduction in the percentage of people who smoke at all. A clinical history of urinary schistosomiasis could explain about 15% of all bladder cancer cases, but only in endemic areas. Prevention and adequate treatment of S. haematobium infection play an important role in prevention of the cancer. Occupational exposure, particularly to aromatic amines and PAH may play a substantial role in about 10% of bladder cancers. The attributable risks of bladder cancer for men employed in any high-risk occupation ranged between 1% and 10%. These results, compared with previous reported, would suggest that the improvement in working conditions during the last decades in Western Europe has been effective in preventing a significant number of bladder cancer cases caused by exposure to occupational carcinogens, particularly aromatic amines. Avoidance of occupational exReferences
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posure whenever possible and appropriate health surveillance among the exposed are proposed in the prevention of the occupational bladder cancers. Drinking water contaminated with arsenic, especially in some areas of the world (e.g., in Bangladesh) or with chlorination by-products, may be a risk factor for bladder cancer. Increased total fluid intake and consumption of fresh fruits and vegetables may be important protective factors for bladder cancer occurrence. Impaired expression of genes (NAT2, GSTM1) involved in the detoxification of aromatic amines may result in their inefficient detoxification, thereby leading to an increased production of carcinogenic metabolites and an increased risk of bladder cancer. Low risk associated with NAT2 and GSTM1 deficiencies and lack of valid bladder cancer screening tests limit the feasibility of identifying people with a high risk of developing bladder cancer. Data of family members with first-degree relatives with bladder cancer should be collected for the mapping and identification of bladder cancer susceptibility genes.

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