Chin-Hsiao Tseng

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.

Evaluation of the Association between Arsenic and Diabetes: A National Toxicology Program Workshop Review

Background: Diabetes affects an estimated 346 million persons globally, and total deaths from diabetes are projected to increase > 50% in the next decade. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. In 2011, the National Toxicology Program (NTP) organized a workshop to assess the literature for evidence of associations between certain chemicals, including inorganic arsenic, and diabetes and/or obesity to help develop a focused research agenda. This review is derived from discussions at that workshop. Objectives: Our objectives were to assess the consistency, strength/weaknesses, and biological plausibility of findings in the scientific literature regarding arsenic and diabetes and to identify data gaps and areas for future evaluation or research. The extent of the existing literature was insufficient to consider obesity as an outcome. Data Sources, Extraction, and Synthesis: Studies related to arsenic and diabetes or obesity were identified through PubMed and supplemented with relevant studies identified by reviewing the reference lists in the primary literature or review articles. Conclusions: Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (≥ 150 µg arsenic/L in drinking water). The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 µg arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association. The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes.

A review on environmental factors regulating arsenic methylation in humans.

Subjects exposed to arsenic show significant inter-individual variation in urinary patterns of arsenic metabolites but insignificant day-to-day intra-individual variation. The inter-individual variation in arsenic methylation can be partly responsible for the variation in susceptibility to arsenic toxicity. Wide inter-ethnic variation and family correlation in urinary arsenic profile suggest a genetic effect on arsenic metabolism. In this paper the environmental factors affecting arsenic metabolism are reviewed. Methylation capacity might reduce with increasing dosage of arsenic exposure. Furthermore, women, especially at pregnancy, have better methylation capacity than their men counterparts, probably due to the effect of estrogen. Children might have better methylation capacity than adults and age shows inconsistent relevance in adults. Smoking and alcohol consumption might be associated with a poorer methylation capacity. Nutritional status is important in the methylation capacity and folate may facilitate the methylation and excretion of arsenic. Besides, general health conditions and medications might influence the arsenic methylation capacity; and technical problems can cause biased estimates. The consumption of seafood, seaweed, rice and other food with high arsenic contents and the extent of cooking and arsenic-containing water used in food preparation may also interfere with the presentation of the urinary arsenic profile. Future studies are necessary to clarify the effects of the various arsenic metabolites including the trivalent methylated forms on the development of arsenic-induced human diseases with the consideration of the effects of confounding factors and the interactions with other effect modifiers.

Arsenic Methylation, Urinary Arsenic Metabolites and Human Diseases: Current Perspective

Arsenic can cause cancerous and non-cancerous human diseases. Inorganic arsenic from drinking water is the most common source of human exposure. Pentavalent arsenate can be reduced to trivalent arsenite in the blood, which is taken up mainly in the liver and metabolized by a sequence of reduction and oxidative methylation. A proportion of the inorganic arsenicals together with methylated metabolites are excreted in urine. Analyses of the urinary arsenic profile can give a hint to the methylation capacity of exposed individuals. All studies evaluating the association between urinary arsenic profiles and human diseases nowadays measure mainly the inorganic arsenate and arsenite and the two organic forms of methylated metabolites: the pentavalent form of monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV). A review of the current literature suggests that reduced methylation capacity with increased MMAV percentage, decreased DMAV percentage, or decreased DMAV/MMAV is associated with skin lesions, skin cancer, bladder cancer, peripheral vascular disease, muscle cramps and structural chromosome aberrations in peripheral lymphocytes obtained from exposed subjects. The detection of the recently identified more toxic trivalent forms of methylated metabolites in urine awaits further confirmation.

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.

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.

Pioglitazone and Bladder Cancer: A population-based study of Taiwanese

OBJECTIVE The association between pioglitazone and bladder cancer has not been investigated in Asians. We aimed to investigate this association. RESEARCH DESIGN AND METHODS A total of 1,000,000 individuals were randomly sampled from the National Health Insurance database, and incident cases of bladder cancer during the period from 1 January 2006 to 31 December 2009 were analyzed among 54,928 patients with type 2 diabetes and without previous bladder cancer. RESULTS Among 165 incident case subjects, 10 (0.39%) were ever users and 155 (0.30%) were never users of pioglitazone (adjusted hazard ratio in full model 1.305 [95% CI 0.661–2.576]). All bladder cancer in ever users occurred within a duration of therapy <24 months, suggesting an early effect of pioglitazone on bladder cancer or late use of pioglitazone in high-risk patients. CONCLUSIONS The association between pioglitazone and bladder cancer was not significant. However, confirmation of this finding is required because of the possible lack of statistical power owing to the small number of events.

The Influence of Type 2 Diabetes and Glucose-Lowering Therapies on Cancer Risk in the Taiwanese

OBJECTIVE To investigate the association between type 2 diabetes, glucose-lowering therapies (monotherapy with either metformin, sulphonylurea or insulin) and cancer risk in Taiwan. METHODS Using Taiwans National Health Research Institutes database of 1,000,000 random subjects from 2000-2008, we found 61777 patients with type 2 diabetes (age ≥20 years) and 677378 enrollees with no record of diabetes. RESULTS After adjusting for age and sex, we found patients with diabetes to have significantly higher risk of all cancers (OR: 1.176; 95% CI: 1.149-1.204, P < 0.001). Diabetic patients treated with insulin or sulfonylureas had significantly higher risk of all cancers, compared to those treated with metformin (OR: 1.583; 95% CI: 1.389-1.805, P < 0.001 and OR: 1.784; 95% CI: 1.406-2.262, P < 0.001). Metformin treatment was associated with a decreased risk of colon and liver cancer compared to sulphonylureas or insulin treatment. Sulfonylureas treatment was associated with an increased risk of breast and lung cancer compared to metformin therapy. CONCLUSIONS Taiwanese with type 2 diabetes are at a high risk of breast, prostate, colon, lung, liver and pancreatic cancer. Those treated with insulin or sulfonylureas monotherapy are more likely to develop colon and liver cancer than those treated with metformin.

Uric acid level as a risk marker for metabolic syndrome: A Chinese cohort study

OBJECTIVE Despite some epidemiologic research demonstrating a positive relationship between serum uric acid (SUA) levels and the prevalence of metabolic syndrome (MetS), prospective data on SUA as a predictor of MetS incidence are limited. METHODS The authors examined SUA as a risk marker for incident MetS in a prospective study of 3857 subjects who were free of MetS at baseline recruitment. Hyperuricemia was defined as SUA ≥7.7 mg/dL for men and ≥6.6 mg/dL for women. The MetS was defined according to a unified criteria set by several major organizations. RESULTS During a mean follow-up of 5.41 years, 476 participants developed MetS. A significantly stepwise increase in the incidence of MetS across tertiles of SUA was observed in the whole group (p for trend <0.001). Among women, this association was more robust than in men. After adjustment for age, variations of blood pressure, triglycerides, HDL-C, glucose, and waist circumference, females in the middle and upper tertiles of SUA had significantly higher risk of developing MetS when compared with subjects in the lowest tertile [adjusted-HR (95% CI) was 1.67 (1.12-2.49) and 3.18 (2.20-4.60), respectively; p for trend <0.001]. Overall, hyperuricemia was a significantly independent risk determinant for MetS in women, but it was a non-significant factor for MetS mediating waist circumference and serum triglycerides in men. CONCLUSION SUA concentration is more closely associated with MetS in females than in males. Future investigations are needed to explore the underlying mechanisms involved in the sex-related association between SUA concentration and MetS risk.

Diabetes and risk of prostate cancer: a study using the National Health Insurance.

OBJECTIVE The link between diabetes and prostate cancer is rarely studied in Asians. RESEARCH DESIGN AND METHODS The trend of age-standardized prostate cancer incidence in 1995–2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men ≥40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors. RESULTS The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40–64, 65–74, and ≥75 years was 5.83 (5.10–6.66), 2.09 (1.60–2.74), 1.35 (1.07–1.71), and 1.39 (1.12–1.71). In logistic regression for all ages or for age ≥40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not. CONCLUSIONS Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40–64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages.