Faculty Bibliography

Arsenic exposure from drinking water is considered to be a risk factor for skin and internal cancers. Animal studies suggest a potential antagonism between arsenic and selenium in the body. We did a case-cohort analysis to prospectively evaluate the association between arsenic-related premalignant skin lesions and prediagnostic blood selenium levels in 303 cases of skin lesions newly diagnosed from November 2002 to April 2004 and 849 subcohort members randomly selected from the 8,092 participants in the Health Effects of Arsenic Longitudinal Study with available baseline blood and urine samples collected in 2000. Incidence rate ratios for skin lesions in increasing blood selenium quintiles were 1.00 (reference), 0.68 [95% confidence interval (95% CI), 0.39-1.18], 0.51 (95% CI, 0.29-0.87), 0.52 (95% CI, 0.30-0.91), and 0.53 (95% CI, 0.31-0.90). Effect estimates remained similar with adjustments for age, sex, body mass index, smoking status, excessive sunlight exposure (in men), well water arsenic concentration at baseline, and nutritional intakes of folate, iron, protein, vitamin E, and B vitamins. At any given arsenic exposure level, the risk of premalignant skin lesions was consistently greater among participants with blood selenium lower than the average level. The findings support the hypothesis that dietary selenium intake may reduce the incidence of arsenic-related premalignant skin lesions among populations exposed to arsenic exposure from drinking water. (Cancer Epidemiol Biomarkers Prev 2007;16(2):207-13)

Background: In human pedigree data age at disease occurrence frequently is missing and is imputed using various methods. However, little is known about the performance of these methods when applied to families. In particular, there is little information about the level of agreement between imputed and actual values of temporal data and their effects on inferences. Methods: We performed two evaluations of five imputation methods used to generate complete data for repositories to be shared by many investigators. Two of the methods are mean substitution methods, two are regression methods and one is a multiple imputation method based on one of the regression methods. To evaluate the methods, we randomly deleted the years of disease diagnosis of some men in a sample of pedigrees ascertained as part of a prostate cancer study. In the first evaluation, we used the five methods to impute the missing diagnosis years and evaluated agreement between imputed and actual values. In the second evaluation, we compared agreement between regression coefficients estimated using imputed diagnosis years with those estimated using the actual years. Results/Conclusions: For both evaluations, we found optimal or near-optimal performance from a regression method that imputes a man's diagnosis year based on the year of birth and year of last observation of all affected men with complete data. The multiple imputation analogue of this method also performed well.

BACKGROUND: Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic-contaminated drinking water. To various degrees, ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes. Consequently, folate nutritional status may influence arsenic methylation and toxicity. OBJECTIVE: The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation. DESIGN: Two hundred adults in a rural region of Bangladesh, previously found to have low plasma concentrations of folate (</=9 nmol/L) were enrolled in a randomized, double-blind, placebo-controlled folic acid-supplementation trial. Plasma concentrations of folate and homocysteine and urinary concentrations of arsenic metabolites were analyzed at baseline and after 12 wk of supplementation with folic acid at a dose of 400 microg/d or placebo. RESULTS: The increase in the proportion of total urinary arsenic excreted as DMA in the folic acid group (72% before and 79% after supplementation) was significantly (P < 0.0001) greater than that in the placebo group, as was the reduction in the proportions of total urinary arsenic excreted as MMA (13% and 10%, respectively; P < 0.0001) and as InAs (15% and 11%, respectively; P < 0.001). CONCLUSIONS: These data indicate that folic acid supplementation to participants with low plasma folate enhances arsenic methylation. Because persons whose urine contains low proportions of DMA and high proportions of MMA and InAs have been reported to be at greater risk of skin and bladder cancers and peripheral vascular disease, these results suggest that folic acid supplementation may reduce the risk of arsenic-related health outcomes

BACKGROUND: The nutritional determinants of hypertension in Bangladesh and other low-income countries are largely unknown. OBJECTIVE: We assessed the associations of general hypertension with nutrient intakes and diet patterns in Bangladesh. DESIGN: This was a cross-sectional analysis of 11 116 participants enrolled in the Health Effects of Arsenic Longitudinal Study in Bangladesh. Dietary intakes were measured by use of a validated food-frequency questionnaire. RESULTS: Three major dietary patterns were identified by using principal component analysis: 1) the 'balanced' pattern, which was characterized by rice, some meat, small fish, fruit, and vegetables; 2) the 'animal protein' pattern, which was more heavily weighted on meat, milk, poultry, eggs, bread, large fish, and fruit; and 3) the 'gourd and root vegetable' pattern, which consisted largely of squashes and root and leafy vegetables. Adjusted prevalence odds ratios for general hypertension in increasing quintiles of balanced pattern scores were 1.00 (reference), 0.81 (95% CI: 0.79, 0.97), 0.82 (0.68, 0.97), 0.79 (0.66, 0.94), and 0.71 (0.59, 0.85) (P for trend < 0.01). Prevalence odds ratios for general hypertension in increasing quintiles of animal protein pattern scores were 1.00 (reference), 1.30 (1.01, 1.52), 1.20 (1.01, 1.47), 1.22 (1.00, 1.44), and 1.21 (1.03, 1.49) (P for trend = 0.23). Markers of high socioeconomic status were positively associated with the animal protein pattern. CONCLUSION: Our findings suggest the importance of dietary patterns in general hypertension in a low-income population undergoing the early stage of the epidemiologic transition

Elevated aflatoxin B(1)-albumin adducts (AFB(1)-Alb) have been associated with an increased risk for HCC development. However, there are no studies in humans, correlating albumin adducts in blood with liver DNA adducts. Forty frozen tumor tissues and 39 paired plasma samples from HCC patients were collected in Taiwan, to determine the relationship between albumin adducts in blood and DNA adducts in liver tissue as well as mutations in p53 and methylation of p16. AFB(1)- and polycyclic aromatic hydrocarbon (PAH)-DNA adducts in tissue and albumin adducts in plasma were determined by immunohistochemistry and competitive ELISA, respectively. Plasma AFB(1)-Alb adducts in subjects with low, medium and high levels of AFB(1)-DNA adducts in tumor tissues were 51.0 +/- 36.5, 70.5 +/- 48.1 and 84.9 +/- 48.2 fmol/mg, respectively (p(trend) = 0.05). No significant correlation was found for PAH. Fourteen of 40 (36%) tissues were positive for mutant p53 protein by immunohistochemistry; 11 of 40 tissue DNA samples (28%) were positive for p53 mutations, but not their corresponding plasma DNAs. p16 was methylated in 24 of 40 (62%) tissues and 12 of 39 (32%) plasma DNAs. Significant correlations were observed between AFB(1)-Alb adducts and p53 mutations and p16 methylation. These data suggest that genetic, epigenetic and environmental exposure biomarkers in plasma may help in estimating the risk for the development of HCC. (c) 2006 Wiley-Liss, Inc

Exposure to arsenic (As)-contaminated drinking water affects millions of people worldwide. Arsenic exposure is associated with skin lesions, skin, lung, kidney and liver cancers, neurologic and cardiovascular effects. Past studies involving biomarkers of As exposure have typically examined urinary As (UAs) (adjusted for urinary creatinine), hair or toenail As, but not blood As (BAs) since blood concentrations are exceedingly low and are not detectable by conventional atomic absorption spectrophotometric techniques. In a case-cohort analysis of 303 newly diagnosed cases of skin lesions, and 849 subcohort members randomly selected from 8092 participants in the health effects of as longitudinal study (HEALS) in Araihazar, Bangladesh, we measured blood, urine and water As concentrations, and examined their associations with each other, and with the risk for skin lesions. BAs concentrations were highly correlated with creatinine-adjusted UAs concentrations (r=0.85) and with water As (WAs) (r=0.75). We observed consistent dose-response relationships between the risk of skin lesions and all the measures of As exposure. Rate ratios (RRs) for skin lesions by quintile of As exposure, adjusted for age and gender, revealed that the two highest quintiles were significantly related to an increased risk of skin lesions for each measure of exposure: BAs, UAs, WAs and a time-weighted water As variable. This prospective study confirms the increased risk of skin lesions in relation to As concentrations in blood, urine and water and also establishes that BAs is a useful biomarker of As exposure in this study population

BACKGROUND:: The risk of skin lesions associated with arsenic exposure from drinking water in Bangladesh is considerably greater in men than in women. METHODS:: Using baseline data from 11,062 cohort members in the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh, we performed a cross-sectional analysis to evaluate whether the association between arsenic exposure from drinking water and the risk of skin lesions is modified by tobacco smoking, excessive sunlight, the use of fertilizer, and the use of pesticides. A time-weighted well arsenic concentration was estimated for each participant by incorporating history of well use. Relative excess risk for interaction (RERI) and its 95% confidence intervals (CIs) were estimated using adjusted prevalence odds ratios. RESULTS:: We observed a synergistic effect between the highest level of arsenic exposure (>113 mug/L) and tobacco smoking on risk of skin lesions in men (RERI = 1.5 [95% CI = 0.3 to 2.7] overall and 1.7 [0.2 to 3.4] for the subpopulation with longer-term arsenic exposure). We also observed suggestive synergistic effects between higher levels (28.1-113.0 mug/L and 113.1-864.0 mug/L) of arsenic exposure and fertilizer use in men (RERI = 1.0 [-0.2 to 2.2] and 1.3 [-0.2 to 2.9] respectively). Furthermore, the risk of skin lesions associated with any given level of arsenic exposure was greater in men with excessive sun exposure. The patterns of effect estimates in women indicate similar-but-weaker interaction effects of arsenic exposure with tobacco smoking and fertilizer use. CONCLUSIONS:: These findings help explain why the risk of arsenic-related skin lesions was much greater in men than in women in Bangladesh. Because most arsenic-induced skin cancers arise from these skin lesions, treatment and remediation plans should take into consideration these etiologic cofactors.

Millions of persons around the world are exposed to low doses of arsenic through drinking water. However, estimates of health effects associated with low-dose arsenic exposure have been extrapolated from high-dose studies. In Bangladesh, many persons have been exposed to a wide range of doses of arsenic from drinking water over a significant period of time. The authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002 for the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for all arsenic exposure measures. Compared with drinking water containing <8.1 microg/liter of arsenic, drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 microg/liter of arsenic was associated with adjusted prevalence odds ratios of skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. These findings provide information that should be considered in future research and policy decisions

Epidemiological studies have linked high levels (>200 microg/L) of chronic exposure to arsenic in drinking-water with elevated risks of several vascular diseases. In this pilot study, the association between low-level arsenic exposure and carotid artery intimal-medial thickness (IMT) was evaluated among 66 healthy, normotensive, relatively young individuals (mean age 35 years) participating in the ongoing Health Effects of Arsenic Longitudinal Study in Bangladesh. Participants with a higher carotid IMT (>0.75 mm) in general had higher levels of past chronic exposure of arsenic than those with a lower carotid IMT (< or = 0.75 mm). Although the differences in average arsenic exposure between the two groups were not statistically significant, the findings suggest a possible association between low-level arsenic exposure from drinking-water and carotid atherosclerosis, warranting the need for larger studies