Elevated Bladder Cancer Risk Research Articles

Total Fluid and Water Consumption and the Joint Effect of Exposure to Disinfection By-Products on Risk of Bladder Cancer

BackgroundFindings on water and total fluid intake and bladder cancer are inconsistent; this may, in part, be due to different levels of carcinogens in drinking water. High levels of arsenic and chlorinated by-products in drinking water have been associated with elevated bladder cancer risk in most studies. A pooled analysis based on six case–control studies observed a positive association between tap water and bladder cancer but none for nontap fluid intake, suggesting that contaminants in tap water may be responsible for the excess risk.ObjectivesWe examined the association between total fluid and water consumption and bladder cancer risk, as well as the interaction between water intake and trihalomethane (THM) exposure, in a large case–control study in Spain.MethodsA total of 397 bladder cancer cases and 664 matched controls were available for this analysis. Odds ratios (OR) were estimated using unconditional logistic regression, controlling for potential confounders.ResultsTotal fluid intake was associated with a decrease in bladder cancer risk [OR = 0.62; 95% confidence interval (CI), 0.40–0.95 for highest vs. lowest quintile comparison]. A significant inverse association was observed for water intake (for > 1,399 vs. < 400 mL/day, OR = 0.47; 95% CI, 0.33–0.66; p for trend < 0.0001), but not for other individual beverages. The inverse association between water intake and bladder cancer persisted within each level of THM exposure; we found no statistical interaction (p for interaction = 0.13).ConclusionFindings from this study suggest that water intake is inversely associated with bladder cancer risk, regardless of THM exposure level.

Bladder cancer and occupation: a report from the belgian case‐control study on bladder cancer risk

The aim of this study was to add to the data on associations between occupation and bladder cancer thereby strengthening the case for focused research on specific occupational categories. Two hundred two cases and 390 controls participated in this population-based case-control study. Age, sex, smoking, and education adjusted odds ratios (ORs) were calculated for each occupation by unconditional logistic regression. The occupational group of domestic helpers, cleaners, and launderers exhibited a significantly elevated risk of bladder cancer. Elevated non-significant risks (OR > 1.5) were observed for painters and varnishers, electronic equipment assemblers, general laborers, building finishers, carpenters and joiners, architects and engineers, and textile and garment workers. This study suggests that domestic helpers, cleaners, and launderers probably experience an increased risk of bladder cancer. Although no other occupations showed significantly increased risks, the non-significantly elevated risks for painters, carpenters, and textile workers could be confirmed by results from earlier studies.

A Prospective Cohort Study of Bladder Cancer Risk in Relation to Active Cigarette Smoking and Household Exposure to Secondhand Cigarette Smoke

Active cigarette smoking is a major risk factor for bladder cancer. Secondhand exposure to cigarette smoke may also contribute to bladder carcinogenesis. The authors conducted a prospective cohort study to examine the influence of both active smoking and household exposure to secondhand smoke (SHS) on subsequent bladder cancer risk. The study population included persons from two cohorts established from private censuses conducted in Washington County, Maryland, in 1963 (n = 45,749; 93 cases) and 1975 (n = 48,172; 172 cases). Poisson regression models were fitted to estimate the relative risk of bladder cancer associated with active and passive smoke exposure in the two cohorts (referent category: never smokers who did not live with any smokers). Current smokers had an elevated risk of bladder cancer in both the 1963 cohort (relative risk (RR) = 2.7, 95% confidence limits (CL): 1.6, 4.7) and the 1975 cohort (RR = 2.6, 95% CL: 1.7, 3.9) after adjustment for age, education, and marital status. Among nonsmoking women, current household SHS exposure was associated with bladder cancer risk in the 1963 cohort (RR = 2.3, 95% CL: 1.0, 5.4) but not in the 1975 cohort (RR = 0.9, 95% CL: 0.4, 2.3). This study further solidifies the evidence that active smoking is causally associated with bladder cancer. Additional studies are needed to determine whether passive smoking is a risk factor for bladder cancer.

Dephenylation of the Rubber Chemical N-Phenyl-2-Naphthylamine to Carcinogenic 2-Naphthylamine: A Classical Problem Revisited

N-Phenyl-2-naphthylamine (PBNA) represents an example of a suspected carcinogen that is found negative in mutagenicity and clastogenicity testing as well as in long-term animal carcinogenicity bioassays in several species, but for which a carcinogenic risk cannot be excluded because of its metabolic conversion to the known human carcinogen 2-naphthylamine. Also, epidemiologic studies failed to indicate an elevated bladder cancer risk in humans occupationally exposed to PBNA. The amounts of 2-naphthylamine found in the urine of different species including humans after exposure to PBNA indicate unequivocally that PBNA is dephenylated to some extent. These are not explained by the 2-naphthylamine impurities in technical-grade PBNA. To explain the metabolic dephenylation process, it has been suggested that PBNA is metabolized by cytochrome P-450 (CYP) enzymes to the phenolic derivative 4′-hydroxy-N-phenyl-2-naphthylamine, followed by its further oxidation to the quinone imine, which subsequently hydrolyses to form the dephenylation product 2-naphthylamine. Phenolic metabolites from the initial CYP-mediated activation step are rapidly conjugated. Quantitatively, dephenylation of PBNA to 2-naphthylamine is a minor pathway. The dog represents an animal model that appears to approximate the human metabolism and biological activation of PBNA. Based on published data, a worst-case scenario indicates that about 1% of total PBNA taken up is transferred into 2-naphthylamine. However, in vitro as well as in vivo findings with PBNA may point to a significantly smaller conversion rate, as metabolites anticipated from the metabolism of 2-naphthylamine were not detected so far. The assumption, which may well be an overestimation, is compatible with findings in animal experiments, and explains the lack of direct evidence of carcinogenicity of PBNA in both experimental and epidemiological studies.

Gonorrhoea and male bladder cancer in a prospective study

In a prospective cohort study, a close to two-fold elevated risk of bladder cancer was found among men reporting a history of gonorrhoea (relative risk=1.92, 95% CI=1.10–3.33). Our finding warrants further examination of the role of gonorrhoea in bladder carcinogenesis.

Risk of second malignant neoplasms among lymphoma patients with a family history of cancer

Radiotherapy and chemotherapy are known risk factors for second cancers after lymphoma. The role of genetic influences, however, remains largely unknown. We assessed risk of second cancers associated with family history of any cancer in 41,181 patients with Hodgkin lymphoma (HL) (n = 7,476), non-Hodgkin lymphoma (NHL) (n = 25,941), or chronic lymphocytic leukemia (CLL) (n = 7,764), using a large population-based database. Family history of cancer was based on a diagnosis of any cancer in 110,862 first-degree relatives. We found increased relative risk (RR) (1.81, 95% confidence interval (CI): 1.04-3.16) of breast cancer among HL patient with positive (vs. negative) family history of cancer. Among CLL patients with positive (vs. negative) family history of cancer, we observed elevated risks of bladder (RR = 3.53, 95% CI: 1.31-9.55) and prostate cancer (RR = 2.15, 95% CI: 1.17-3.94). For NHL patients with positive (vs. negative) family history of cancer, we observed non-significantly increased risk of non-melanoma skin cancer (RR = 1.94, 95% CI: 0.86-4.38) and lung cancer (RR = 1.99, 95% CI: 0.73-5.39). Our observations suggest that genetic factors, as measured by positive family history of cancer, may be influential risk-factors for selected second tumors following lymphoproliferative disorders.

Meat intake and bladder cancer risk in 2 prospective cohort studies

Nitrosamines, which are known bladder carcinogens, or their precursors are found in certain meat items, and concentrations of these compounds are especially high in bacon. Only 3 cohort studies, all with <100 case subjects, have examined the relation between meat intake and bladder cancer, and few studies have examined the relation of different meat types with bladder cancer. The aim was to examine the association between specific meat items and bladder cancer in 2 large prospective studies. We analyzed data from 2 cohorts with up to 22 y of follow-up and 808 incident bladder cancer cases. Detailed data on meat were obtained from multiple food-frequency questionnaires administered over time. Multivariate relative risks (RRs) and 95% CIs were estimated by using Cox proportional hazards models with control for potential confounders, including detailed smoking history. Men and women with a high intake of bacon (>/=5 servings/wk) had an elevated risk of bladder cancer compared with those who never ate bacon (multivariate RR = 1.59; 95% CI = 1.06, 2.37), although the overall association was not statistically significant (P for trend = 0.06). However, the association with bacon was stronger and became statistically significant after the removal of individuals who indicated having "greatly" changed their red meat (men) or bacon (women) intake during the 10 y before baseline (multivariate RR = 2.10; 95% CI = 1.24, 3.55; P for trend = 0.006). A positive association was also detected for intake of chicken without skin, but not for chicken with skin or for other meats, including processed meats, hot dogs, and hamburgers. In these 2 cohorts combined, frequent consumption of bacon was associated with an elevated risk of bladder cancer. Other studies with data on specific meat items are necessary to confirm our findings.

Determination of Three Carcinogenic Aromatic Amines in Urine of Smokers and Nonsmokers

Aromatic amines (arylamines) such as o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl occur in the environment and are constituents of tobacco smoke. Human exposure to these aromatic amines has long been associated with an elevated risk of bladder cancer. A validated, specific, and sensitive method for measuring o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl in cigarette smokers and nonsmokers was developed. The method uses acid hydrolysis of the arylamine conjugates in urine, extraction with n-hexane, derivatization with pentafluoropropionic anhydride, and subsequent analysis with gas chromatography combined with mass spectrometry using negative ion chemical ionization. The limits of detection were 4 ng/L for o-toluidine and 1 ng/L for 2-aminonaphthalene and 4-aminobiphenyl. Smokers (N = 10) excreted significantly higher amounts of o-toluidine (204 versus 104 ng/24 h), 2-aminonaphthalene (20.8 versus 10.7 ng/24 h), and 4-aminobiphenyl (15.3 versus 9.6 ng/24 h) than nonsmokers (N = 10). Urinary arylamine excretion in smokers was associated with the extent of smoking as assessed by daily cigarette consumption, urinary excretion of nicotine equivalents (nicotine plus its five major metabolites), cotinine in saliva, and carbon monoxide in exhaled breath. All nonsmokers investigated had quantifiable amounts of o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl in their urine, confirming that other environmental sources of exposure to these compounds also occur. In conclusion, the analytical method is suitable for measuring short-term exposure to arylamines in urine of non-occupationally exposed smokers and nonsmokers.

Bladder Cancer Predisposition: A Multigenic Approach to DNA-Repair and Cell-Cycle–Control Genes

The candidate-gene approach in association studies of polygenic diseases has often yielded conflicting results. In this hospital-based case-control study with 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls, we applied a multigenic approach to examine the associations with bladder cancer risk of a comprehensive panel of 44 selected polymorphisms in two pathways, DNA repair and cell-cycle control, and to evaluate higher-order gene-gene interactions, using classification and regression tree (CART) analysis. Individually, only XPD Asp312Asn, RAG1 Lys820Arg, and a p53 intronic SNP exhibited statistically significant main effects. However, we found a significant gene-dosage effect for increasing numbers of potential high-risk alleles in DNA-repair and cell-cycle pathways separately and combined. For the nucleotide-excision repair pathway, compared with the referent group (fewer than four adverse alleles), individuals with four (odds ratio [OR] = 1.52, 95% CI 1.05-2.20), five to six (OR = 1.81, 95% CI 1.31-2.50), and seven or more adverse alleles (OR = 2.50, 95% CI 1.69-3.70) had increasingly elevated risks of bladder cancer (P for trend <.001). Each additional adverse allele was associated with a 1.21-fold increase in risk (95% CI 1.12-1.29). For the combined analysis of DNA-repair and cell-cycle SNPs, compared with the referent group (<13 adverse alleles), the ORs for individuals with 13-15, 16-17, and >or=18 adverse alleles were 1.22 (95% CI 0.84-1.76), 1.57 (95% CI 1.05-2.35), and 1.77 (95% CI 1.19-2.63), respectively (P for trend = .002). Each additional high-risk allele was associated with a 1.07-fold significant increase in risk. In addition, we found that smoking had a significant multiplicative interaction with SNPs in the combined DNA-repair and cell-cycle-control pathways (P<.01). All genetic effects were evident only in "ever smokers" (persons who had smoked >or=100 cigarettes) and not in "never smokers." A cross-validation statistical method developed in this study confirmed the above observations. CART analysis revealed potential higher-order gene-gene and gene-smoking interactions and categorized a few higher-risk subgroups for bladder cancer. Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrene diol-epoxide (BPDE)-induced chromatid breaks (by mutagen-sensitivity assay) and DNA damage (by comet assay) for individuals in higher-risk subgroups among cases of bladder cancer in smokers. The P for the trend was .0348 for bleomycin-induced chromosome breaks, .0036 for BPDE-induced chromosome breaks, and .0397 for BPDE-induced DNA damage, indicating that these higher-order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA-repair capacity. Thus, genotype/phenotype analyses support findings from CART analyses. This is the first comprehensive study to use a multigenic analysis for bladder cancer, and the data suggest that individuals with a higher number of genetic variations in DNA-repair and cell-cycle-control genes are at an increased risk for bladder cancer, confirming the importance of taking a multigenic pathway-based approach to risk assessment.

CANCER INCIDENCE AMONG PESTICIDE APPLICATORS EXPOSED TO METOLACHLOR IN THE AGRICULTURAL HEALTH STUDY

ISEE-250 Introduction: Metolachlor, a chloroacetanilide herbicide, is used for general weed control in many agricultural food and feed crops and in residential applications. One of the two most widely used herbicides in the U.S., metolachlor has been classified by the EPA as a “possible human carcinogen,” based on increased liver tumours in female rats. Studies in humans, however, are few, despite the considerable potential for occupational exposure and environmental exposure via drinking water. Investigations in the Agricultural Health Study (AHS) have shown an increased risk for haematopoetic cancers with increasing lifetime days exposure to another chloroacetanilide herbicide, alachlor, and an increased risk for lung cancer with metolachlor exposure. Aim: These results motivated further investigation of the cancer risk among applicators in the AHS who used metolachlor. Methods: We obtained detailed pesticide exposure information from 57,311 licensed pesticide applicators in Iowa and North Carolina, using a self-administered questionnaire completed at the time of enrolment (1993–1997). Cancer incidence was followed through December 31, 2001. We used adjusted Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs) for several types of cancer among metolachlor-exposed applicators, while adjusting for many potential confounders. Two exposure metrics were used: tertiles of lifetime days of exposure (LD) and tertiles of intensity-weighted lifetime days of exposure (IWLD). The IWLD metric incorporates a measure of potential exposure intensity based on application and methods, repair of application equipment and use of personal protective equipment. Results: 23,396 (41%) of the AHS applicators reported ever using metolachlor. Exposure was not associated with overall cancer incidence. Applicators in the highest tertile of LD had a significantly elevated risk for lung cancer (RR=2.5; 95%CI, 1.2–5.4, p-trend =0.01) and bladder cancer (RR=3.19; 95%CI, 1.05–9.74, p-trend=0.02), a non-significantly elevated risk for rectum cancer (RR=3.6; 95%CI, 0.9–14.7, p-trend =0.05), and a significantly decreased risk for prostate cancer (RR=0.7; 95%CI, 0.5–0.9, p-trend =0.04), compared with those in the lowest tertile. Results were similar for the IWLD metric, but non-significant. When we compared tertiles of exposure among metolachlor-exposed applicators to those who never applied metolachlor, results were null. No other cancer appeared to be associated with use of metolachlor. Discussion: There was an increased risk for lung cancer and a decreased risk for prostate cancer, with increasing LD exposure among metolachlor exposed applicators, however, there were inconsistencies between the two exposure metrics and with the comparison to applicators not exposed to metolachlor. There was a suggested increased risk for rectum cancer with increasing LD exposure, however, this estimate was based on 17 cases and should be interpreted with caution. Taking into consideration both exposure metrics, our analyses did not find any clear associations between metolachlor and these cancers.

Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay

A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory. To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer. Twenty-three academic, private practice, and veterans' facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner. Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ. The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test results available during the patient visit.

An Association of UDP-Glucuronosyltransferase 2B7 C802T (His268Tyr) Polymorphism with Bladder Cancer in Benzidine-Exposed Workers in China

UDP-Glucuronyltransferase 2B7 (UGT2B7) is involved in benzidine metabolism, as demonstrated by in vitro experiments with liver slices. To evaluate the possible association of UGT2B7 gene polymorphism with bladder cancer risk for benzidine-exposed subjects, diagnosed bladder cancer cases (n = 36) who were members of a cohort of benzidine-exposed workers in the Chinese dyestuff industry were investigated. UGT2B7 polymorphism at locus C802T (His268Tyr) was detected using a PCR-RFLP based procedure. Nondiseased cohort members (156 men, 95 women) were taken as work-related control, and unexposed healthy individuals (113 men, 105 women) were taken as community control. The data showed that the polymorphism at locus UGT2B7 C802T in a general Chinese population significantly differs from that in a Caucasian population (p = 0.00018), displaying a distinctly lower frequency of T/T genotypes (9.2 vs. 25.3%), while no significant difference to a Japanese population could be detected (p = 0.17). A higher prevalence of T/T genotype carriers was found in the cancer cases, compared with unexposed healthy controls (25 vs. 9%, odds ratio [OR] 3.30, 95% confidence interval [95% CI] 1.37-7.98, p = 0.006). A higher presentation of T allele carriers in the patients group was also confirmed (46 vs. 33%, OR 1.73, 95% CI 1.05-2.87, p = 0.03). A higher portion of the T/T genotype was also observed in bladder cancer patients compared with nondiseased members of the same benzidine-exposed cohort, although some of them displayed different degrees of cellular alterations in their exfoliated urothelial cells. This study points for the first time to an association between a homozygous mutant genotype of human UDP-glucuronosyltransferase 2B7 catalyzing the biotransformation of benzidine and an elevated bladder cancer risk for formerly benzidine-exposed workers of the dyestuff industry.

Gender, smoking, glutathione- S-transferase variants and bladder cancer incidence: a population-based study

Objective. Male gender, tobacco smoking and occupational exposure to arylamines and polycyclic aromatic hydrocarbons are the primary risk factors for bladder cancer. Emerging, and consistent data indicate that risk may be modified by polymorphisms in carcinogen metabolism genes, including those involving the glutathione- S-transferases. Recent work further suggests that susceptibility to the carcinogenic effects of tobacco on the bladder may differ among men and women. Method. We investigated the gender specific risk of bladder cancer associated with glutathione- S-transferase M1 ( GSTM1) and T1 ( GSTT1) polymorphisms in a population-based case-control study of 354 bladder cancer cases and 542 controls. Results. We found an increased risk of bladder cancer associated with GSTM1 null genotype among women (OR 1.7; 95% CI 1.0–3.0), but not men (OR 0.9; 95% CI 0.7–1.3). Among women, the GSTM1 null genotype was associated with an elevated bladder cancer risk only among smokers (OR 2.3; 95% CI 1.1–4.5 in ever smokers versus OR 0.9; 95% CI 0.3–2.5 in never smokers). There was no apparent association between bladder cancer and the GSTT1 null polymorphism in either men or women, and we did not detect evidence of any GSTT1–smoking or GSTT1–GSTM1 gene–gene interaction. Conclusion. Our data suggest that a subset of women may be particularly susceptible to tobacco-induced bladder cancer.

Occupation and bladder cancer risk in a population-based case-control study in New Hampshire.

To identify occupations with excess bladder cancer risk in New Hampshire, where bladder cancer mortality rates have been elevated for decades. Lifetime occupational histories were obtained from interviews with 424 cases and 645 controls in a population-based case-control study. Unconditional logistic regression models were used to estimate odds ratios (Ors) and 95% confidence intervals (CI) for each occupation, adjusted for age and smoking. Analyses by duration of employment were carried out and interactions with smoking were examined. Male tractor-trailer truck drivers had an elevated risk for bladder cancer (OR = 2.4, CI = 1.4-4.1), with a significant positive trend in risk with increasing duration of employment (P (trend) = 0.0003). Male metal/plastic processing machine operators also had a significant excess (OR = 4.9, CI = 1.6-15.1), attributable mainly to molding/casting machine operators (OR = 16.6, CI = 2.1-131). Elevated risk was also observed for male fabricators, assemblers, and hand workers (OR = 1.8, CI = 1.0-3.4). Women in certain sales occupations (sales clerks, counter clerks, and cashiers) had a significant excess risk (OR = 2.2, CI = 1.3-3.9) and a significant trend with duration of employment (P (trend) = 0.016), as did female health service workers (OR = 4.1, CI = 1.6-10.7; P (trend) = 0.014). There was a positive interaction between smoking and employment as a health service worker (p = 0.036). These findings are generally consistent with previous studies. Elevated risks for male molding/casting machine operators, female salesworkers, and female health service workers, especially those with a history of smoking, require further investigation.

Benzo[a]pyrene diol epoxide-induced 9p21 aberrations associated with genetic predisposition to bladder cancer.

CDKN2A, 9p21, encodes two alternatively spiked, functionally distinct, tumor-suppressor proteins, P16INK4A and P14ARF, which play active roles in the RB1 and TP53 pathways, respectively. Deletion of 9p is one of the most frequent genomic alterations in bladder cancer. In addition, alterations of 9p21 and P16 are frequently seen in the epithelial cells of chronic smokers. This pilot study evaluated whether 9p21 aberrations induced by exposure in vitro to benzo[a]pyrene diol epoxide (BPDE), the metabolic product of benzo[a]pyrene, a constituent of tobacco smoke, were more common in the peripheral blood lymphocytes of 61 bladder cancer patients compared to 64 matched controls. Our hypothesis was that 9p21 sensitivity to BPDE reflects the susceptibility of a specific locus to damage from carcinogens in tobacco smoke. We found that BPDE-induced chromosome band 9p21 aberrations were significantly higher in lymphocytes of bladder cancer cases (24.97 +/- 5.26 per 1,000) than in controls (20.72 +/- 4.51 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control locus. After adjustment for age, sex, ethnicity, and smoking status, 9p BPDE sensitivity had an odds ratio (OR) of 9.01 [95% confidence interval (95% CI) 3.75, 21.67] for bladder cancer. We further observed a gradient of elevated bladder cancer risk associated with increasing chromosomal damage. The adjusted ORs for subjects in the second, third, and highest quartiles of BPDE-induced 9p21 aberrations relative to the first quartile were 0.48 (0.04, 5.69), 5.14 (1.12, 23.59), and 21.51 (4.75, 97.34), respectively, providing increasing dose-response evidence of the locus-specific alterations. Thus, 9p21 may be a molecular target for BPDE-induced damage in bladder cancer cases.

Bladder tumours in rubber workers: a factory study 1946-1995.

Prior to December 1949, some British rubber industry workers were inadvertently exposed to the human bladder carcinogen beta-naphthylamine, which was present as a contaminant (at 0.25%) in antioxidants used in manufacturing. This study follows a composite cohort of 6450 men employed at a large tyre factory either during the 'at-risk' period or just after it. A group of 2090 at-risk men (employed 1945-1949) and 3038 men, first employed only after January 1950, when the carcinogen had been removed, were followed for their bladder cancer morbidity and mortality experiences. Fifty-eight tumours were registered for those at risk, whereas only 33.9 were expected at national standardized registration rates [SRRN = 171 and 95% confidence interval (CI) = 130-221]. Thirty-nine bladder tumours were reported for the post-1950 intake, whereas 38.3 were expected (SRRN = 102 and 95% CI = 72-139). The use of mortality data did not reveal any underlying hazard because 12 of the 58 at-risk workers with tumours were still alive at the study end date. In only 16 instances was bladder cancer actually certified as the underlying cause of death. Plotting cases by their location of work on a factory plan assisted the interpretation. A statistically significant elevated risk of bladder cancer for the exposed workforce was evident, but this reversed when the carcinogen was removed from processing in October 1949. The use of morbidity (incidence) data in long-term studies of occupational bladder cancer should be the required methodology if the hazard and risk are not to be underestimated.

Peptic ulcer disease and the risk of bladder cancer in a prospective study of male health professionals.

Helicobacter pylori is a risk factor for gastric and duodenal ulcers, but gastric ulcers generally occur in individuals who have low acid production and diffuse gastritis, whereas duodenal ulcers are more likely to occur with high acid output and antrum-predominant gastritis. Low acid production, gastritis, and ulcer healing each contribute to poor antioxidant absorption, oxidative stress, and elevated nitrite levels in the stomach. N-Nitrosamines are known carcinogens, and nitrate ingestion has been related to bladder cancer risk. Consequently, we hypothesized that the gastric conditions associated with gastric ulcers may contribute to elevated bladder cancer risk. We thus examined the association between self-reported history of peptic ulcer disease and the risk of bladder cancer (414 cases) over 14 years of follow-up in the Health Professional Follow-Up Study. Cox proportional hazards models were performed to adjust for known risk factors of bladder cancer. Men who reported a gastric ulcer before 1986 had a significantly higher risk of bladder cancer compared with those with no history of gastric ulcer (relative risk = 1.55, 95% confidence interval = 1.03-2.33, controlling for smoking and other potential confounders). No association was observed for duodenal ulcers (multivariate relative risk = 0.97, 95% confidence interval = 0.68-1.38). The ulcers in this study were based solely on self-report and not medical records; consequently, misclassification of ulcers may have occurred. Although intriguing, these findings need to be replicated.

Aromatic Amines and Human Urinary Bladder Cancer: Exposure Sources and Epidemiology#

Human exposure to aromatic amines has long been associated with an elevated risk of urinary bladder cancer. Nonetheless, use of these materials has continued due to their industrial and commercial value. Commercial value, chemical reactivity and biological effect are closely linked, making it difficult to select materials that are commercially useful and safe. The chemical structure of carcinogenic aromatic amines is discussed in this paper along with some past and current sources of exposure and the overall epidemiological data supporting the carcinogenicity of these materials. The low dose effects of aromatic amines in tobacco smoke are considered. In addition, the possibility that such widely used commercial products as hair dyes may be related to urinary bladder cancer in humans is reviewed. Research questions either now being currently addressed or may potentially be addressed by the application of biomarkers to human aromatic amine exposure assessment are highlighted. This is the first of a series of two reviews on Aromatic Amines and Human Urinary Bladder Cancer. The second review, focusing on biomarker issues, will be published in the next issue of this journal

An association between NQO1 genetic polymorphism and risk of bladder cancer

NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that plays a critical role in protecting cells against chemically induced oxidative stress, cytotoxicity, mutagenicity, and carcinogenicity. NQO1 protects cells from oxidative damage by preventing the generation of reactive oxygen species and reducing certain environmental carcinogens, such as nitroaromatic compounds, heterocyclic amines, and possible cigarette smoke condensate. A C→T single nucleotide polymorphism in exon 6 was shown to reduce NQO1 enzyme activity, which may diminish the protection provided by NQO1. Therefore, we hypothesized that people with the variant allele genotypes of NQO1 are at higher risk for bladder cancer. In an ongoing case-control study, the NQO1 genotypes were successfully identified by polymerase chain reaction restriction fragment length polymorphism in 265 bladder cancer patients and 261 control subjects matched for age, sex, and ethnicity. The frequency of the variant NQO1 allele was 18% for controls and 21% for cases. The variant allele genotypes of NQO1 were associated with a higher risk of bladder cancer in Caucasians (odds ratio (OR)=1.51; 95% confidence interval (CI)=1.01–2.25). Further analysis in Caucasians showed an elevated bladder cancer risk in men (OR=1.75; 95% CI=1.08–2.85) but not in women (OR=1.16; 95% CI=0.57–2.37). In addition, the variant allele genotypes were associated with higher bladder cancer risk in ever smokers (OR=1.78; 95% CI=1.06–3.00), but not in never smokers (OR=1.19; 95% CI=0.65–2.20). These results suggest that the NQO1 genetic polymorphism modulates bladder cancer risk, especially in men and ever smokers.

Smoking and Other Risk Factors for Bladder Cancer in Women

Background. Bladder cancer is three to five times more frequent in men than in women, and hence only a few studies have focused only on females. Methods. A case–control study was conducted between 1985 and 1992 in two areas of northern Italy, and included 110 women with histologically confirmed bladder cancer and 298 controls, admitted to the same network of hospitals of cases for acute, non-neoplastic, non-urinary or genital tract diseases. Multivariate odds ratios (ORs) were computed using unconditional multiple logistic regression. Results. Compared to never smokers, current smokers (OR = 2.87) had significantly elevated risks of bladder cancer. High intake of vegetables was inversely related to the disease (OR = 0.32), while history of occupation in chemical, dyes/paints or pharmaceutical industry (OR = 3.01) was directly associated to risk of bladder cancer. The OR was 3.29 for ever use of menopause hormone replacement therapy. Conclusions. This study confirms that cigarette smoking is the prominent risk factor for bladder cancer in women as in men, with similar relations in both sexes. It also confirms that selected occupational factors are related to bladder cancer risk, and supports a favourable role of vegetables. The apparent relation with hormone replacement therapy in menopause needs interpretation and further investigation.