Yu Mei Hsueh

Biological Gradient Between Long-Term Arsenic Exposure and Carotid Atherosclerosis

Background—Long-term exposure to ingested arsenic has been documented to induce peripheral vascular disease, ischemic heart disease, and cerebral infarction in a dose-response relationship. This study further examined the biological gradient between ingested inorganic arsenic and carotid atherosclerosis. Methods and Results—We studied 199 male and 264 female adult residents from the southwestern area of endemic arseniasis in Taiwan. The extent of carotid atherosclerosis was assessed by duplex ultrasonography. Diabetes mellitus was determined by oral glucose tolerance test, hypertension by mercury sphygmomanometers, and serum lipid profiles by autoanalyzers. Information regarding the consumption of high-arsenic artesian well water, cigarette smoking, and alcohol consumption was obtained through standardized questionnaire interviews. Logistic regression analysis was used to estimate the odds ratio and its 95% CI of carotid atherosclerosis for various risk factors. Three indices of long-term exposure to ingested arsenic, including the duration of consuming artesian well water, the average arsenic concentration in consumed artesian well water, and cumulative arsenic exposure, were all significantly associated with prevalence of carotid atherosclerosis in a dose-response relationship. The biological gradient remained significant after adjustment for age, sex, hypertension, diabetes mellitus, cigarette smoking, alcohol consumption, waist-to-hip ratio, and serum levels of total cholesterol and LDL cholesterol. The multivariate-adjusted odds ratio was 3.1 (95% CI 1.3 to 7.4) for those who had a cumulative arsenic exposure of ≥20 mg/L-years compared with those without exposure to arsenic from drinking artesian well water. Conclusions—Carotid atherosclerosis is associated with ingested inorganic arsenic, showing a significant biological gradient.

Long-term arsenic exposure and ischemic heart disease in arseniasis-hyperendemic villages in Taiwan.

The association between long-term arsenic exposure and peripheral vascular disease has been well documented in our previous epidemiologic studies. The purpose of this study was to evaluate whether long-term arsenic exposure could be associated with ischemic heart disease (IHD). A total of 462 subjects living in the blackfoot disease-hyperendemic villages along the southwestern coast of Taiwan and characterized by long-term arsenic exposure from drinking artesian well water was studied. The subjects were recruited from an epidemiologic cohort who participated in a health examination. IHD was diagnosed by coding the resting electrocardiograms with the Minnesota code. History of arsenic exposure was estimated through information obtained from a personal interview according to a structured questionnaire and the arsenic content in artesian well water of the villages. Cumulative arsenic exposure (CAE) was calculated as the sum of the products multiplying the arsenic concentration in artesian well water (mg/l) by the duration of drinking the water (years) in consecutive periods of living in the different villages. Among the subjects, 78 cases (16.9%) were diagnosed as having IHD. The prevalence rates of IHD for the age groups of 30-39, 40-49, 50-59, and >/=60 years were 4.9, 7.5, 16.8, and 30.7%, respectively (P<0.001). For those with CAE of 0, 0.1-14.9 and >/=15 mg/l-years, the prevalence rates of IHD were 5.2, 10.9 and 24.1%, respectively (P<0.001). The odds ratios (95% confidence intervals) for IHD were 1.60 (0.48, 5.34), and 3.60 (1.11, 11.65), respectively, for those with CAE of 0.1-14.9 and >/=15.0 mg/l-years, when compared with those lacking drinking water exposure to arsenic after multivariate adjustment. It is concluded that IHD in the arseniasis-hyperendemic villages in Taiwan was associated with long-term arsenic exposure.

Epidemiologic evidence of diabetogenic effect of arsenic

It is well documented that arsenic can lead to skin lesions, atherosclerotic diseases and cancers. The association between arsenic exposure and diabetes mellitus is a relatively new finding. Up to now, there are six epidemiologic reports linking diabetes mellitus with arsenic exposure from environmental and occupational sources. Two reports in Taiwan carried out in the blackfoot disease-hyperendemic villages, one cross-sectional and one prospective follow-up of the same cohort, indicate that arsenic exposure from drinking artesian well water is associated with prevalence and incidence of diabetes mellitus in a dose-responsive pattern. The observation of the relation between arsenic exposure and diabetes mellitus is further supported by studies carried out in Sweden and Bangladesh. In Sweden, case-control analyses of death records of copper smelters and glass workers revealed a trend of increasing diabetes mellitus with increasing arsenic exposure from inhalation. In Bangladesh, prevalence of diabetes mellitus among arsenic-exposed subjects with keratosis was about five times higher than unexposed subjects. Increasing trends of diabetes mellitus with indices of arsenic exposure in drinking water seems to be independent of the presence of skin lesions associated with arsenic exposure. Although these studies consistently show an association between arsenic exposure and diabetes mellitus, the weak study designs of cross-sectional or case-control, the use of glucosuria or diabetes death as diagnostic criteria and the lack of adjustment for possible confounders in some studies, are major limitations that may reduce the strength of the evidence.

Urinary levels of inorganic and organic arsenic metabolites among residents in an arseniasis-hyperendemic area in Taiwan

In order to elucidate whether urinary levels of inorganic and organic arsenic metabolites are associated with previous exposure to high-arsenic artesian well water, a total of 302 residents of age 30 yr or older were recruited from three arseniasis-hyperendemic villages in Taiwan. Most study subjects had stopped consuming high-arsenic artesian well water for more than 20 yr. The mean total arsenic (Ast) determined by inductively coupled plasma mass spectrometer (ICPMS) was 267.05 +/- 20.95 microg/L, and the mean level of inorganic arsenic and its metabolites (Asi) was 86.08 +/- 3.43 microg/L. In the multivariate analysis, urinary dimethylarsinic acid (DMA) levels were significantly inversely associated with age, with women exhibiting significantly lower urinary amounts of arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMA), organic arsenic (Aso), and Ast compared to men. After adjustment for age and sex, previous cumulative arsenic exposure through consumption of artesian well water was significantly associated with elevated urinary levels of MMA and DMA, but not As(III) + As(V), Aso and Ast. In the multivariate analysis, the percentage of Aso in Ast was significantly higher in men than women, but this was not significantly associated with age. The percentage of As(III) + As(V) in Asi increased significantly with age, while the reverse was noted with DMA in Asi. Women had a significantly higher DMA percentage but lower As(III) + As(V) and MMA percentages in Asi than men. After adjustment for age and sex, the percentages of As(III) + As(V) in Asi were significantly inversely associated with previous arsenic exposure through consumption of artesian well water. Data suggested that women seem to possess a more efficient arsenic methylation capability than men, and aging diminishes this methylation capability; furthermore, the higher the cumulative arsenic exposure, the greater is the body burden of inorganic arsenic, mainly in the form of MMA and DMA.

Low serum carotene level and increased risk of ischemic heart disease related to long-term arsenic exposure

To elucidate the association between arsenic-related ischemic heart disease (ISHD) and serum antioxidant micronutrient level, residents aged 30 or older living in arseniasis-hyperendemic villages in Taiwan were recruited in a community-based health survey. A structured questionnaire was used to obtain a history of long-term exposure to arsenic through consuming artesian well water and fasting serum samples were also collected at the recruitment. A total of 74 patients affected with ISHD, who were diagnosed through both electrocardiography and Rose questionnaire interview, and 193 age-sex-matched healthy controls were selected for the examination of serum levels of micronutrients by high performance liquid chromatography (HPLC). There was a significant biological gradient between the risk of ISHD and the duration of consuming high-arsenic artesian well water. A significant reverse dose-response relationship with arsenic-related ISHD was observed for serum level of alpha- and beta-carotene, but not for serum levels of retinol, lycopene and alpha-tocopherol. Multivariate analysis showed a synergistic interaction on arsenic-related ISHD between duration of consuming artesian well water and low serum carotene level. An increased risk of arsenic-related ISHD was also associated with hypertension and elevated body mass index, but not with serum lipid profile, cigarette smoking and alcohol drinking. The findings seem to suggest that arsenic-related ISHD has a pathogenic mechanism which is at least partially different from that of ISHD unrelated to long-term exposure to arsenic.

Arsenic in Drinking Water and Risk of Urinary Tract Cancer: A Follow-up Study from Northeastern Taiwan

The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 μg/L), whereas studies from lower exposure areas (<100 μg/L) reported inconsistent results. A previous study conducted in northeastern Taiwan, where residents were exposed to relatively lower concentrations, reported increased risk of urinary cancer in a dose-response way. Using the same cohort with longer follow-up, we conducted analysis to elucidate the relationship between ingested arsenic and urinary cancer in lower exposure groups and assessed the influence of duration, recency, and latency of drinking arsenic-containing well water. A total of 8,086 residents from northeastern Taiwan were followed for 12 years. Incident urinary cancer was ascertained through linkage with the national cancer registry. All analysis was done by Cox proportional hazards regression models. There were 45 incidences of urinary cancer and a monotonic increased risk of urinary cancer was found with increasing arsenic concentration (P < 0.001). For the highly exposed (>100 μg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (<100 μg/L). Relative to the arsenic concentration <10 μg/L, those who drank well water with higher concentration from birth [RR, 3.69; 95% confidence interval (95% CI), 1.31-10.4], still drank at enrollment (RR, 3.50; 95% CI, 1.33-9.22), and drank for >50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher. Cancer Epidemiol Biomarkers Prev; 19(1); 101–10

Determinants of inorganic arsenic methylation capability among residents of the Lanyang Basin, Taiwan: arsenic and selenium exposure and alcohol consumption

The objective of this study was to assess individual variation in inorganic arsenic methylation capability and the association between selenium levels in urine and blood, and inorganic arsenic methylation capability among residents of the Lanyang Basin who drank groundwater and were exposed to high concentrations of inorganic arsenic. According to the arsenic concentration of their drinking water, they were equally and randomly classified into four groups of 252 persons. It turned out that the higher the concentration of arsenic in well water was and thus the cumulative arsenic exposure, the higher the total inorganic arsenic metabolites in urine (total As(i)) and the overall inorganic and organic arsenic in urine (overall As(i+o)) were. The percentage of inorganic arsenic significantly decreased and the DMA percentage significantly increased as the concentration of urinary selenium and serum alpha-tocopherol increased. It appeared that urinary selenium levels increased the metabolism by methylation of arsenic, a finding that requires further investigation.

Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.

Urinary arsenic speciation in subjects with or without restriction from seafood dietary intake

In order to understand whether ingestion of seafood affects the urinary arsenic metabolites. About 42 women and 36 men were recruited from the students, parents and teachers in Taipei Medical University and National Taiwan University. The study subjects were interviewed about dietary habits, cigarette smoking habits, drug and vitamin intake, and consumption of seafood. Urine samples were collected from study subjects before and after refraining from eating seafood for 3 days, respectively. The urine samples were frozen at -20 degrees C separated by high-performance liquid chromatography (HPLC), and on line linked to hydride generator atomic absorption spectrometry (HGAAS) to quantify the levels of various species of inorganic arsenic and its metabolites. The levels of arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), total inorganic arsenic metabolites, inorganic arsenic percent, MMA percent and DMA percent were similar before and after refraining from eating seafood for 3 days. The frequencies of fish, shellfish and seaweed dietary intake were not significantly correlated with urinary arsenic species.

Polymorphisms in arsenic metabolism genes, urinary arsenic methylation profile and cancer

Arsenic-metabolism-related genes can regulate the arsenic methylation process and may influence susceptibility to cancer. We evaluated the roles of arsenic metabolism genes on urinary arsenic profiles of repeated measurement with 15-year follow-up (1988–2004) through general linear model (GLM) and assessed the effect of the changed extent of urinary arsenic profiles on cancer risk. Questionnaire information and blood samples and two urines (1988 and 2004) were collected from 208 subjects in an arseniasis hyperendemic area in Taiwan. Profiles for concentrations of urinary arsenic were determined using HPLC-HG-AAS. The relative proportion of each arsenic species was calculated by dividing the concentration of each arsenic species by the total arsenic concentration. Genotyping was done using the 5′ nuclease allelic discrimination (Taqman) assay. The incidence of cancer was identified through linking to the National Cancer Registry Systems. The Cox proportional hazards model and survival curves were used in the analyses. After a 15-year follow-up, baseline monomethylarsonic acid percentage (MMA%) and change in MMA% exhibited a significant dose–response relationship with cancer risk. Individuals with a higher baseline MMA% and a lower change in MMA% had the earliest cancer incidence (statistically significant). Through GLM, significant gene effects of arsenic (+3 oxidation state)-methyltransferase (AS3MT) on MMA%, dimethylarsinic acid percentage (DMA%) and DMA/MMA, purine nucleoside phosphorylase (PNP) on DMA% and glutathione S-transferase omega 2 (GSTO2) on inorganic arsenics (InAs%) were found. Our results show that MMA% might be a potential predictor of cancer risk. The change in MMA% was linked to individual cancer susceptibility related to AS3MT rs3740393.