Faculty Bibliography

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

Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes, including premalignant and malignant skin tumors, total mortality, pregnancy outcomes, and children's cognitive development. In this paper, we provide descriptions of the study methods including study design, study population, data collection, response rates, and exposure and outcome assessments. We also present characteristics of the study participants including the distribution of exposure and the prevalence of skin lesion at baseline recruitment. A total of 11,746 married men and women between 18 and 75 years of age participated in the study at baseline (a response rate of 98%) and completed a full questionnaire interview that included a food frequency questionnaire, with a response rate of 98%. Among the 98% of the participants who completed the clinical evaluation, over 90% provided blood samples and spot urine samples. Higher educational status, male gender, and presence of premalignant skin lesions were associated with an increased likelihood of providing blood and urine samples. Older participants were less likely to donate a blood sample. About one-third of the participants consumed water from a well with As concentration in each of three groups: >100 mug/l, 25-100 mug/l, and <25 mug/l. Average urinary As concentrations were 140 and 136 mug/l for males and females, respectively. HEALS has several unique features, including a prospective study design, comprehensive assessments of both past and future changes in As exposure at the individual level, a large repository of biological samples, and a full dose range of As exposures in the study population. HEALS is a valuable resource for examining novel research questions on the health effects of As exposure.Journal of Exposure Analysis and Environmental Epidemiology advance online publication, 14 September 2005; doi:10.1038/sj.jea.7500449

We conducted a population-based prevalence survey in Araihazar, Bangladesh, to describe the distribution of arsenic exposure in a rural Bangladeshi population and to assess the population's awareness to this problem as well as to possible remediation options. Water samples from 5,967 contiguous tube wells in a defined geographic area were tested using laboratory-based methods. Additionally, for each well, the owner/caretaker (or a close relative) was interviewed regarding his or her awareness of the health consequences of As exposure. Arsenic exposure data and demographic characteristics for the 65,876 users of these wells were also collected from the 5,967 respondents. Among the 65,876 residents, more than half (54%) regularly consumed well water with an As concentration > or = 50 microg/L--above the acceptable government standard in Bangladesh. Respondents were 15-92 years of age, with an average age of 42 years, and 43% were male. Presence of awareness was significantly related to male sex, nonlabor head of household occupation, better housing, and having had the well tested for As concentration. Most respondents (92%) expressed a willingness to take steps to reduce their exposure, with switching to a safe well the most favored option (46.2%). Willingness to reduce exposure was positively related to awareness of the health risks of As. However, the association between awareness and switching to a safe well [odds ratio (OR) = 1.25; 95% confidence interval (CI), 1.01-1.54] was no stronger than the associations between awareness and using surface water (with or without treatments) (OR = 1.54; 95% CI, 1.22-1.95) or using an existing well after treatment or increasing the depth (OR = 1.34; 95% CI, 1.08-1.67). These findings suggest that health education programs may need to target individuals with lower socioeconomic status and that well switching should be encouraged with more appropriate health education. Increasing knowledge of the health consequences of As may be an important element in facilitating remediation