Maria Tellez-Plaza

Blood Cadmium and Lead and Chronic Kidney Disease in US Adults: A Joint Analysis

Environmental cadmium and lead exposures are widespread, and both metals are nephrotoxic at high exposure levels. Few studies have evaluated the associations between low-level cadmium and clinical renal outcomes, particularly with respect to joint cadmium and lead exposure. The geometric mean levels of blood cadmium and lead were 0.41 microg/L (3.65 nmol/L) and 1.58 microg/dL (0.076 micromol/L), respectively, in 14,778 adults aged >or=20 years who participated in the National Health and Nutrition Examination Survey (1999-2006). After adjustment for survey year, sociodemographic factors, chronic kidney disease risk factors, and blood lead, the odds ratios for albuminuria (>or=30 mg/g creatinine), reduced estimated glomerular filtration rate (eGFR) (<60 mL/minute/1.73 m(2)), and both albuminuria and reduced eGFR were 1.92 (95% confidence interval (CI): 1.53, 2.43), 1.32 (95% CI: 1.04, 1.68), and 2.91 (95% CI: 1.76, 4.81), respectively, comparing the highest with the lowest blood cadmium quartiles. The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were 2.34 (95% CI: 1.72, 3.18) for albuminuria, 1.98 (95% CI: 1.27, 3.10) for reduced eGFR, and 4.10 (95% CI: 1.58, 10.65) for both outcomes. These findings support consideration of cadmium and lead as chronic kidney disease risk factors in the general population and provide novel evidence of risk with environmental exposure to both metals.

Cadmium Exposure and Hypertension in the 1999–2004 National Health and Nutrition Examination Survey (NHANES)

Introduction Cadmium induces hypertension in animal models. Epidemiologic studies of cadmium exposure and hypertension, however, have been inconsistent. Objective We aimed to investigate the association of blood and urine cadmium with blood pressure levels and with the prevalence of hypertension in U.S. adults who participated in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Methods We studied participants ≥ 20 years of age with determinations of cadmium in blood (n = 10,991) and urine (n = 3,496). Blood and urine cadmium were measured by atomic absorption spectrometry and inductively coupled plasma–mass spectrometry, respectively. Systolic and diastolic blood pressure levels were measured using a standardized protocol. Results The geometric means of blood and urine cadmium were 3.77 nmol/L and 2.46 nmol/L, respectively. After multivariable adjustment, the average differences in systolic and diastolic blood pressure comparing participants in the 90th vs. 10th percentile of the blood cadmium distribution were 1.36 mmHg [95% confidence interval (CI), −0.28 to 3.00] and 1.68 mmHg (95% CI, 0.57–2.78), respectively. The corresponding differences were 2.35 mmHg and 3.27 mmHg among never smokers, 1.69 mmHg and 1.55 mmHg among former smokers, and 0.02 mmHg and 0.69 mmHg among current smokers. No association was observed for urine cadmium with blood pressure levels, or for blood and urine cadmium with the prevalence of hypertension. Conclusions Cadmium levels in blood, but not in urine, were associated with a modest elevation in blood pressure levels. The association was stronger among never smokers, intermediate among former smokers, and small or null among current smokers. Our findings add to the concern of renal and cardiovascular cadmium toxicity at chronic low levels of exposure in the general population.

Cadmium exposure and incident cardiovascular disease.

Background: Cadmium is a widespread toxic metal with potential cardiovascular effects, but no studies have evaluated cadmium and incident cardiovascular disease. We evaluated the association of urine cadmium concentration with cardiovascular disease incidence and mortality in a large population-based cohort. Methods: We conducted a prospective cohort study of 3348 American Indian adults 45–74 years of age from Arizona, Oklahoma, and North and South Dakota, who participated in the Strong Heart Study in 1989–1991. Urine cadmium was measured using inductively coupled plasma mass spectrometry. Follow-up extended through 31 December 2008. Results: The geometric mean cadmium level in the study population was 0.94 &mgr;g/g (95% confidence interval [CI] = 0.92–0.96). We identified 1084 cardiovascular events, including 400 deaths. After adjustment for sociodemographic and cardiovascular risk factors, the hazard ratios (HRs) (comparing the 80th to the 20th percentile of urine cadmium concentrations) was 1.43 for cardiovascular mortality (95% CI = 1.21–1.70) and 1.34 for coronary heart disease mortality (1.10–1.63). The corresponding HRs for incident cardiovascular disease, coronary heart disease, stroke, and heart failure were 1.24 (1.11–1.38), 1.22 (1.08–1.38), 1.75 (1.17–2.59), and 1.39 (1.01–1.94), respectively. The associations were similar in most study subgroups, including never-smokers. Conclusions: Urine cadmium, a biomarker of long-term exposure, was associated with increased cardiovascular mortality and increased incidence of cardiovascular disease. These findings support that cadmium exposure is a cardiovascular risk factor.

Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population.

Background: Urine cadmium concentrations were associated with all-cause and cardiovascular mortality in men in the 1988–1994 U.S. National Health and Nutrition Examination Survey (NHANES) population. Since 1988, cadmium exposure has decreased substantially in the United States. The associations between blood and urine cadmium and cardiovascular disease (CVD) mortality at more recent levels of exposure are unknown. Objectives: We evaluated the prospective association of blood and urine cadmium concentrations with all-cause and CVD mortality in the 1999–2004 U.S. population. Methods: We followed 8,989 participants who were ≥ 20 years of age for an average of 4.8 years. Hazard ratios for mortality end points comparing the 80th to the 20th percentiles of cadmium distributions were estimated using Cox regression. Results: The multivariable adjusted hazard ratios [95% confidence intervals (CIs)] for blood and urine cadmium were 1.50 (95% CI: 1.07, 2.10) and 1.52 (95% CI: 1.00, 2.29), respectively, for all-cause mortality, 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for CVD mortality, 1.98 (95% CI: 1.11, 3.54) and 2.53 (95% CI: 1.54, 4.16) for heart disease mortality, and 1.73 (95% CI: 0.88, 3.40) and 2.09 (95% CI: 1.06, 4.13) for coronary heart disease mortality. The population attributable risks associated with the 80th percentile of the blood (0.80 μg/L) and urine (0.57 μg/g) cadmium distributions were 7.0 and 8.8%, respectively, for all-cause mortality and 7.5 and 9.2%, respectively, for CVD mortality Conclusions: We found strongly suggestive evidence that cadmium, at substantially low levels of exposure, remains an important determinant of all-cause and CVD mortality in a representative sample of U.S. adults. Efforts to further reduce cadmium exposure in the population could contribute to a substantial decrease in CVD disease burden.

Blood Lead Level and Kidney Function in US Adolescents The Third National Health and Nutrition Examination Survey

BACKGROUND Chronic, high-level lead exposure is a known risk factor for kidney disease. The effect of current low-level environmental lead exposure is less well known, particularly among children, a population generally free from kidney disease risk factors such as hypertension and diabetes mellitus. Therefore, in this study, we investigated the association between lead exposure and kidney function in a representative sample of US adolescents. METHODS Participants included 769 adolescents aged 12 to 20 years for whom whole blood lead and serum cystatin C were measured in the Third National Health and Nutrition Examination Survey, conducted from 1988-1994. The association between blood lead level and level of kidney function (glomerular filtration rate [GFR]), determined by cystatin C-based and creatinine-based estimating equations, was examined. RESULTS Median whole blood lead level was 1.5 microg/dL (to convert to micromoles per liter, multiply by 0.0483), and median cystatin C-estimated GFR was 112.9 mL/min/1.73 m(2). Participants with lead levels in the highest quartile (> or =3.0 microg/dL) had 6.6 mL/min/1.73 m(2)-lower estimated GFR (95% confidence interval, -0.7 to -12.6 mL/min/1.73 m(2)) compared with those in the first quartile (<1 microg/dL). A doubling of blood lead level was associated with a 2.9 mL/min/1.73 m(2)-lower estimated GFR (95% confidence interval, -0.7 to -5.0 mL/min/1.73 m(2)). Lead levels were also associated with lower creatinine-based estimated GFR levels, but the association was weaker than with cystatin C-based GFR and not statistically significant. CONCLUSIONS Higher blood lead levels in a range below the current Centers for Disease Control and Prevention-designated level of concern (10 microg/dL) were associated with lower estimated GFRs in a representative sample of US adolescents. This finding contributes to the increasing epidemiologic evidence indicating an adverse effect of low-level environmental lead exposure.

Reduction in cadmium exposure in the United States population, 1988-2008: the contribution of declining smoking rates.

Background: Public health policies such as tobacco control, air pollution reduction, and hazardous waste remediation may have reduced cadmium exposure among U.S. adults. However, trends in urine cadmium, a marker of cumulative cadmium exposure, have not been evaluated. Objectives: We estimated the trends in urine cadmium concentrations in U.S. adults using data from the National Health and Nutrition Examination Surveys (NHANES) from 1988 to 2008. We also evaluated the impact of changes in the distribution of available cadmium determinants (age, sex, race, education, body mass index, smoking, and occupation) at the population level to explain cadmium trends. Methods: The study population included 19,759 adults ≥ 20 years of age with measures of urine cadmium and cadmium determinants. Results: Age-adjusted geometric means of urine cadmium concentrations were 0.36, 0.35, 0.27, 0.27, 0.28, 0.25, and 0.26 µg/g creatinine in 1988–1991, 1991–1994, 1999–2000, 2001–2002, 2003–2004, 2005–2006, and 2007–2008, respectively. The age, sex, and race/ethnicity-adjusted percent reduction in urine cadmium geometric means comparing 1999–2002 and 2003–2008 with 1988–1994 were 27.8% (95% confidence interval: 22.3%, 32.9%) and 34.3% (29.9%, 38.4%), respectively (p-trend < 0.001), with reductions in all participant subgroups investigated. In never smokers, reductions in serum cotinine accounted for 15.6% of the observed reduction. In ever smokers, changes in smoking cessation, and cumulative and recent dose accounted for 17.1% of the observed reduction. Conclusions: Urine cadmium concentrations decreased markedly between 1988 and 2008. Declining smoking rates and changes in exposure to tobacco smoke may have played an important role in the decline of urine cadmium concentrations, benefiting both smokers and nonsmokers. Cadmium has been associated to several health outcomes in NHANES 1999–2008. Consequently, despite the observed decline, further reduction in cadmium exposure is needed.

Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence

Current evidence supports the notion that environmental exposures are associated with DNA-methylation and expression changes that can impact human health. Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between environmental chemicals with DNA methylation levels in adults. After excluding arsenic, recently evaluated in a systematic review, we identified a total of 17 articles (6 on cadmium, 4 on lead, 2 on mercury, 1 on nickel, 1 on antimony, 1 on tungsten, 5 on persistent organic pollutants and perfluorinated compounds, 1 on bisphenol A, and 3 on polycyclic aromatic hydrocarbons). The selected articles reported quantitative methods to determine DNA methylation including immunocolorimetric assays for total content of genomic DNA methylation, and microarray technologies, methylation-specific quantitative PCR, Luminometric Methylation Assay (LUMA), and bisulfite pyrosequencing for DNA methylation content of genomic sites such as gene promoters, LINE-1, Alu elements, and others. Considering consistency, temporality, strength, dose-response relationship, and biological plausibility, we concluded that the current evidence is not sufficient to provide inference because differences across studies and limited samples sizes make it difficult to compare across studies and to evaluate sources of heterogeneity. Important questions for future research include the need for larger and longitudinal studies, the validation of findings, and the systematic evaluation of the dose-response relationships. Future studies should also consider the evaluation of epigenetic marks recently in the research spotlight such as DNA hydroxymethylation and the role of underlying genetic variants.

Cadmium Exposure and Cancer Mortality in a Prospective Cohort: The Strong Heart Study

Background: Cadmium (Cd) is a toxic metal classified as a human carcinogen by the International Agency for Research on Cancer. Objective: We evaluated the association of long-term Cd exposure, as measured in urine, with cancer mortality in American Indians from Arizona, Oklahoma, and North and South Dakota who participated in the Strong Heart Study during 1989–1991. Methods: The Strong Heart Study was a prospective cohort study of 3,792 men and women 45–74 years of age who were followed for up to 20 years. Baseline urinary Cd (U-Cd) was measured using inductively coupled plasma mass spectrometry. We assessed cancer events by annual mortality surveillance. Results: The median (interquintile range) U-Cd concentration was 0.93 (0.55, 1.63) μg/g creatinine. After adjusting for sex, age, smoking status, cigarette pack-years, and body mass index, the adjusted hazard ratios (HRs) comparing the 80th versus the 20th percentiles of U-Cd were 1.30 (95% CI: 1.09, 1.55) for total cancer, 2.27 (95% CI: 1.58, 3.27) for lung cancer, and 2.40 (95% CI: 1.39, 4.17) for pancreatic cancer mortality. For all smoking-related cancers combined, the corresponding HR was 1.56 (95% CI: 1.24, 1.96). Cd was not significantly associated with liver, esophagus and stomach, colon and rectum, breast, prostate, kidney, or lymphatic and hematopoietic cancer mortality. On the basis of mediation analysis, we estimated that the percentage of lung cancer deaths due to tobacco smoking that could be attributed to Cd exposure was 9.0% (95% CI: 2.8, 21.8). Conclusions: Low-to-moderate Cd exposure was prospectively associated with total cancer mortality and with mortality from cancers of the lung and pancreas. The implementation of population-based preventive measures to decrease Cd exposure could contribute to reducing the burden of cancer. Citation: García-Esquinas E, Pollan M, Tellez-Plaza M, Francesconi KA, Goessler W, Guallar E, Umans JG, Yeh J, Best LG, Navas-Acien A. 2014. Cadmium exposure and cancer mortality in a prospective cohort: the Strong Heart Study. Environ Health Perspect 122:363–370; http://dx.doi.org/10.1289/ehp.1306587

Arsenic species and selected metals in human urine: validation of HPLC/ICPMS and ICPMS procedures for a long-term population-based epidemiological study

Exposure to high inorganic arsenic concentrations in drinking water has been related to detrimental health effects, including cancers and possibly cardiovascular disease, in many epidemiological studies. Recent studies suggest that arsenic might elicit some of its toxic effects also at lower concentrations. The Strong Heart Study, a large epidemiological study of cardiovascular disease in American Indian communities, collected urine samples and performed medical examinations on 4,549 participants over a 10-year period beginning in 1989. We used anion-exchange HPLC/ICPMS to determine concentrations of arsenic species (methylarsonate, dimethylarsinate and arsenate) in 5,095 urine samples from the Strong Heart Study. We repeated the chromatography on a portion of the urine sample that had been oxidised, by addition of H(2)O(2), to provide additional information on the presence of As(III) species and thio-arsenicals, and by difference, of arsenobetaine and other non-retained cations. Total concentrations for As, Cd, Mo, Pb, Sb, Se, U, W, and Zn were also determined in the urine samples by ICPMS. The dataset will be used to evaluate the relationships between the concentrations of urinary arsenic species and selected metals with various cardiometabolic health endpoints. We present and discuss the analytical protocol put in place to produce this large and valuable dataset.

Cadmium and Peripheral Arterial Disease: Gender Differences in the 1999–2004 US National Health and Nutrition Examination Survey

Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ≥40 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population.