Mary L. Biggs

Bladder cancer mortality associated with arsenic in drinking water in Argentina.

Inorganic arsenic (In-As) is known to be a human carcinogen, causing lung cancer by inhalation and skin cancer by ingestion. Ecologic studies in Taiwan have found a dose-response relation between ingestion of In-As from drinking water and bladder cancer, but questions have been raised concerning the validity and generalizability of the findings. Several areas of Argentina have had high exposures to arsenic from naturally contaminated drinking water, particularly the eastern region of the province of Córdoba. In this study, we investigated bladder cancer mortality for the years 1986–1991 in Córdobas 26 counties, using rates for all of Argentina as the standard for comparison. Bladder cancer standardized mortality ratios (SMRs) were consistently higher in counties with documented arsenic exposure. We grouped counties into low-, medium-, and high-exposure categories; the corresponding SMRs [with 95% confidence intervals (CI)] were 0.80 (95% CI = 0.66–0.96), 1.42 (95% CI = 1.14–1.74), and 2.14 (95% CI = 1.78–2.53) for men, and 1.21 (95% CI = 0.85–1.64), 1.58 (95% CI = 1.01–2.35), and 1.82 (95% CI = 1.19–2.64) for women. The clear trends found in a population with different genetic composition and a high-protein diet support the findings in Taiwan.

Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study

Background:Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods:Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors. Results:For internal carotid, mean IMT was 1.17 ± 0.50 mm for HIV-infected participants and 1.06 ± 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm [95% confidence interval (CI) 0.113–0.263, P < 0.0001]. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072–0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010–0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm). Conclusion:Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.

Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis.

The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood sources (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant sources (alpha-linolenic acid, ALA) and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95 % CI. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n = 13 studies; RR per 100 g/d = 1·12, 95 % CI = 0·94, 1·34); nor were consumption of EPA+DHA (n = 16 cohorts; RR per 250 mg/d = 1·04, 95 % CI = 0·97, 1·10) nor circulating levels of EPA+DHA biomarkers (n = 5 cohorts; RR per 3 % of total fatty acids = 0·94, 95 % CI = 0·75, 1·17). Both dietary ALA (n = 7 studies; RR per 0·5 g/d = 0·93, 95 % CI = 0·83, 1·04) and circulating ALA biomarker levels (n = 6 studies; RR per 0·1 % of total fatty acid = 0·90, 95 % CI = 0·80, 1·00, P = 0·06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I²~80 %) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity ( < 55 %) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-interaction ≤ 0·02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.

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 persons 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 &mgr;g/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.

Association between adiposity in midlife and older age and risk of diabetes in older adults.

CONTEXT Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults. OBJECTIVE To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later. MAIN OUTCOME MEASURE Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater. RESULTS Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+/-2 kg), those who gained the most weight from 50 years of age to baseline (> or = 9 kg), and from baseline to the third follow-up visit (> or = 6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less. CONCLUSION Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.

Serum 25-Hydroxyvitamin D Concentration and Risk for Major Clinical Disease Events in a Community-Based Population of Older Adults: A Cohort Study

BACKGROUND Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration. OBJECTIVE To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D. DESIGN Cohort study. SETTING The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis. PARTICIPANTS 1621 white older adults. MEASUREMENTS Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death. RESULTS Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively. LIMITATION The observational study was restricted to white participants. CONCLUSION Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk. PRIMARY FUNDING SOURCE National Institutes of Health.

Plasma omega-3 fatty acids and incident diabetes in older adults

BACKGROUND Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs. OBJECTIVE We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes. DESIGN We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks. RESULTS During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03). CONCLUSIONS With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.

Genetic Polymorphisms in MTHFR 677 and 1298, GSTM1 and T1, and Metabolism of Arsenic

Methylation is the primary route of metabolism of inorganic arsenic in humans, and previous studies showed that interindividual differences in arsenic methylation may have important impacts on susceptibility to arsenic-induced cancer. To date, the factors that regulate arsenic methylation in humans are mostly unknown. Urinary arsenic methylation patterns and genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) were investigated in 170 subjects from an arsenic-exposed region in Argentina. Previous studies showed that subjects with the TT/AA polymorphisms at MTHFR 677 and 1298 have lower MTHFR activity than others. In this study, it was found that subjects with the TT/AA variant of MTHFR 677/1298 excreted a significantly higher proportion of ingested arsenic as inorganic arsenic and a lower proportion as dimethylarsinic acid. Women with the null genotype of GSTM1 excreted a significantly higher proportion of arsenic as monomethylarsonate than women with the active genotype. No associations were seen between polymorphisms in GSTT1 and arsenic methylation. This is the first study to report (1) associations between MTHFR and arsenic metabolism in humans, and (2) gender differences between genetic polymorphisms and urinary arsenic methylation patterns. Overall, this study provides evidence that MTHFR and GSTM1 are involved in arsenic metabolism in humans, and polymorphisms in the genes that encode these enzymes may play a role in susceptibility to arsenic-induced cancer.

Arsenic in drinking water and bladder cancer.

Inorganic arsenic is a metallic element found throughout the earths crust. Human exposure to high levels of this element is primarily through inhalation of contaminated dusts in occupational settings or ingestion of drinking water contaminated with arsenic from naturally occurring sources. Despite limited findings in animal testing, there is extensive human epidemiologic evidence that inhaled arsenic causes lung cancer and ingested arsenic causes skin cancer. Based on this evidence, the International Agency for Research on Cancer has classified arsenic as an established human carcinogen (1). In addition to skin cancer, mounting evidence shows that ingested arsenic is also carcinogenic to various internal organs. Results from highly exposed populations in Taiwan and other countries have shown that ingested arsenic may cause cancer of the bladder, lung, and kidney. which are cancers that have a greater impact on mortality than skin cancer (2-8). Moreover, these results provide evidence that significant cancer risks may be associated with arsenic exposures at or below the current U.S. drinking water standard of 50 pg/l(9,10). Because millions of people throughout the world are currently drinking water contaminated with arsenic at or above this level, ingested arsenic may be causing extensive preventable cancer mortality. Research that links drinking water arsenic to internal cancers has not been without controversy (1 l) , and the use of this research to estimate cancer risks at low doses and to establish a potentially costly new arsenic drinking water standard has been hotly debated. After a brief overview of the general pharmacokinetics of arsenic, this article reviews the major epidemiologic evidence linking ingested arsenic to bladder cancer and discusses the controversy surrounding this research. Our present focus is on bladder cancer because evidence indicates that it has higher mortality ratios associated with ingested arsenic than other target organs (2,6). We then review the current controversy regarding the estimated cancer risks from ar-

Maternal, delivery, and perinatal characteristics associated with cryptorchidism: a population-based case-control study among births in Washington State.

Background. The etiology of cryptorchidism is largely unknown. To identify maternal, perinatal, and delivery characteristics associated with cryptorchidism at birth, we conducted a population-based case-control study using Washington State birth certificates linked to birth hospitalization records. Methods. We identified 2,395 cases of cryptorchidism among male infants born in Washington State during 1986–1996, and, for comparison, we randomly selected four controls per case (N = 9,580), frequency-matched by year of birth. Results. Infant characteristics associated with cryptorchidism included low birth weight (OR = 1.5; 95% CI = 1.3–1.8), small size for gestational age (OR = 1.9; 95% CI = 1.6–2.2), and breech presentation (OR = 1.7; 95% CI = 1.4–2.1). In addition to cryptorchidism, cases were more likely to have another type of congenital malformation (OR = 3.7; 95% CI = 3.2–4.2), particularly digestive (OR = 6.8; 95% CI = 3.7–12.7) or genitourinary (OR = 4.1; 95% CI = 3.0–5.6). Maternal and pregnancy characteristics associated with cryptorchidism included nulliparity (OR = 1.2; 95% CI = 1.1–1.3), maternal smoking during pregnancy (OR = 1.2; 95% CI = 1.1–1.4), and the following pregnancy complications: oligohydramnios (OR = 1.8; 95% CI = 1.3–2.6), placental abnormality (OR = 1.3; 95% CI = 1.0–1.8), and pregnancy-induced hypertension (OR = 1.6; 95% CI = 1.4–1.9). Odds ratios were similar when the analysis was restricted to term infants. Conclusions. These findings suggest that factors affecting fetal growth and development may increase the risk of cryptorchidism.