Silver Spring, MD, United States
Silver Spring, MD, United States

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Colt J.S.,U.S. National Institutes of Health | Karagas M.R.,Dartmouth College | Schwenn M.,Maine Cancer Registry | Baris D.,U.S. National Institutes of Health | And 12 more authors.
Occupational and Environmental Medicine | Year: 2011

Objectives: We used data from a large, population-based case-control study inMaine, NewHampshire, and Vermont to examine relationships between occupation, industry and bladder cancer risk. Methods: Lifetime occupational histories were obtained by personal interview from 1158 patients newly diagnosed with urothelial carcinoma of the bladder in 2001-2004, and from 1402 population controls. Unconditional logistic regression was used to calculate ORs and 95% CIs, adjusted for demographic factors, smoking and employment in other high-risk occupations. Results: Male precision metalworkers and metalworking/ plasticworking machine operators had significantly elevated risks and significant trends in risk with duration of employment (precision metalworkers: OR 2.2, 95% CI 1.4 to 3.4, ptrend=0.0065; metalworking/plasticworking machine operators: OR 1.6, 95% CI 1.01 to 2.6, ptrend=0.047). Other occupations/industries for which risk increased significantly with duration of employment included: for men, textile machine operators, mechanics/repairers, automobile mechanics, plumbers, computer systems analysts, information clerks, and landscape industry workers; for women, service occupations, health services, cleaning and building services, management-related occupations, electronic components manufacturing and transportation equipment manufacturing. Men reporting use of metalworking fluids (MWF) had a significantly elevated bladder cancer risk (OR 1.7, 95% CI 1.1 to 2.5). Conclusions: Our findings support the hypothesis that some component(s) of MWF may be carcinogenic to the bladder. Our results also corroborate many other previously reported associations between bladder cancer risk and various occupations. More detailed analyses using information from the study's job-specific questionnaires may help to identify MWF components that may be carcinogenic, and other bladder carcinogens associated with a variety of occupations.


Lenz P.,U.S. National Cancer Institute | Pfeiffer R.,U.S. National Cancer Institute | Baris D.,U.S. National Cancer Institute | Takikita M.,U.S. National Cancer Institute | And 9 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Cell-cycle proteins are important predictive markers in urothelial carcinoma but may also exhibit exposure-specific heterogeneity. Methods: Tumor tissue from 491 bladder cancer cases enrolled in the Maine and Vermont component of the New England Bladder Cancer Study was assembled as tissue microarrays and examined for aberrant expression of p53, p63, p16, cyclin D1, Rb, and Ki-67. The association between expression and histopathology, demographics, and cigarette smoking was examined using c2 tests, multivariable Poisson, and multinomial regression models. Results: We found that overexpression of p53 and Ki-67 was associated with high-stage/grade tumors [relative risk (RR), 1.26; Ptrend = 0.003; and RR, 3.21; P trend < 0.0001, respectively], whereas expression of p63 and p16 was decreased in high-stage/grade tumors (RR, 0.52; Ptrend < 0.0001; and RR, 0.88; Ptrend = 0.04, respectively). No significant aberrations of cell-cycle proteins were identified using various smoking variables and multiple statistical models. Conclusion: The results of this population-based study of histologically confirmed urothelial carcinomas show significant aberration of cell-cycle proteins p53, p63, p16, and Ki-67, but not Rb or cyclin D1. p53 showed the most significant heterogeneity with respect to tumor stage and grade, especially when stratified for different staining intensities using novel digital image analysis techniques. Our findings do not support that smoking modifies expression of cell-cycle proteins. Impact: Our study shows significant heterogeneity in the expression of key cell-cycle proteins that are associated with disease progression in bladder cancer. Further studies may lead to the identification of biomarkers and their multiplexed interactions as useful prognostic and therapeutic targets. ©2012 AACR.


Cantor K.P.,U.S. National Cancer Institute | Cantor K.P.,KP Cantor Environmental LLC | Villanueva C.M.,Center for Research in Environmental Epidemiology | Villanueva C.M.,Institute Municipal dInvestigacio Medica Hospital del Mar | And 24 more authors.
Environmental Health Perspectives | Year: 2010

Background: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water. Objectives: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain. Methods: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms.Results: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively.Conclusions: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.


Amaral A.F.S.,Genetic and Molecular Epidemiology Group | Porta M.,Autonomous University of Barcelona | Porta M.,CIBER ISCIII | Silverman D.T.,U.S. National Cancer Institute | And 14 more authors.
Gut | Year: 2012

Background and Aims: Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. Methods: The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. Results: Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; ptrend=5×10 -6), arsenic (OR 2.02, 95% CI 1.08 to 3.78; ptrend=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; ptrend=3×10- 5) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; ptrend=8×10-11) and nickel (OR 0.27, 95% CI 0.12 to 0.59; ptrend=2×10-4) were inversely associated with the risk of EPC. Conclusion: Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.


Steinmaus C.,University of California at Berkeley | Steinmaus C.,U.S. Environmental Protection Agency | Ferreccio C.,University of Santiago de Chile | Acevedo J.,University of Santiago de Chile | And 15 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2014

Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer. Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls. Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110,110 to 800, and >800 μg/L were 1.00,1.88 [95% confidence interval (CI), 0.96-3.71], and 5.24 (3.05-9.00; Ptrend < 0.001) for lung cancer, and 1.00,2.94 (1.29-6.70), and 8.11 (4.31-15.25; Ptrend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed. Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure. Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. © 2014 American Association for Cancer Research. doi: 10.1158/1055-9965.EPI-14- 0059.


Wu J.W.,U.S. National Institutes of Health | Cross A.J.,U.S. National Institutes of Health | Baris D.,U.S. National Institutes of Health | Ward M.H.,U.S. National Institutes of Health | And 9 more authors.
British Journal of Cancer | Year: 2012

Background: Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet.Methods:We conducted a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (<65 years) and Center for Medicaid and Medicare Services (65-79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00-1.65; P trend=0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08-1.84; P trend=0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61-0.99; P=0.019). Conclusion: Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk. © 2012 Cancer Research UK.


Nuckols J.R.,U.S. National Institutes of Health | Nuckols J.R.,Colorado State University | Beane Freeman L.E.,U.S. National Institutes of Health | Lubin J.H.,U.S. National Institutes of Health | And 13 more authors.
Environmental Health Perspectives | Year: 2011

Background: Ingestion of inorganic arsenic in drinking water is recognized as a cause of bladder cancer when levels are relatively high (≥ 150 μg/L). The epidemiologic evidence is less clear at the low-to-moderate concentrations typically observed in the United States. Accurate retrospective exposure assessment over a long time period is a major challenge in conducting epidemiologic studies of environmental factors and diseases with long latency, such as cancer. Objective: We estimated arsenic concentrations in the water supplies of 2,611 participants in a population-based case-control study in northern New England. Methods: Estimates covered the lifetimes of most study participants and were based on a combination of arsenic measurements at the homes of the participants and statistical modeling of arsenic concentrations in the water supply of both past and current homes. We assigned a residential water supply arsenic concentration for 165,138 (95%) of the total 173,361 lifetime exposure years (EYs) and a workplace water supply arsenic level for 85,195 EYs (86% of reported occupational years). Results: Three methods accounted for 93% of the residential estimates of arsenic concentration: direct measurement of water samples (27%; median, 0.3 μg/L; range, 0.1-11.5), statistical models of water utility measurement data (49%; median, 0.4 μg/L; range, 0.3-3.3), and statistical models of arsenic concentrations in wells using aquifers in New England (17%; median, 1.6 μg/L; range, 0.6-22.4). Conclusions: We used a different validation procedure for each of the three methods, and found our estimated levels to be comparable with available measured concentrations. This methodology allowed us to calculate potential drinking water exposure over long periods.


Tajuddin S.M.,Genetic and Molecular Epidemiology Group | Amaral A.F.S.,Genetic and Molecular Epidemiology Group | Fernandez A.F.,Instituto Universitario Of Oncologia Del Principado Of Asturias Iuopa | Rodriguez-Rodero S.,Instituto Universitario Of Oncologia Del Principado Of Asturias Iuopa | And 19 more authors.
Environmental Health Perspectives | Year: 2013

Background: Altered DNA methylation has been associated with various diseases. Objective: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study. Methods: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression. Results: Women had lower levels of LINE-1 methylation than men (β = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = -3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217- per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10-7; rs9621049-TT, β = 4.2, p = 4.7 × 10-9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = -0.8, global p = 0.05) were associated with LINE-1 methylation. Conclusions: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.


Brock K.E.,University of Sydney | Ke L.,University of Sydney | Gridley G.,U.S. National Cancer Institute | Chiu B.C.-H.,University of Chicago | And 5 more authors.
British Journal of Nutrition | Year: 2012

The association between renal cell cancer (RCC) and intake of fruit, vegetables and nutrients was examined in a population-based case-control study of 323 cases and 1827 controls; dietary intake was obtained using a mailed questionnaire. Cancer risks were estimated by OR and 95% CI, adjusting for age, sex, smoking, obesity, hypertension, proxy status, alcohol consumption and dietary fat intake and energy. Intake of vegetables was associated with a decreased risk of RCC (OR 0.5; 95% CI 0.3, 0.7; P trend=0.002), (top compared to the bottom quartile of intake). When intake of individual nutrients was investigated, vegetable fibre intake was associated with decreased risks (OR 0.4; 95% CI 0.2, 0.6; P<0.001), but this was not the case with fruit fibre (OR 0.7; 95% CI 0.4, 1.1) or grain fibre (OR 1.0; 95% CI 0.6, 1.5). β-Cryptoxanthin and lycopene were also associated with decreased risks, but when both were included in a mutually adjusted backwards stepwise regression model, only β-cryptoxanthin remained significant (OR 0.5; 95% CI 0.3, 0.8). When other micronutrients and types of fibre were investigated together, only vegetable fibre and β-cryptoxanthin had significant trends (P<0.01) (OR 0.6; 95% CI 0.3, 0.9) (OR 0.5; 95% CI 0.3, 0.9), respectively. These findings were stronger in those aged over 65 years (P interaction=0.001). Among non-smokers, low intake of cruciferous vegetables and fruit fibre was also associated with increased risk of RCC (P interaction=0.03); similar inverse associations were found for β-cryptoxanthin, lycopene and vitamin C. When nutrients were mutually adjusted by backwards regression in these subgroups, only β-cryptoxanthin remained associated with lower RCC risk. These findings deserve further investigation in ongoing prospective studies when sample size becomes sufficient. © 2011 The Authors.


Amaral A.F.S.,Spanish National Cancer Research Center | Cantor K.P.,KP Cantor Environmental LLC | Silverman D.T.,U.S. National Cancer Institute | Malats N.,Spanish National Cancer Research Center
Cancer Epidemiology Biomarkers and Prevention | Year: 2010

Background: Selenium is considered to be an antioxidant, and its high levels have been inversely associated with cancer risk of several sites. This meta-analysis examined the relationship between levels of selenium measured in serum and toenails, and the risk of bladder cancer. Methods: A meta-analysis using data from seven published epidemiologic studies (three case-control, three nested case-control, one case-cohort) published before March 2010 was done to examine the association between levels of selenium and bladder cancer. Fixed and random effects analyses were done to calculate meta-odds ratio (mOR) and 95% confidence intervals (CI). Heterogeneity among studies was measured by the I2 statistic. Results: Overall, the risk of bladder cancer was inversely associated with elevated levels of selenium according to a random-effects model (mOR = 0.61; 95% CI, 0.42-0.87). The mORs were 0.95 (95% CI, 0.69-1.27) and 0.55 (95% CI, 0.32-0.95) among men and women, respectively. Sex, type of sample specimen, smoking status, and study design were found to be potential sources of heterogeneity. Conclusions: A significant protective effect of selenium, observed mainly among women, may result from gender-specific differences in its accumulation and excretion. The heterogeneity found among studies was mainly linked to the different biological sample specimens used to measure the selenium concentrations and the small size of the studies. Although these results suggest a protective effect of selenium for bladder cancer risk, additional large studies are warranted to support these preliminary evidence. Impact: The present results suggest a beneficial effect of high selenium intake for bladder cancer risk. ©2010 AACR.

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