Arsenic concentrations in prediagnostic toenails and the risk of bladder cancer in a cohort study of male smokers

At high concentrations, inorganic arsenic can cause bladder cancer in humans. However, it is unclear whether low exposure to inorganic arsenic in drinking water (<100 microg/liter) is related to bladder cancer risk. No study has been known to use biomarkers to assess the relation between individual arsenic exposure and bladder cancer risk. Toenail samples provide an integrated measure of internal arsenic exposure and reflect long-term exposure. The authors examined the relation between toenail arsenic levels and bladder cancer risk among participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort of Finnish male smokers aged 50-69 years. Data for 280 incident bladder cancer cases, identified between baseline (1985-1988) and April 1999, were available for analysis. One control was matched to each case on the basis of age, toenail collection date, intervention group, and smoking duration. Arsenic levels in toenail samples were determined by using neutron activation analysis. Logistic regression analyses were performed to estimate odds ratios. Arsenic toenail concentrations in this Finnish study were similar to those reported in US studies (range: 0.02-17.5 microg/g). The authors observed no association between inorganic arsenic concentration and bladder cancer risk (odds ratio = 1.13, 95% confidence interval: 0.70, 1.81 for the highest vs. lowest quartile). These findings suggest that low-level arsenic exposure is unlikely to explain a substantial excess risk of bladder cancer.     

Nitrate in public water supplies and risk of bladder cancer

BACKGROUND: Nitrate is a precursor compound in the formation of N-nitroso compounds, most of which are potent animal carcinogens. N-nitroso compounds and their precursors have not been extensively evaluated as bladder cancer risk factors. METHODS: We conducted a population-based case-control study of bladder cancer in Iowa. Cases were men and women newly diagnosed with bladder cancer in 1986-1989. Nitrate data for Iowa public water supplies were sparse before the 1960s. To reduce misclassification by unknown nitrate levels, we included only those who used public supplies with nitrate data for 70% or more of their person-years since 1960 (808 cases, 1259 controls). RESULTS: Among controls, the median average nitrate level for their Iowa residences with public water supplies was 1.3 mg/liter nitrate-nitrogen (interquartile range = 0.6-3.0). After adjustment for confounders, we found no increased risk of bladder cancer with increasing average nitrate levels in drinking water; the highest quartile odds ratio for women was 0.8 (95% confidence interval = 0.4-0.8), and for men 0.5 (0.4-0.8). We observed no association among those with high water nitrate exposure (>median) and low (相似文献   

Arsenic methylation and bladder cancer risk in case-control studies in Argentina and the United States

OBJECTIVE: We sought to assess whether the metabolism of arsenic impacts a person's susceptibility to bladder cancer. METHODS: Urinary methylation products were measured in subjects from Argentina (114 cases and 114 controls) and the United States (23 cases and 49 controls). RESULTS: In Argentina, the adjusted odds ratio (OR) for subjects with a high proportion of ingested arsenic excreted as monomethylarsonate (%MMA) was 2.17 (95% confidence interval [CI] = 1.02-4.63) in smokers and 0.48 (95% CI = 0.17-1.33) in nonsmokers. In the United States, the adjusted ORs for high %MMA in subjects with arsenic intakes less than and greater than 100 microg/d were 1.20 (95% CI = 0.27-5.38) and 2.70 (95% CI = 0.39-18.6). CONCLUSIONS: Overall, these results are consistent with data from Taiwan suggesting that some individuals who excrete a higher proportion of ingested arsenic as MMA are more susceptible to arsenic-related cancer.     

Occupation and bladder cancer risk.

This study examines the estimated risk of bladder cancer associated with various occupations among 1,465 cases identified in Orange County, California, during 1984-1988. The annual age-adjusted incidence rate per 100,000 population in Orange County was similar to that of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute: 25.7 in males and 6.2 in females. Cases were compared with a sample of Orange County residents relative to broad category of current occupation, adjusted for age and cigarette smoking. The estimated relative risks were significant for males in machine trades (relative risk (RR) = 2.69, 95% confidence interval (CI) 1.24-5.82) and processing occupations (RR = 5.77, 95% CI 1.43-23.27) and for females in machine trades (RR = 8.34, 95% CI 1.14-61.17) and homemakers (RR = 5.37, 95% CI 2.40-11.99) as compared with individuals of the same sex in professional, technical, and managerial occupations.     

Arsenic in Mexican children exposed to contaminated well water

This cross-sectional study measures the arsenic level in school children exposed to contaminated well water in a rural area in México. Arsenic was measured in hair by hydride generation atomic absorption spectrophotometry. Overall, 110 children were included (average 10 years-old). Among 55 exposed children, mean arsenic level on hair was 1.3 mg/kg (range <0.006-5.9). All unexposed children had undetectable arsenic levels. The high level of arsenic in water was associated to the level in hair. However, exposed children drank less well water at school or at home than unexposed children, suggesting that the use of contaminated water to cook beans, broths or soups may be the source of arsenic exposure.     

Arsenic and bladder cancer: observations and suggestions

Arsenic from drinking water is a well-known risk factor for bladder cancer. The purpose of this paper is to systematize some important yet often overlooked facts considering the relationship between arsenic exposure and the occurrence of bladder cancer. Since the exposure to inorganic arsenic from food, inhaled air, and skin absorption as well as arsenic methylation ability are not fully investigated, our assumption is that the exposure of arsenic only from drinking water is underestimated and its role as a risk factor is highly overestimated. This paper proposes some qualitative and quantitative parameters of arsenic as a risk factor for bladder cancer. The recommended qualitative parameters of arsenic intake are first, pathways of exposure, and second, toxicity and metabolism. The suggested quantitative parameters of arsenic intake include amounts of arsenic absorbed in the body, duration of arsenic exposure, and duration of arsenic presence in the urinary bladder. This approach can be implemented in a systematic classification and explanation of various risk factors and their mutual interactions for other types of cancer or diseases in general.     

Arsenic in drinking-water and risk for cancer in Denmark

BACKGROUND: Arsenic is a well-known carcinogen, which is often found in drinking-water. Epidemiologic studies have shown increased cancer risks among individuals exposed to high concentrations of arsenic in drinking-water, whereas studies of the carcinogenic effect of low doses have had inconsistent results. OBJECTIVE: Our aim was to determine if exposure to low levels of arsenic in drinking-water in Denmark is associated with an increased risk for cancer. METHODS: The study was based on a prospective Danish cohort of 57,053 persons in the Copenhagen and Aarhus areas. Cancer cases were identified in the Danish Cancer Registry, and the Danish civil registration system was used to trace and geocode residential addresses of the cohort members. We used a geographic information system to link addresses with water supply areas, then estimated individual exposure to arsenic using residential addresses back to 1970. Average exposure for the cohort ranged between 0.05 and 25.3 microg/L (mean = 1.2 microg/L). Cox's regression models were used to analyze possible relationships between arsenic and cancer. RESULTS: We found no significant association between exposure to arsenic and risk for cancers of the lung, bladder, liver, kidney, prostate, or colorectum, or melanoma skin cancer; however, the risk for non-melanoma skin cancer decreased with increasing exposure (incidence rate ratio = 0.88/microg/L average exposure; 95% confidence interval, 0.84-0.94). Results adjusted for enrollment area showed no association with non-melanoma skin cancer. CONCLUSIONS: The results indicate that exposure to low doses of arsenic might be associated with a reduced risk for skin cancer.     

Exposure to natural fluoride in well water and hip fracture: a cohort analysis in Finland.

In the retrospective cohort study based on record linkage, the authors studied a cohort of persons born in 1900-1930 (n = 144,627), who had lived in the same rural location at least from 1967 to 1980. Estimates for fluoride concentrations (median, 0.1 mg/liter; maximum, 2.4 mg/liter) in well water in each member of the cohort were obtained by a weighted median smoothing method based on ground water measurements. Information on hip fractures was obtained from the Hospital Discharge Registry for 1981-1994. No association was observed between hip fractures and estimated fluoride concentration in the well water in either men or women when all age groups were analyzed together. However, the association was modified by age and sex so that among younger women, those aged 50-64 years, higher fluoride levels increased the risk of hip fractures. Among older men and women and younger men, no consistent association was seen. The adjusted rate ratio was 2.09 (95% confidence interval: 1.16, 3.76) for younger women who were the most exposed (>1.5 mg/liter) when compared with those who were the least exposed (< or =0.1 mg/liter). The results suggest that fluoride increases the risk of hip fractures only among women.     

Chlorinated drinking water and bladder cancer: effect of misclassification on risk estimates

Data are presented from the Iowa portion of the National Bladder Cancer Case-Control Study demonstrating the effect of misclassification on depressing odds ratio estimates for years of exposure to chlorinated drinking water and bladder cancer. Four methods (METHODS 1 through 4) of quantifying chlorination exposure with sequentially decreasing degrees of misclassification are presented for the 268 bladder cancer cases and 658 population-based controls fulfilling criteria for inclusion in this study. Twenty-eight other risk factors for bladder cancer were considered along with chlorinated drinking water exposure estimated by METHOD 4. Stepwise regression models included as significant factors cigarette smoking (p less than .001), chlorination exposure (p = .038), and irradiation to the pelvic area (p = .040). Replacement of chlorinated drinking water exposure estimated by METHOD 4 with any of the remaining three methods resulted in models that included cigarette smoking and irradiation to the pelvic area, but not chlorination exposure. Thus, misclassification of chlorination exposure signified the difference between observing and not observing an association with bladder cancer.     

Arsenic methylation and skin cancer risk in southwestern Taiwan

Arsenic is a known carcinogen, but data are especially lacking on the health effects of low-level exposure, and on the health significance of methylation ability. We conducted a case-control study (76 cases and 224 controls from 1996 to 1999) in southwestern Taiwan to explore the association among primary and secondary arsenic methylation index (PMI and SMI, respectively), cumulative arsenic exposure (CAE), and the risk of skin cancer. As compared with the controls, the skin cancer group reported more sun exposure (P = 0.02) and had a lower BMI (P = 0.03), as well as lower education level (P = 0.01). Skin cancer patients and controls were similar with regard to age, gender, smoking and alcohol consumption. Given a low SMI (< or = 5), CAE > 15 mg/L-year was associated with an increased risk of skin cancer (OR, 7.48; 95% CI, 1.65-33.99) compared to a CAE < or = 2 mg/L-year. Given the same level of PMI, SMI, and CAE, men had a higher risk of skin cancer (OR, 4.04; 95% CI, 1.46-11.22) when compared to women. Subjects with low SMI and high CAE have a substantially increased risk of skin cancer. Males in all strata of arsenic exposure and methylation ability had a higher risk of skin cancer than women.     

Arsenic risk assessment.

We review recent publications by Hopenhayn-Rich et al. and Smith et al. regarding two critical issues in arsenic risk assessment: the role of methylation in the dose-response relationship and the role of internal cancers. Hopenhayn-Rich et al. applied simple linear regression to data from several studies to determine whether the percentage of inorganic arsenic in urine increases with increasing dose. Although their results failed to show a correlation between percent inorganic arsenic and urinary arsenic concentration, their evaluation does not demonstrate the absence of a methylation threshold because of the relatively low level of arsenic in urine and the use of grab samples in evaluating methylating capacity. Using data from an epidemiological study in Taiwan, Smith et al. have indicated that arsenic could be an important risk factor not only for skin cancer (the basis of the current EPA cancer slope factor), but also for several internal cancers including lung, liver, bladder, and kidney. We note the following deficiencies in the analysis of Smith et al: 1) the likely underestimated exposure estimate due to lack of consideration on nonwater sources of arsenic and the underestimate of water consumption, 2) lack of consideration of detoxification in estimating potential risks from low-level exposures typical of the U.S. population, and 3) lack of consideration of key differences, particularly nutritional differences, between the Taiwanese and U.S. populations that could affect potential risks.     

Phenobarbital use and bladder cancer risk

Background: Two epidemiologic studies have reported an inverse association between use of phenobarbital (PB) and bladder cancer development. It was proposed that PB use protects against bladder cancer by inducing enzymes that participate in the detoxification of human bladder carcinogens, such as the aminobiphenyls and naphthylamines, which are found in cigarette smoke. Methods: A population-based case–control study was conducted in Los Angeles, California, involving 815 incident bladder cancer cases and an equal number of controls who were matched to the index cases by neighborhood, sex, date of birth (within 5years), and race. Detailed information on lifetime use of PB was collected through in-person interviews. Results: Ever use (20 or more times over lifetime) of PB was not associated with risk of bladder cancer (OR: 0.86; 95% CI: 0.54, 1.39). Regular use of PB also was not associated with risk of bladder cancer in either men or women, in either smokers or non-smokers, although the number of regular users in cases and controls were relatively small (21 cases vs. 15 controls, OR: 1.20; 95%CI: 0.59, 2.45). In fact, compared with non-users, subjects in the highest category of lifetime PB consumption were at a non-significant 2.46-fold increased risk of bladder cancer (95% CI: 0.90, 6.78). Conclusions: The present study did not observe a protective role of PB use in bladder cancer development in the general population.     

Occupation and the risk of bladder cancer

The relationship between bladder cancer, occupation and exposure to a number of occupational agents was assessed in a case-control study conducted in the greater Milan area, Northern Italy. The case series consisted of 263 cases (219 males, 44 females) with histologically confirmed invasive bladder cancer, admitted to a network including major teaching and general hospitals in the area under surveillance. The controls were 287 patients (210 males, 77 females), admitted for acute, non-neoplastic or urinary tract diseases to the same network of hospitals. Cases more frequently reported occupation in dyestuff production (relative risk (RR) = 4.6), painting/spraying work (RR = 1.8), chemical industry (RR = 1.7), pharmaceuticals (RR = 1.7) and coal/gas production (RR = 3.1). Only for dyestuff production however, was the excess statistically significant. There was no association with agriculture or related activities, rubber manufacturing, printing, the petroleum industry, food processing and mechanics. In relation to exposure to occupational agents, significant positive trends in risk were observed for dyes/paints (RR = 4.8 for greater than ten years of exposure), herbicides (RR = 4.1), chemicals (RR = 2.4) and gases/fumes (RR = 4.8). No association was found with metals or metal dusts, plastic resins or glues, oil, wood dust, solvents or benzene, asbestos, electricity or radar and coal tar. Besides confirming the well known association between bladder cancer risk and dyestuff production and, to a lesser extent, a wide spectrum of chemical-related activities, this study provides statistically significant evidence of an independent role of herbicides on the risk of bladder cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tuberculosis chemotherapy and risk of bladder cancer

In a population-based study of 2982 bladder cancer patients and 5782 population controls from 10 geographical areas of the US, no excess risk was associated with medications used for tuberculosis treatment or prophylaxis (relative risk (RR) = 0.95). The findings agree with other epidemiological studies that have not confirmed earlier reports linking isoniazid (INH) exposure to bladder cancer.     

Validity of spatial models of arsenic concentrations in private well water

OBJECTIVE: Arsenic is a pervasive contaminant in underground aquifers worldwide, yet documentation of health effects associated with low-to-moderate concentrations (<100microg/L) has been stymied by uncertainties in assessing long-term exposure. A critical component of assessing exposure to arsenic in drinking water is the development of models for predicting arsenic concentrations in private well water in the past; however, these models are seldom validated. The objective of this paper is to validate alternative spatial models of arsenic concentrations in private well water in southeastern Michigan. METHODS: From 1993 to 2002, the Michigan Department of Environmental Quality analyzed arsenic concentrations in water from 6050 private wells. This dataset was used to develop several spatial models of arsenic concentrations in well water: proxy wells based on nearest-neighbor relationships, averages across geographic regions, and geostatistically derived estimates based on spatial correlation and geologic factors. Output from these models was validated using arsenic concentrations measured in 371 private wells from 2003 to 2006. RESULTS: The geostatisical model and nearest-neighbor approach outperformed the models based on geographic averages. The geostatistical model produced the highest degree of correlation using continuous data (Pearson's r=0.61; Spearman's rank rho=0.46) while the nearest-neighbor approach produced the strongest correlation (kappa(weighted)=0.58) using an a priori categorization of arsenic concentrations (<5, 5-9.99, 10-19.99, > or = 20microg/L). When the maximum contaminant level was used as a cut-off in a two-category classification (<10, > or =10microg/L), the nearest-neighbor approach and geostatistical model had similar values for sensitivity (0.62-0.63), specificity (0.80), negative predictive value (0.85), positive predictive value (0.53), and percent agreement (75%). DISCUSSION: This validation study reveals that geostatistical modeling and nearest-neighbor approaches are effective spatial models for predicting arsenic concentrations in private well water. Further validation analyses in other regions are necessary to indicate how widely these findings may be generalized.     

Arsenic cancer risk confounder in southwest Taiwan data set

Quantitative analysis for the risk of human cancer from the ingestion of inorganic arsenic has been based on the reported cancer mortality experience in the blackfoot disease (BFD) -endemic area of southwest Taiwan. Linear regression analysis shows that arsenic as the sole etiologic factor accounts for only 21% of the variance in the village standardized mortality ratios for bladder and lung cancer. A previous study had reported the influence of confounders (township, BFD prevalence, and artesian well dependency) qualitatively, but they have not been introduced into a quantitative assessment. In this six-township study, only three townships (2, 4, and 6) showed a significant positive dose-response relationship with arsenic exposure. The other three townships (0, 3, and 5) demonstrated significant bladder and lung cancer risks that were independent of arsenic exposure. The data for bladder and lung cancer mortality for townships 2, 4, and 6 fit an inverse linear regression model (p < 0.001) with an estimated threshold at 151 microg/L (95% confidence interval, 42 to 229 microg/L) . Such a model is consistent with epidemiologic and toxicologic literature for bladder cancer. Exploration of the southwest Taiwan cancer mortality data set has clarified the dose-response relationship with arsenic exposure by separating out township as a confounding factor. Key words: arsenic, blackfoot disease, bladder cancer, cancer risk, confounder, dose-response relationship, southwest Taiwan, threshold model.     

Arsenic methylation patterns before and after changing from high to lower concentrations of arsenic in drinking water.

Inorganic arsenic (In-As), an occupational and environmental human carcinogen, undergoes biomethylation to monomethylarsonate (MMA) and dimethylarsinate (DMA). It has been proposed that saturation of methylation capacity at high exposure levels may lead to a threshold for the carcinogenicity of In-As. The relative distribution of urinary In-As, MMA, and DMA is used as a measure of human methylation capacity. The most common pathway for elevated environmental exposure to In-As worldwide is through drinking water. We conducted a biomarker study in northern Chile of a population chronically exposed to water naturally contaminated with high arsenic content (600 micrograms/l). In this paper we present the results of a prospective follow-up of 73 exposed individuals, who were provided with water of lower arsenic content (45 micrograms/l) for 2 months. The proportions of In-As, MMA, and DMA in urine were compared before and after intervention, and the effect of other factors on the distribution of arsenic metabolites was also analyzed. The findings of this study indicate that the decrease in arsenic exposure was associated with a small decrease in the percent In-As in urine (from 17.8% to 14.6%) and in the MMA/DMA ratio (from 0.23 to 0.18). Other factors such as smoking, gender, age, years of residence, and ethnicity were associated mainly with changes in the MMA/DMA ratio, with smoking having the strongest effect. Nevertheless, the factors investigated accounted for only about 20% of the large interindividual variability observed. Genetic polymorphisms in As-methylating enzymes and other co-factors are likely to contribute to some of the unexplained variation. The changes observed in the percent In-As and in the MMA/DMA ratio do not support an exposure-based threshold for arsenic methylation in humans.