Characterization of bone aluminum, a potential biomarker of cumulative exposure, within an occupational population from Zunyi, China.

OBJECTIVES: Aluminum (Al) is a neurotoxicant; however, efforts to understand Al toxicity are limited by the lack of a quantitative biomarker of cumulative exposure. Bone Al measurements may address this need. Here, we describe and compare non-invasive bone Al measurements with fingernail Al and Al cumulative exposure indices (CEIs). METHODS: We completed a cross-sectional study of 43 factory workers in Zunyi, China. Bone Al measurements were taken with a compact in-vivo neutron activation analysis system (IVNAA). Fingernail samples were analyzed using inductively coupled plasma mass spectrometry. CEIs, based on self-reported work history and prior literature, were calculated for the prior 5, 10, 15, 20 years and lifetime work history. Linear regressions adjusted for age and education compared fingernail Al and Al CEIs with bone Al. RESULTS: Median (interquartile range (IQR)) Al measurements were: 15 µg/g dry bone (IQR = 28) for bone Al; 34.9 µg/g (43.3) for fingernail; and 24 (20) for lifetime CEI. In adjusted regression models, an increase in 15-year CEI was significantly associated with increased bone Al (ß = 0.91, 95% confidence interval (CI): 0.16, 1.66). Associations of bone Al with 10- and 20-year CEI were approaching statistical significance (ß = 0.98, 95% CI: -0.14, 2.1; ß = 0.59, 95% CI: -0.01, 1.18, respectively). Other models were not statistically significant. CONCLUSIONS: Bone Al was significantly associated with 15-year Al CEI, but not other Al CEIs or fingernail Al. Bone Al may be a useful measure of cumulative, rather than short-term, Al exposure. Additional refinement of this method is ongoing.

Reversibility of Neuroimaging Markers Influenced by Lifetime Occupational Manganese Exposure.

Manganese (Mn) is a neurotoxicant that many workers are exposed to daily. There is limited knowledge about how changes in exposure levels impact measures in magnetic resonance imaging (MRI). We hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABAThal). As part of a prospective cohort study, 17 welders were recruited and imaged on 2 separate occasions approximately 2 years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]Air) and cumulative exposure indexes of Mn (Mn-CEI) for the past 3 months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, whereas toenails were collected for analysis of internal Mn body burden. Finally, welders' motor function was examined using the Unified Parkinson's Disease Rating Scale (UPDRS). Median exposure decreased for all exposure measures between the first and second scan. ΔGABAThal was significantly correlated with ΔMn-CEI3M (ρ = 0.66, adjusted p = .02), ΔMn-CEI12M (ρ = 0.70, adjusted p = .006), and Δ[Mn]Air (ρ = 0.77, adjusted p = .002). ΔGABAThal significantly decreased linearly with ΔMn-CEI3M (quantile regression, ß = 15.22, p = .02) as well as Δ[Mn]Air (ß = 1.27, p = .04). Finally, Mn-CEILife interacted with Δ[Mn]Air in the substantia nigra where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = .005). Although R1 and GABA changed with Mn exposure, UPDRS was unaffected. In conclusion, our study shows that effects from changes in Mn exposure are reflected in thalamic GABA levels and brain Mn levels, as measured by R1, in most brain regions.

Association between blood lead level and subsequent Alzheimer's disease mortality.

BACKGROUND: Previous studies suggest that cumulative lead exposure is associated with cognitive decline, but its relation with Alzheimer's disease (AD) remains unclear. Therefore, this study investigated the longitudinal association between blood lead level (BLL) and AD mortality. METHODS: This study included 8,080 elders (60 years or older) with BLL data from the 1999 to 2008 US National Health and Nutrition Examination Survey. Mortality was determined from linked 1999-2014 National Death Index data. A causal diagram presented causal assumptions and identified a sufficient set of confounders: age, sex, poverty, race/ethnicity, and smoking. Cox proportional hazard models were used to determine the association between BLL and subsequent AD mortality. Impacts of competing risks and design effect were also assessed. Adjusted hazard rate ratio (HRR) and 95% confidence interval (CI) were reported. RESULTS: Follow-up ranged from <1 to 152 months (median, 74). Eighty-one participants died from AD over 632,075 total person-months at risk. An increase in BLL was associated with an increase in AD mortality after adjusting for identified confounders. We estimated that those with BLL of 1.5 and 5 µg/dl had 1.2 (95% CI = 0.70, 2.1) and 1.4 (95% CI = 0.54, 3.8) times the rate of AD mortality compared to those with BLL of 0.3 µg/dl, respectively, after accounting for competing risks. Adjusted HRRs were 1.5 (95% CI = 0.81, 2.9) and 2.1 (95% CI = 0.70, 6.3), respectively, after considering design effect. CONCLUSIONS: This longitudinal study demonstrated a positive, albeit not statistically significant, association between BLL and AD mortality after adjustment for competing risks or design effect.

The association of bone, fingernail and blood manganese with cognitive and olfactory function in Chinese workers.

Occupational manganese (Mn) exposure has been associated with cognitive and olfactory dysfunction; however, few studies have incorporated cumulative biomarkers of Mn exposure such as bone Mn (BnMn). Our goal was to assess the cross-sectional association between BnMn, blood Mn (BMn), and fingernail Mn (FMn) with cognitive and olfactory function among Mn-exposed workers. A transportable in vivo neutron activation analysis (IVNAA) system was designed and utilized to assess BnMn among 60 Chinese workers. BMn and FMn were measured using inductively coupled plasma mass spectrometry. Cognitive and olfactory function was assessed using Animal and Fruit Naming tests, World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test (AVLT) and the University of Pennsylvania Smell Identification Test (UPSIT). Additional data were obtained via questionnaire. Regression models adjusted for age, education, factory of employment, and smoking status (UPSIT only), were used to assess the relationship between Mn biomarkers and test scores. In adjusted models, increasing BnMn was significantly associated with decreased performance on average AVLT scores [ß (95% confidence interval (CI)) = -0.65 (-1.21, -0.09)] and Animal Naming scores [ß (95% CI) = -1.54 (-3.00, -0.07)]. Increasing FMn was significantly associated with reduced performance measured by the average AVLT [ß (95% CI) = -0.35 (-0.70, -0.006)] and the difference in AVLT scores [ß (95% CI) = -0.40 (-0.77, -0.03)]. BMn was not significantly associated with any test scores; no significant associations were observed with Fruit Naming or UPSIT tests. BnMn and FMn, but not BMn, are associated with cognitive function in Mn-exposed workers. None of the biomarkers were significantly associated with olfactory function.

Evidence Regarding the Impact of Conflicts of Interest on Environmental and Occupational Health Research.

PURPOSE OF REVIEW: This review describes published literature providing evidence for financial conflicts of interest in environmental and occupational health research. Secondary goals were to describe evidence that (a) utilized quantitative methods to evaluate the association of conflicts with study outcomes, and (b) assessed undisclosed as well as disclosed conflicts of interest. RECENT FINDINGS: Forty-three studies were identified which contained descriptions of the impact of financial conflicts of interest on research results; 11 of these conducted quantitative analyses to demonstrate these relationships. All 11 articles which quantified associations identified significant associations of the presence of financial conflicts of interest with study findings. In studies which measured undisclosed conflicts, these comprised a substantial proportion of all conflicts. Suggestions for improving understanding and interpretation of research results are presented.

Methyl mercury, but not inorganic mercury, associated with higher blood pressure during pregnancy.

Prior studies addressing associations between mercury and blood pressure have produced inconsistent findings; some of this may result from measuring total instead of speciated mercury. This cross-sectional study of 263 pregnant women assessed total mercury, speciated mercury, selenium, and n-3 polyunsaturated fatty acids in umbilical cord blood and blood pressure during labor and delivery. Models with a) total mercury or b) methyl and inorganic mercury were evaluated. Regression models adjusted for maternal age, race/ethnicity, prepregnancy body mass index, neighborhood income, parity, smoking, n-3 fatty acids and selenium. Geometric mean total, methyl, and inorganic mercury concentrations were 1.40µg/L (95% confidence interval: 1.29, 1.52); 0.95µg/L (0.84, 1.07); and 0.13µg/L (0.10, 0.17), respectively. Elevated systolic BP, diastolic BP, and pulse pressure were found, respectively, in 11.4%, 6.8%, and 19.8% of mothers. In adjusted multivariable models, a one-tertile increase of methyl mercury was associated with 2.83mmHg (0.17, 5.50) higher systolic blood pressure and 2.99mmHg (0.91, 5.08) higher pulse pressure. In the same models, an increase of one tertile of inorganic mercury was associated with -1.18mmHg (-3.72, 1.35) lower systolic blood pressure and -2.51mmHg (-4.49, -0.53) lower pulse pressure. No associations were observed with diastolic pressure. There was a non-significant trend of higher total mercury with higher systolic blood pressure. We observed a significant association of higher methyl mercury with higher systolic and pulse pressure, yet higher inorganic mercury was significantly associated with lower pulse pressure. These results should be confirmed with larger, longitudinal studies.

Reference Ranges and Association of Age and Lifestyle Characteristics with Testosterone, Sex Hormone Binding Globulin, and Luteinizing Hormone among 1166 Western Chinese Men.

Decreased total testosterone (TT) is the recommended metric to identify age-related hypogonadism. However, average TT and the extent to which it varies by age, can vary substantially among different populations. Population-specific reference ranges are needed to understand normal versus abnormal TT levels. Therefore, the goal for this study was to describe androgen concentrations and their correlates among Western Chinese men. We completed a population-based, cross-sectional study including 227 young adults (YA) (20-39 years) and 939 older adults (OA) (40-89 years). We measured TT, sex-hormone binding globulin (SHBG), luteinizing hormone (LH), testosterone secreting index (TSI), and calculated free testosterone (cFT). Reference ranges for this population were determined using average YA concentrations. Multivariable regression models were used to predict hormone concentrations adjusting for age, waist-to-height ratio (WHR), marital status, education, occupation, smoking, alcohol, blood glucose, and blood pressure. Among OA, 3.8% had low TT, 15.2% had low cFT, 26.3% had low TSI, 21.6% had high SHBG, and 6.1% had high LH. Average cFT was significantly lower in OA (0.30 nmol/L; standard deviation (SD): 0.09) versus YA (0.37; SD: 0.11) but TT was not different in OA (16.82 nmol/L; SD: 4.80) versus YA (16.88; SD: 5.29). In adjusted models increasing age was significantly associated with increased SHBG or LH, and decreased cFT or TSI; however, TT was not significantly associated with age (ß = 0.02 nmol/L; 95% confidence interval (CI): -0.01, 0.04). Higher WHR was associated with significantly decreased TT, SHBG, TSI, and LH. The only variable significantly related to cFT was age (ß = -0.0033; 95% CI:-0.0037, -0.0028); suggesting that cFT measurements would not be confounded by other lifestyle factors. In conclusion, cFT, but not TT, varies with age in this population, suggesting cFT may be a better potential marker for age-related androgen deficiency than TT among Western Chinese men.

Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex.

BACKGROUND: Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. OBJECTIVE: Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. METHODS: This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004-2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). RESULTS: Geometric mean cord blood MeHg was 0.94 µg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, ßln(MeHg) = -0.045 (g/cm(3)) × 100 (95% CI: -0.084, -0.005). There was no evidence of a MeHg × sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg × n-3 HUFAs interaction with birth length [among low n-3 HUFAs, ßln(MeHg) = 0.40 cm, 95% CI: -0.02, 0.81; among high n-3 HUFAs, ßln(MeHg) = -0.15, 95% CI: -0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, ßln(MeHg) = 0.01 cm, 95% CI: -0.27, 0.29; among high n-3 HUFAs, ßln(MeHg) = -0.37, 95% CI: -0.63, -0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, ßln(MeHg) without these variables was -16.8 g (95% CI: -75.0, 41.3) versus -29.7 (95% CI: -93.9, 34.6) with all covariates. Corresponding values for ponderal index were -0.030 (g/cm(3)) × 100 (95% CI: -0.065, 0.005) and -0.045 (95% CI: -0.084, -0005). CONCLUSION: We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies.

Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns.

BACKGROUND: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. METHODS: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. RESULTS: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. CONCLUSIONS: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.

The relationship of blood lead with immunoglobulin E, eosinophils, and asthma among children: NHANES 2005-2006.

Early life lead exposure may alter immune function and predispose a child to develop asthma. In an initial exploration of this hypothesis, we examined the association between blood lead, and serum immunoglobulin E (IgE), eosinophils, and asthma prevalence in a cross-sectional study of 1788 children from the National Health and Nutrition Examination Survey 2005-2006. Geometric mean blood lead, serum IgE, and percent eosinophils were 1.13 µg/dL (95% confidence interval (CI): 1.04, 1.22), 46.3 kU/L (95% CI: 40.3, 53.1), and 2.82 percent (95% CI 2.67, 2.98), respectively. Prevalence of asthma, atopic asthma, and atopy were 11.8% (95% CI: 9.5, 14.2), 8.1% (6.2, 9.9), and 44.4% (40.1, 48.7), respectively. Regression models controlled for season, age, sex, race/ethnicity, education, passive smoke exposure, and body mass index. Based on these models, there was an 11.1% (95% CI: 5.6, 16.9) increase in IgE and a 4.9% (95% CI: 2.3, 7.6) increase in eosinophils per 1 µg/dL increase in blood lead. In independent stratified analyses, lead was found to increase IgE and eosinophils among non-Hispanic whites, but not other children; and stronger associations were observed among children who lived with a smoker vs. not. Lead was not associated with asthma, atopic asthma, or general atopy. This study provides additional evidence of a cross-sectional association between lead with IgE and new evidence for eosinophils. This may be a mechanism for development of downstream allergic disease. The mechanisms that determine ultimate development of allergic disease are currently unknown, but are the focus of ongoing studies.

Activity change in response to bad air quality, National Health and Nutrition Examination Survey, 2007-2010.

Air pollution contributes to poor respiratory and cardiovascular health. Susceptible individuals may be advised to mitigate effects of air pollution through actions such as reducing outdoor physical activity on days with high pollution. Our analysis identifies the extent to which susceptible individuals changed activities due to bad air quality. This cross-sectional study included 10,898 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Participants reported if they did something differently when air quality was bad. Susceptible categories included respiratory conditions, cardiovascular conditions and older age (≥ 65 years). Analyses accounted for complex survey design; logistic regression models controlled for gender, race, education, smoking, and body mass index. 1305 individuals reported doing something differently (12.0%, 95% confidence interval (CI): 10.9, 13.1). This percentage was 14.2% (95% CI: 11.6, 16.8), 25.1% (95% CI: 21.7, 28.6), and 15.5% (95% CI: 12.2, 18.9) among older adults, those with a respiratory condition, and those with a cardiovascular condition, respectively. In adjusted regression models the following were significantly more likely to have changed activity compared to those who did not belong to any susceptible group: respiratory conditions (adjusted odds ratio (aOR): 2.61, 95% CI: 2.03, 3.35); respiratory and cardiovascular conditions (aOR: 4.36, 95% CI: 2.47, 7.69); respiratory conditions and older age (aOR: 3.83; 95% CI: 2.47, 5.96); or all three groups (aOR: 3.52; 95% CI: (2.33, 5.32). Having cardiovascular conditions alone was not statistically significant. Some individuals, especially those with a respiratory condition, reported changing activities due to poor air quality. However, efforts should continue to educate the public about air quality and health.

Selenium and maternal blood pressure during childbirth.

Evidence suggests selenium concentrations outside the nutritional range may worsen cardiovascular health. This paper examines the relationship between selenium and maternal blood pressure (BP) among 270 deliveries using umbilical cord serum as a proxy for maternal exposure levels. Multivariable models used linear splines for selenium and controlled for gestational age, maternal age, race, median household income, parity, smoking, and prepregnancy body mass index. Non-parametric analysis of this dataset was used to select spline knots for selenium at 70 and 90 µg/l. When selenium was <70 µg/l, increasing selenium levels were related to a non-statistically significant decrease in BP. For selenium 70-90 µg/l, a 1 µg/l increase was related to a 0.37 mm Hg (95% confidence interval (CI): 0.005, 0.73) change in systolic and a 0.35 mm Hg (0.07, 0.64) change in diastolic BP. There were very few selenium values >90 µg/l. Other studies indicate that the maternal/cord selenium ratio is 1.46 (95% CI: 1.28, 1.65). This u-shaped relationship between selenium and BP is consistent with a dual role of selenium as an essential micronutrient that is nonetheless a toxicant at higher concentrations; however, this needs to be studied further.

Body burdens of mercury, lead, selenium and copper among Baltimore newborns.

Umbilical cord blood or serum concentrations of mercury, lead, selenium and copper were measured with inductively coupled plasma mass spectrometry in a population of 300 infants born in Baltimore, Maryland. Geometric mean values were 1.37 µg/L (95% confidence interval: 1.27, 1.48) for mercury; 0.66 µg/dL (95% CI: 0.61, 0.71) for lead; and 38.62 µg/dL (95% CI: 36.73, 40.61) for copper. Mean selenium was 70.10 µg/L (95% CI: 68.69, 70.52). Mercury, selenium and copper levels were within exposure ranges reported among similar populations, whereas the distribution of lead levels was lower than prior reports; only one infant had a cord blood lead above 10 µg/dL. Levels of selenium were significantly correlated with concentrations of lead (Spearman's ρ=0.20) and copper (Spearman's ρ=0.51). Multivariable analyses identified a number of factors associated with one of more of these exposures. These included: increase in maternal age (increased lead); Asian mothers (increased mercury and lead, decreased selenium and copper); higher umbilical cord serum n-3 fatty acids (increased mercury, selenium and copper), mothers using Medicaid (increased lead); increasing gestational age (increased copper); increasing birthweight (increased selenium); older neighborhood housing stock (increased lead and selenium); and maternal smoking (increased lead). This work provides additional information about contemporary prenatal element exposures and can help identify groups at risk of atypical exposures.

Low-level lead exposure and elevations in blood pressure during pregnancy.

BACKGROUND: Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear. OBJECTIVES: Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy. METHODS: We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values. RESULTS: Geometric mean cord blood lead was 0.66 µg/dL (95% confidence interval, 0.61-0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51-12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21-8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83-13.60) and 8.33 (1.14-15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 µg/dL blood lead for all blood pressure end points. CONCLUSIONS: A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 µg/dL.