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1.  Placental transfer and concentrations of cadmium, mercury, lead, and selenium in mothers, newborns, and young children 
There is an emerging hypothesis that exposure to cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in utero and early childhood could have long-term health consequences. However, there are sparse data on early life exposures to these elements in US populations, particularly in urban minority samples. This study measured levels of Cd, Hg, Pb, and Se in 50 paired maternal, umbilical cord, and postnatal blood samples from the Boston Birth Cohort (BBC). Maternal exposure to Cd, Hg, Pb, and Se was 100% detectable in red blood cells (RBCs), and there was a high degree of maternal–fetal transfer of Hg, Pb, and Se. In particular, we found that Hg levels in cord RBCs were 1.5 times higher than those found in the mothers. This study also investigated changes in concentrations of Cd, Hg, Pb, and Se during the first few years of life. We found decreased levels of Hg and Se but elevated Pb levels in early childhood. Finally, this study investigated the association between metal burden and preterm birth and low birthweight. We found significantly higher levels of Hg in maternal and cord plasma and RBCs in preterm or low birthweight births, compared with term or normal birthweight births. In conclusion, this study showed that maternal exposure to these elements was widespread in the BBC, and maternal–fetal transfer was a major source of early life exposure to Hg, Pb, and Se. Our results also suggest that RBCs are better than plasma at reflecting the trans-placental transfer of Hg, Pb, and Se from the mother to the fetus. Our study findings remain to be confirmed in larger studies, and the implications for early screening and interventions of preconception and pregnant mothers and newborns warrant further investigation.
doi:10.1038/jes.2014.26
PMCID: PMC4329243  PMID: 24756102
cadmium (Cd); mercury (Hg); lead (Pb) and selenium (Se); maternal–fetal transfer; early life exposure
2.  Environmental Chemicals and Type 2 Diabetes: An Updated Systematic Review of the Epidemiologic Evidence 
Current diabetes reports  2013;13(6):831-849.
The burden of diabetes is increasing globally. Identifying novel preventable risk factors is an urgent need. In 2011, the U.S. National Toxicological Program (NTP) conducted a workshop to evaluate the epidemiologic and experimental evidence on the relationship of environmental chemicals with obesity, diabetes and metabolic syndrome. Although the evidence was insufficient to establish causality, the NTP workshop review identified an overall positive association between some environmental chemicals and diabetes. In this systematic review, our objective was to summarize the epidemiological research published since the NTP workshop. We identified a total of 29 articles (7 on arsenic, 3 on cadmium, 2 on mercury, 11 on persistent organic pollutants, 3 on phthalates and 4 on bisphenol A) including 7 prospective studies. Considering consistency, temporality, strength, dose-response, and biological plausibility (confounding), we concluded that the evidence is suggestive but not sufficient for a relationship between arsenic and persistent organic pollutants, and insufficient for mercury, phthalates and bisphenol A. For cadmium the epidemiologic evidence does not seem to suggest an association with diabetes. Important research questions include the need of additional prospective studies and the evaluation of the dose-response relationship, the role of joint exposures, and effect modification with other comorbidities and genetic variants.
doi:10.1007/s11892-013-0432-6
PMCID: PMC4327889  PMID: 24114039
Systematic review; environmental chemicals; diabetes; arsenic; cadmium; mercury; persistent organic pollutants; bisphenol A; phthalates; type 2 diabetes; epidemiology
3.  THE EFFECT OF EX VIVO CDDO-ME ACTIVATION ON NUCLEAR FACTOR ERYTHROID 2–RELATED FACTOR 2 PATHWAY IN WHITE BLOOD CELLS FROM PATIENTS WITH SEPTIC SHOCK 
Shock (Augusta, Ga.)  2014;42(5):392-399.
Nuclear factor erythroid 2–related factor 2 (NRF2) has been shown to protect against experimental sepsis in mice and lipopolysaccharide (LPS)-induced inflammation in ex vivo white blood cells from healthy subjects by upregulating cellular antioxidant genes. The objective of this study was to test the hypothesis that ex vivo methyl 2-cyano-3, 12-dioxoolean-1,9-dien-28-oate (CDDO-Me) activates NRF2-regulated antioxidant genes in white blood cells from patients with septic shock and protects against LPS-induced inflammation and reactive oxidative species production. Peripheral blood was collected from 18 patients with septic shock who were being treated in medical and surgical intensive care units. Real-time polymerase chain reaction was used to quantify the expression of NRF2 target genes (NQO1, HO-1, GCLM, and FTL) and IL-6 in peripheral blood mononuclear cells (PBMCs), monocytes, and neutrophils after CDDO-Me treatment alone or after subsequent LPS exposure. Superoxide anion (O2−) was measured to assess the effect of CDDO-Me pretreatment on subsequent LPS exposure. Treatment with CDDO-Me increased the gene expression of NQO1 (P = 0.04) and decreased the expression of HO-1 (P = 0.03) in PBMCs from patients with septic shock. Purified monocytes exhibited significant increases in the expression of NQO1 (P = 0.01) and GCLM (P = 0.003) after CDDO-Me treatment. Levels of other NRF2 target genes (HO-1 and FTL) remained similar to those of vehicle-treated cells. Peripheral blood mononuclear cells showed a trend toward increased IL-6 gene expression after CDDO-Me treatment, whereas purified monocytes showed a trend toward decreased IL-6. There was no discernible trend in the IL-6 expression subsequent to LPS treatment in either vehicle-treated or CDDO-Me–treated PBMCs and monocytes. Treatment with CDDO-Me significantly increased O2− production in PBMCs (P = 0.04). Although CDDO-Me pretreatment significantly attenuated O2− production to subsequent LPS exposure (P = 0.03), the change was comparable to that observed in vehicle-treated PBMCs. Pretreatment with CDDO-Me followed by LPS exposure had no significant effect on O2− levels in purified monocytes. These data suggest that the NRF2 pathway is differentially responsive to CDDO-Me activation in peripheral blood cells from patients with septic shock and results in increased O2− production. The data may also suggest a suppressed NRF2 pathway in white blood cells from critically ill patients.
doi:10.1097/SHK.0000000000000236
PMCID: PMC4322931  PMID: 25105464
Critical illness; septic shock; NRF2; CDDO-Me; antioxidants; reactive oxygen species
4.  SLCO1B1 Variants and Urine Arsenic Metabolites in the Strong Heart Family Study 
Toxicological Sciences  2013;136(1):19-25.
Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p = .0003) and higher %DMA (p = .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p = .0006) and higher %DMA (p = .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks.
doi:10.1093/toxsci/kft181
PMCID: PMC3829571  PMID: 23970802
American Indians; arsenic metabolism; arsenic species; SLCO1B1; OATPC; Strong Heart Study.
5.  Arsenic Exposure and Cancer Mortality in a US-based Prospective Cohort: the Strong Heart Study 
Background
Inorganic arsenic, a carcinogen at high exposure levels, is a major global health problem. Prospective studies on carcinogenic effects at low-moderate arsenic levels are lacking.
Methods
We evaluated the association between baseline arsenic exposure and cancer mortality in 3,932 American Indians 45–74 years from Arizona, Oklahoma and North/South Dakota who participated in the Strong Heart Study in 1989–1991 and were followed through 2008. We estimated inorganic arsenic exposure as the sum of inorganic and methylated species in urine. Cancer deaths (386 overall, 78 lung, 34 liver, 18 prostate, 26 kidney, 24 esophagus/stomach, 25 pancreas, 32 colon/rectal, 26 breast, 40 lymphatic/hematopoietic) were assessed by mortality surveillance reviews. We hypothesized an association with lung, liver, prostate and kidney cancer.
Results
Median (interquartile range) urine concentration for inorganic plus methylated arsenic species was 9.7 (5.8–15.6) μg/g creatinine. The adjusted hazard ratios (95% CI) comparing the 80th versus 20th percentiles of arsenic were 1.14 (0.92–1.41) for overall cancer, 1.56 (1.02–2.39) for lung cancer, 1.34 (0.66, 2.72) for liver cancer, 3.30 (1.28–8.48) for prostate cancer, and 0.44 (0.14, 1.14) for kidney cancer. The corresponding hazard ratios were 2.46 (1.09–5.58) for pancreatic cancer, and 0.46 (0.22–0.96) for lymphatic and hematopoietic cancers. Arsenic was not associated with cancers of the esophagus and stomach, colon and rectum, and breast.
Conclusions
Low to moderate exposure to inorganic arsenic was prospectively associated with increased mortality for cancers of the lung, prostate and pancreas.
Impact
These findings support the role of low-moderate arsenic exposure in lung, prostate and pancreas cancer development and can inform arsenic risk assessment.
doi:10.1158/1055-9965.EPI-13-0234-T
PMCID: PMC3843229  PMID: 23800676
American Indians; arsenic; cancer; mortality
6.  Association of Arsenic and Metals with Concentrations of 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D among Adolescents in Torreón, Mexico 
Environmental Health Perspectives  2014;122(11):1233-1238.
Background: Limited data suggest that lead (Pb), cadmium (Cd), and uranium (U) may disrupt vitamin D metabolism and inhibit production of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active vitamin D metabolite, from 25-hydroxyvitamin D [25(OH)D] in the kidney.
Objectives: We evaluated the association between blood lead (BPb) and urine arsenic (As), Cd, molybdenum (Mo), thallium (Tl), and U with markers of vitamin D metabolism [25(OH)D and 1,25(OH)2D].
Methods: We conducted a cross-sectional study of 512 adolescents in Torreón, a town in Mexico with a Pb smelter near residential areas. BPb was measured using atomic absorption spectrometry. Urine As, Cd, Mo, Tl, and U were measured using inductively coupled plasma mass spectrometry. Serum 25(OH)D and 1,25(OH)2D were measured using a chemiluminescent immunoassay and a radioimmunoassay, respectively. Multivariable linear models with vitamin D markers as the outcome were used to estimate associations of BPb and creatinine-corrected urine As and metal concentrations with serum vitamin D concentrations, controlling for age, sex, adiposity, smoking, socioeconomic status, and time outdoors.
Results: Serum 25(OH)D was positively associated with urine Mo and Tl [1.5 (95% CI: 0.4, 2.6) and 1.2 (95% CI: 0.3, 2.1) ng/mL higher with a doubling of exposure, respectively]. Serum 1,25(OH)2D was positively associated with urine As and U [3.4 (95% CI: 0.9, 5.9) and 2.2 (95% CI: 0.7, 3.7) pg/mL higher, respectively], with little change in associations after additional adjustment for serum 25(OH)D. Pb and Cd were not associated with 25(OH)D or 1,25(OH)2D concentrations.
Conclusions: Overall, our findings did not support a negative effect of As or metal exposures on serum 1,25(OH)2D concentrations. Additional research is needed to confirm positive associations between serum 1,25(OH)2D and urine U and As concentrations and to clarify potential underlying mechanisms.
Citation: Zamoiski RD, Guallar E, García-Vargas GG, Rothenberg SJ, Resnick C, Rubio Andrade M, Steuerwald AJ, Parsons PJ, Weaver VM, Navas-Acien A, Silbergeld EK. 2014. Association of arsenic and metals with concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D among adolescents in Torreón, Mexico. Environ Health Perspect 122:1233–1238; http://dx.doi.org/10.1289/ehp.1307861
doi:10.1289/ehp.1307861
PMCID: PMC4216165  PMID: 25095279
7.  Cadmium Exposure and Incident Peripheral Arterial Disease 
Background
Cadmium has been associated with peripheral arterial disease in cross-sectional studies but prospective evidence is lacking. Our goal was to evaluate the association of urine cadmium concentrations with incident peripheral arterial disease in a large population-based cohort.
Methods and Results
A prospective cohort study was performed with 2,864 adult American Indians 45-74 years old from Arizona, Oklahoma and North and South Dakota who participated in the Strong Heart Study in 1989-91 and were followed through two follow-up examination visits in 1993-1995 and 1997-1999. Participants were free of peripheral arterial disease, defined as an ankle brachial index <0.9 or >1.4, at baseline and had complete baseline information on urine cadmium, potential confounders and ankle brachial index determinations in the follow-up examinations. Urine cadmium was measured using inductively coupled plasma mass spectrometry (ICPMS) and corrected for urinary dilution by normalization to urine creatinine.. Multivariable-adjusted hazard ratios (HR) were computed using Cox-proportional hazards models for interval-censored data. A total of 470 cases of incident peripheral arterial disease, defined as an ankle brachial index <0.9 or >1.4, were identified. After adjustment for cardiovascular disease risk factors including smoking status and pack-years, the hazard ratio comparing the 80th to the 20th percentile of urine cadmium concentrations was 1.41 (1.05, 1.81). The hazard ratio comparing the highest to the lowest tertile was 1.96 (1.32, 2.81). The associations persisted after excluding participants with ankle brachial index > 1.4 only as well as in subgroups defined by sex and smoking status.
Conclusions
Urine cadmium, a biomarker of long-term cadmium exposure, was independently associated with incident peripheral arterial disease, providing further support for cadmium as a cardiovascular disease risk factor.
doi:10.1161/CIRCOUTCOMES.112.000134
PMCID: PMC4190067  PMID: 24255048
Cadmium; peripheral arterial disease; prospective cohort study; Strong Heart Study
8.  Cadmium Exposure and Clinical Cardiovascular Disease: a Systematic Review 
Current atherosclerosis reports  2013;15(10):10.1007/s11883-013-0356-2.
Mounting evidence supports that cadmium, a toxic metal found in tobacco, air and food, is a cardiovascular risk factor. Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between cadmium exposure and cardiovascular disease. Twelve studies were identified. Overall, the pooled relative risks (95% confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were: 1.36 (95%CI: 1.11, 1.66), 1.30 (95%CI: 1.12, 1.52), 1.18 (95%CI: 0.86, 1.59), and 1.49 (95%CI: 1.15, 1.92), respectively. The pooled relative risks for cardiovascular disease in men, women and never smokers were 1.29 (1.12, 1.48), 1.20 (0.92, 1.56) and 1.27 (0.97, 1.67), respectively. Together with experimental evidence, our review supports the association between cadmium exposure and cardiovascular disease, especially for coronary heart disease. The number of studies with stroke, HF and PAD endpoints was small. More studies, especially studies evaluating incident endpoints, are needed.
doi:10.1007/s11883-013-0356-2
PMCID: PMC3858820  PMID: 23955722
Cadmium; Cardiovascular disease; Meta-analysis; Systematic Review
9.  Association between Low to Moderate Arsenic Exposure and Incident Cardiovascular Disease. A Prospective Cohort Study 
Annals of internal medicine  2013;159(10):649-659.
Background
Inorganic arsenic exposure in water and food is a global public health problem. Chronic exposure to high levels of arsenicis consistently associated with increased risk of cardiovascular disease, whereas prospective data on low to moderate chronic arsenic exposure (<100μg/L in drinking water) are lacking.
Objective
To evaluate the association between chronic low to moderate arsenic exposure and incident cardiovascular disease.
Design
Prospective cohort study.
Setting
The Strong Heart Study baseline visit in 1989-1991, with follow-up through 2008.
Patients
3,575 American Indian men and women aged 45-74 years living in Arizona, Oklahoma, and North and South Dakota.
Measurements
The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of chronic arsenic exposure. Participants were followed for incident fatal and non-fatal cardiovascular disease, including coronary heart disease and stroke.
Results
1,184 participants developed fatal and non-fatal cardiovascular disease and 439 participants developed fatal cardiovascular disease. Comparing the highest to lowest quartile arsenic concentrations (>15.7 vs. <5.8 μg/g creatinine), the hazard ratios (95% confidence interval) for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for socio-demographic factors, smoking, body mass index, and lipids were 1.65 (1.20, 2.27; p-trend<0.001), 1.71 (1.19, 2.44; p-trend<0.001) and 3.03 (1.08, 8.50; p-trend=0.061), respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (1.09, 1.59; p-trend=0.002), 1.30 (1.04, 1.62; p-trend=0.006), and 1.47 (0.97, 2.21; p-trend=0.032), respectively. These associations varied by study region and were attenuated following further adjustment for diabetes, hypertension, and measures of kidney disease.
Limitations
Direct measurement of individual arsenic in drinking water was unavailable. Residual confounding and differences in potential confounders across study regions may exist.
Conclusions
Low to moderate chronic arsenic exposure, as measured in urine, was prospectively associated with cardiovascular disease incidence and mortality.
doi:10.7326/0003-4819-159-10-201311190-00719
PMCID: PMC4157936  PMID: 24061511
10.  Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples 
Environmental Health Perspectives  2014;122(9):946-954.
Background: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.
Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989–1991 (visit 1) and 1998–1999 (visit 3).
Methods: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation.
Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population.
Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies.
Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. 2014. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect 122:946–954; http://dx.doi.org/10.1289/ehp.1306674
doi:10.1289/ehp.1306674
PMCID: PMC4154208  PMID: 24769358
11.  Cadmium Exposure and Incident Cardiovascular Disease 
Epidemiology (Cambridge, Mass.)  2013;24(3):421-429.
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 3,348 American Indian adults aged 45–74 years 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 μg/g (95% confidence interval= 0.92 – 0.93). We identified 1,084 cardiovascular events, including 400 deaths. After adjustment for sociodemographic and cardiovascular risk factors, the hazard ratios (comparing the 80th to the 20th percentile of urine cadmium concentrations) was 1.43 for cardiovascular mortality (95% confidence interval=1.21 – 1.70), and 1.34 for coronary heart disease mortality (1.10 – 1.63). The corresponding hazard ratios 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 with increased incidence of cardiovascular disease. These findings support that cadmium exposure is a cardiovascular risk factor.
doi:10.1097/EDE.0b013e31828b0631
PMCID: PMC4142588  PMID: 23514838
12.  Smoking, Menthol Cigarettes, and Peripheral Artery Disease in U.S. Adults 
Nicotine & Tobacco Research  2012;15(7):1183-1189.
Introduction:
Cigarette flavorings, with the exception of menthol, have been banned in the United States under the Family Smoking Prevention and Tobacco Control Act. Given the large number of menthol cigarette smokers in the United States, we investigated whether cigarette type (nonmenthol or menthol) is associated with peripheral artery disease (PAD).
Methods:
The authors studied 5,973 adults, 40 years of age and older, who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. Smoking status and cigarette type were derived from self-reported questionnaires. PAD was defined as an ankle-brachial blood pressure index <0.9 in at least 1 leg.
Results:
Fifty percent of participants were never-smokers compared to 31%, 14%, and 5% of former, current nonmenthol, and current menthol cigarette smokers, respectively. The weighted prevalence of PAD in the study population was 5%. After multivariable adjustment, the odds ratios for PAD were 1.44 (95% CI: 0.97, 2.15), 3.65 (95% CI: 1.57, 8.50), and 2.51 (95% CI: 1.09, 5.80) comparing former, current nonmenthol cigarette smokers, and current menthol cigarette smokers to never-smokers. The associations between smoking and PAD were similar for smokers of nonmenthol and menthol cigarettes (p value for heterogeneity = .59).
Conclusions:
In a representative sample of the U.S. population, current use of both menthol and nonmenthol cigarettes was associated with increased prevalence of PAD, with no difference in risk between cigarette types.
doi:10.1093/ntr/nts253
PMCID: PMC3682841  PMID: 23212436
13.  Kidney Function and Tobacco Smoke Exposure in US Adolescents 
Pediatrics  2013;131(5):e1415-e1423.
BACKGROUND AND OBJECTIVE:
Active smoking and secondhand smoke (SHS) are known risk factors for kidney disease in adults. We evaluated the association between exposure to active smoking or SHS and kidney function in US adolescents.
METHODS:
This is a cross-sectional study in 7516 adolescents aged 12–17 who participated in NHANES 1999–2010 and had serum creatinine and cotinine measures. Active smoking was defined as self-reported smoking or serum cotinine concentrations >10 ng/mL. SHS was defined as nonactive smokers who self-reported living with ≥1 smokers or serum cotinine concentrations ≥ 0.05 ng/mL. Kidney function was determined by using the chronic kidney disease in children estimated glomerular filtration rate (eGFR) equation.
RESULTS:
Median (interquartile range) eGFR and serum cotinine concentrations were 96.8 (85.4–109.0) mL/minute per 1.73 m2 and 0.07 (0.03–0.59) ng/mL, respectively. After multivariable adjustment, eGFR decreased 1.1 mL/minute per 1.73 m2 (95% confidence interval [CI]: −1.8 to −0.3) per interquartile range increase in serum cotinine concentrations. The mean (95%CI) difference in eGFR for serum cotinine tertiles 1, 2, and 3 among children exposed to SHS compared to unexposed were −0.4 (−1.9 to 1.2), −0.9 (−2.7 to 0.9), and −2.2 (−4.0 to −0.4) mL/minute per 1.73 m2, respectively (P = .03). The corresponding values among tertiles of active smokers compared to unexposed were 0.2 (−2.2 to 2.6), −1.9 (−3.8 to 0.0), and −2.6 (−4.6 to −0.6) mL/minute per 1.73 m2 (P = .01).
CONCLUSIONS:
Tobacco smoke exposure was associated with decreased eGFR in US adolescents, supporting the possibility that tobacco smoke effects on kidney function begin in childhood.
doi:10.1542/peds.2012-3201
PMCID: PMC4074657  PMID: 23569089
adolescents; cotinine; creatinine; secondhand smoke; smoking; tobacco smoke pollution
14.  Protecting the World From Secondhand Tobacco Smoke Exposure: Where Do We Stand and Where Do We Go From Here? 
Nicotine & Tobacco Research  2012;15(4):789-804.
Introduction:
Article 8 of the Framework Convention on Tobacco Control mandates all signatory countries to “protect citizens from exposure to tobacco smoke in workplaces, public transport and indoor public places.” Even though there has been great progress in the implementation of Article 8, still most of the world population remains exposed to secondhand smoke (SHS). In this article, we sought to summarize the research that supports Article 8, where do we stand, and current research gaps and future directions.
Discussion:
Secondhand smoke is an established cause of heart disease and several types of cancer. Additional research is needed to reach final conclusions for diseases where evidence is only suggestive of causality. The only solution to SHS exposure in public places is banning smoking indoors. Research on the gaming industry and nightclubs, particularly in developing countries, needs to be disseminated to support their inclusion in smoke-free laws. Aside from indoor bans, additional research is needed for outdoor and multiunit housing bans and in support of measures that protect children and other vulnerable populations. The impact of smoke-free laws on other health outcomes, besides heart disease and respiratory outcomes, is another area where further research is needed. Thirdhand smoke assessment and health effects are also likely to be a topic of further research. As new tobacco products emerge, evaluating SHS exposure and effects will be vital.
Conclusions:
Furthering research in support of Article 8 can contribute to reach the final goal of protecting everyone from SHS exposure.
doi:10.1093/ntr/nts200
PMCID: PMC3601911  PMID: 23072872
15.  Cadmium Exposure and Cancer Mortality in a Prospective Cohort: The Strong Heart Study 
Environmental Health Perspectives  2014;122(4):363-370.
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
doi:10.1289/ehp.1306587
PMCID: PMC3984227  PMID: 24531129
16.  Urine Arsenic and Prevalent Albuminuria: Evidence From a Population-Based Study 
Background
Chronic arsenic exposure is a major global health problem. Few epidemiologic studies, however, have evaluated the association of arsenic with kidney measures. Our objective was to evaluate the cross-sectional association between inorganic arsenic exposure and albuminuria in American Indian adults from rural areas of Arizona, Oklahoma and North and South Dakota.
Study Design
Cross-sectional.
Setting & Partipants
Strong Heart Study locations in Arizona, Oklahoma, and North and South Dakota. 3,821 American Indian men and women 45 to 74 years of age with urine arsenic and albumin measures.
Predictor
Urine arsenic.
Outcomes
Urine albumin/creatinine ratio and albuminuria status.
Measurements
Arsenic exposure was estimated by measuring total urine arsenic and urine arsenic species using inductively coupled plasma-mass spectrometry (ICPMS) and high performance liquid chromatography-ICPMS, respectively. Urine albumin was measured by automated nephelometric immunochemistry.
Results
The prevalence of albuminuria (albumin-creatinine ratio, ≥30 mg/g) was 30%. The median value for the sum of inorganic and methylated arsenic species was 9.7 (IQR, 5.8-15.6) μg/g creatinine. The multivariable-adjusted prevalence ratios of albuminuria (albumin-creatinine ratio. ≥30 mg/g) comparing the three highest to lowest quartiles of the sum of inorganic and methylated arsenic species were 1.16 (95% CI, 1.00-1.34), 1.24 (95% CI, 1.07-1.43), and 1.55 (95% CI, 1.35-1.78), respectively (P for trend <0.001). The association between urine arsenic and albuminuria was observed across all participant subgroups evaluated and was evident for both micro and macroalbuminuria.
Limitations
The cross-sectional design cannot rule out reverse causation.
Conclusions
Increasing urine arsenic concentrations were cross-sectionally associated with increased albuminuria in a rural US population with a high burden of diabetes and obesity. Prospective epidemiologic and mechanistic evidence is needed to understand the role of arsenic as a kidney disease risk factor.
doi:10.1053/j.ajkd.2012.09.011
PMCID: PMC3578134  PMID: 23142528
17.  Menthol Cigarettes, Race/Ethnicity and Biomarkers of Tobacco Use in US Adults: The 1999- 2010 National Health and Nutrition Examination Survey (NHANES) 
Background
In the US, cigarette flavorings are banned, with the exception of menthol. The cooling effects of menthol could facilitate the absorption of tobacco toxicants. We examined levels of biomarkers of tobacco exposure among US smokers of menthol and non-menthol cigarettes.
Methods
We studied 4,603 White, African-American, and Mexican-American current smokers ≥ 20 years of age who participated in the National Health and Nutrition Examination Survey from 1999 through 2010 and had data on cigarette type and serum cotinine, blood cadmium, and blood lead concentrations. Urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL) was studied in 1,607 participants with available measures.
Results
A total of 3,210 (74.3%) participants smoked non-menthol cigarettes compared to 1,393 (25.7%) participants who smoked menthol cigarettes. The geometric mean concentrations comparing smokers of non-menthol to menthol cigarettes were 163.1 vs. 175.9 ng/mL for serum cotinine; 0.95 vs. 1.02 μg/L for blood cadmium; 1.87 vs. 1.75 μg/dL for blood lead; and 0.27 vs. 0.23 ng/mL for urine NNAL. After multivariable adjustment, the ratios (95% confidence interval [CI]) comparing smokers of menthol to non-menthol cigarettes were 1.03 (0.95, 1.11) for cotinine, 1.10 (1.04, 1.16) for cadmium, 0.95 (0.90, 1.01) for lead, and 0.81 (0.65, 1.01) for NNAL.
Conclusions
In a representative sample of US adult smokers, current menthol cigarette use was associated with increased concentration of blood cadmium, an established carcinogen and highly toxic metal, but not with other biomarkers.
Impact
These findings provide information regarding possible differences in exposure to toxic constituents among menthol cigarette smokers compared to non-menthol cigarette smokers.
doi:10.1158/1055-9965.EPI-12-0912
PMCID: PMC3565051  PMID: 23250935
cigarette smoking; menthol; biomarkers
18.  Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study 
Environmental Health  2013;12:107.
Objective
The objective of this study was to evaluate the association between measures of body composition and patterns of urine arsenic metabolites in the 1989–1991 baseline visit of the Strong Heart Study, a cardiovascular disease cohort of adults recruited from rural communities in Arizona, Oklahoma, North Dakota and South Dakota.
Methods
We evaluated 3,663 Strong Heart Study participants with urine arsenic species above the limit of detection and no missing data on body mass index, % body fat and fat free mass measured by bioelectrical impedance, waist circumference and other variables. We summarized urine arsenic species patterns as the relative contribution of inorganic (iAs), methylarsonate (MMA) and dimethylarsinate (DMA) species to their sum. We modeled the associations of % arsenic species biomarkers with body mass index, % body fat, fat free mass, and waist circumference categories in unadjusted regression models and in models including all measures of body composition. We also considered adjustment for arsenic exposure and demographics.
Results
Increasing body mass index was associated with higher mean % DMA and lower mean % MMA before and after adjustment for sociodemographic variables, arsenic exposure, and for other measures of body composition. In unadjusted linear regression models, % DMA was 2.4 (2.1, 2.6) % higher per increase in body mass index category (< 25, ≥25 & <30, ≥30 & <35, ≥35 kg/m2), and % MMA was 1.6 (1.4, 1.7) % lower. Similar patterns were observed for % body fat, fat free mass, and waist circumference measures in unadjusted models and in models adjusted for potential confounders, but the associations were largely attenuated or disappeared when adjusted for body mass index.
Conclusion
Measures of body size, especially body mass index, are associated with arsenic metabolism biomarkers. The association may be related to adiposity, fat free mass or body size. Future epidemiologic studies of arsenic should consider body mass index as a potential modifier for arsenic-related health effects.
doi:10.1186/1476-069X-12-107
PMCID: PMC3883520  PMID: 24321145
American Indians; Arsenic; Arsenic metabolism; Arsenic species; Obesity; Body mass index; Strong Heart Study
19.  Arsenic Exposure and Cardiovascular Disease: An Updated Systematic Review 
Current atherosclerosis reports  2012;14(6):542-555.
In epidemiologic studies, high-chronic arsenic exposure has been associated with cardiovascular disease, despite methodological limitations. At low-moderate arsenic levels, the evidence was inconclusive. Here, we update a previous systematic review (Am J Epidemiol 2005;162: 1037–49) examining the association between arsenic exposure and cardiovascular disease. Eighteen studies published since 2005 were combined with 13 studies from the previous review. We calculated pooled relative risks by comparing the highest versus the lowest exposure category across studies. For high exposure (arsenic in drinking water > 50 μg/L), the pooled relative risks (95 % confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were 1.32 (95 % CI: 1.05–1.67), 1.89 (95 % CI: 1.33–2.69), 1.08 (95 % CI: 0.98–1.19), and 2.17 (95 % CI: 1.47–3.20), respectively. At low-moderate arsenic levels, the evidence was inconclusive. Our review strengthens the evidence for a causal association between high-chronic arsenic exposure and clinical cardiovascular endpoints. Additional high quality studies are needed at low-moderate arsenic levels.
doi:10.1007/s11883-012-0280-x
PMCID: PMC3483370  PMID: 22968315
Arsenic; Cardiovascular disease; Meta-analysis; Systematic review
20.  Arsenic Exposure, Diabetes Prevalence, and Diabetes Control in the Strong Heart Study 
American Journal of Epidemiology  2012;176(10):865-874.
This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, Oklahoma, and North and South Dakota (1989–1991). We studied 3,925 men and women 45–74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 µg/L (interquartile range, 7.9–24.2). Diabetes prevalence was 49.4%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c ≥8%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed.
doi:10.1093/aje/kws153
PMCID: PMC3626061  PMID: 23097256
American Indians; arsenic; diabetes; glycated hemoglobin; insulin resistance
21.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
22.  Smoking, Menthol Cigarettes and All-Cause, Cancer and Cardiovascular Mortality: Evidence from the National Health and Nutrition Examination Survey (NHANES) and a Meta-Analysis 
PLoS ONE  2013;8(10):e77941.
Background
The U.S. Food and Drug Administration has the authority to regulate tobacco product constituents, including menthol, if the scientific evidence indicates harm. Few studies, however, have evaluated the health effects of menthol cigarette use.
Objective
To investigate associations of cigarette smoking and menthol cigarette use with all-cause, cancer and cardiovascular risk in U.S. adults.
Methods
We studied 10,289 adults ≥ 20 years of age who participated in the National Health and Nutrition Examination Survey from 1999-2004 and were followed through December 2006. We also identified studies comparing risk of all-cause mortality, cardiovascular disease and cancer for menthol and nonmenthol cigarette smokers and estimates were pooled using random-effects models.
Results
Fifty-five percent of participants were never smokers compared to 23%, 17% and 5% of former, current nonmenthol and current menthol cigarette smokers, respectively. The adjusted hazard ratios (95% CI) for former, current nonmenthol and current menthol cigarette smokers compared to never smokers were 1.24 (0.96, 1.62), 2.40 (1.56, 3.71) and 2.07 (1.20, 3.58), respectively, for all-cause mortality; 0.92 (0.62, 1.37), 2.10 (1.02, 4.31) and 3.48 (1.52, 7.99) for cardiovascular mortality; and 1.91 (1.21, 3.00), 3.82 (2.19, 6.68) and 2.03 (1.00, 4.13) for cancer mortality. Using data from 3 studies of all-cause mortality, 5 of cardiovascular disease and 13 of cancer, the pooled relative risks (95% CI) comparing menthol cigarette smokers to nonmenthol cigarette smokers was 0.94 (0.85, 1.05) for all-cause mortality, 1.28 (0.91, 1.80) for cardiovascular disease and 0.84 (0.76, 0.92) for any cancer.
Conclusions
In a representative sample of U.S. adults, menthol cigarette smoking was associated with increased all-cause, cardiovascular and cancer mortality with no differences compared to nonmenthol cigarettes. In the systematic review, menthol cigarette use was associated with inverse risk of cancer compared to nonmenthol cigarette use with some evidence of an increased risk for cardiovascular disease.
doi:10.1371/journal.pone.0077941
PMCID: PMC3808303  PMID: 24205038
23.  Secondhand Tobacco Smoke: An Occupational Hazard for Smoking and Non-Smoking Bar and Nightclub Employees 
Tobacco control  2012;22(5):308-314.
Background
In the absence of comprehensive smoking bans in public places, bars and nightclubs have the highest concentrations of secondhand tobacco smoke, posing a serious health risk for workers in these venues.
Objective
To assess exposure of bar and nightclub employees to secondhand smoke, including non-smoking and smoking employees.
Methods
Between 2007 and 2009, we recruited approximately 10 venues per city and up to 5 employees per venue in 24 cities in the Americas, Eastern Europe, Asia and Africa. Air nicotine concentrations were measured for 7 days in 238 venues. To evaluate personal exposure to secondhand smoke, hair nicotine concentrations were also measured for 625 non-smoking and 311 smoking employees (N=936).
Results
Median (interquartile range [IQR]) air nicotine concentrations were 3.5 (1.5, 8.5) µg/m3 and 0.2 (0.1, 0.7) µg/m3 in smoking and smoke-free venues, respectively. Median (IQR) hair nicotine concentrations were 6.0 (1.6, 16.0) ng/mg and 1.7 (0.5, 5.5) ng/mg in smoking and non-smoking employees, respectively. After adjustment for age, sex, education, living with a smoker, hair treatment and region, a 2-fold increase in air nicotine concentrations was associated with a 30% (95% confidence interval 23%, 38%) increase in hair nicotine concentrations in non-smoking employees and with a 10% (2%, 19%) increase in smoking employees.
Conclusions
Occupational exposure to secondhand smoke, assessed by air nicotine, resulted in elevated concentrations of hair nicotine among non-smoking and smoking bar and nightclub employees. The high levels of airborne nicotine found in bars and nightclubs and the contribution of this exposure to employee hair nicotine concentrations support the need for legislation measures that ensure complete protection from secondhand smoke in these venues.
doi:10.1136/tobaccocontrol-2011-050203
PMCID: PMC3701027  PMID: 22273689
nicotine; tobacco smoke pollution; workplace
24.  Blood Lead Level and Measured Glomerular Filtration Rate in Children with Chronic Kidney Disease 
Environmental Health Perspectives  2013;121(8):965-970.
Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement.
Objective: We evaluated the association between lead exposure and GFR in children with CKD.
Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study.
Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was –2.1 (95% CI: –6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a –12.1 (95% CI: –22.2, –1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a –0.3 (95% CI: –7.2, 6.6) and –4.6 (95% CI: –8.9, –0.3) percent change in GFR, respectively.
Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD.
doi:10.1289/ehp.1205164
PMCID: PMC3734488  PMID: 23694739
children; chronic kidney disease; kidney; lead; nephrotoxicity; pediatric
25.  Blood Lead Level and Kidney Function in US Adolescents 
Archives of internal medicine  2010;170(1):75-82.
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 μg/dL (to convert to micromoles per liter, multiply by 0.0483), and median cystatin C–estimated GFR was 112.9 mL/min/1.73 m2. Participants with lead levels in the highest quartile (≥3.0 μg/dL) had 6.6 mL/min/1.73 m2–lower estimated GFR (95% confidence interval, −0.7 to −12.6 mL/min/1.73 m2) compared with those in the first quartile (<1 μg/dL). A doubling of blood lead level was associated with a 2.9 mL/min/1.73 m2–lower estimated GFR (95% confidence interval, −0.7 to −5.0 mL/min/1.73 m2). 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 μg/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.
doi:10.1001/archinternmed.2009.417
PMCID: PMC3718466  PMID: 20065202

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