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1.  Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA Normative Aging Study 
Neurotoxicology  2013;35:154-161.
Background and Aims
Lead exposure in children and occupationally-exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally-exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure—as measured by lead in bone—and performance on the Grooved Pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS).
Methods
GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (sec) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome.
Results
The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7) μg/g and 19.2 (14.6) μg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (β per 15 μg/g bone = 4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (β per 20 μg/g = 3.93, 95% CI: 1.11, 6.76, p = 0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (β per 15 μg/g bone = 1.27, 95% CI: 0.24, 2.29, p = 0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption.
Conclusions
Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.
doi:10.1016/j.neuro.2013.01.005
PMCID: PMC3602137  PMID: 23370289
Grooved pegboard; lead; NAS; fine motor; visuomotor
2.  Cumulative Lead Exposure and Age at Menopause in the Nurses’ Health Study Cohort 
Environmental Health Perspectives  2014;122(3):229-234.
Background: Early menopause has been associated with many adverse health outcomes, including increased risk of cardiovascular disease morbidity and mortality. Lead has been found to be adversely associated with female reproductive function, but whether exposures experienced by the general population are associated with altered age at menopause has not been explored.
Objective: Our goal was to assess the association between cumulative lead exposure and age at natural menopause.
Methods: Self-reported menopausal status and bone lead concentration measured with K-shell X-ray fluorescence—a biomarker of cumulative lead exposure—were obtained from 434 women participants in the Nurses’ Health Study.
Results: The mean (± SD) age at natural menopause was 50.8 ± 3.6 years. Higher tibia lead level was associated with younger age at menopause. In adjusted analyses, the average age of menopause for women in the highest tertile of tibia lead was 1.21 years younger (95% CI: –2.08, –0.35) than for women in the lowest tertile (p-trend = 0.006). Although the number of cases was small (n = 23), the odds ratio for early menopause (< 45 years of age) was 5.30 (95% CI: 1.42, 19.78) for women in the highest tertile of tibia lead compared with those in the lowest tertile (p-trend = 0.006). There was no association between patella or blood lead and age at menopause.
Conclusions: Our results support an association between low-level cumulative lead exposure and an earlier age at menopause. These data suggest that low-level lead exposure may contribute to menopause-related health outcomes in older women through effects on age at menopause.
Citation: Eum KD, Weisskopf MG, Nie LH, Hu H, Korrick SA. 2014. Cumulative lead exposure and age at menopause in the Nurses’ Health Study Cohort. Environ Health Perspect 122:229–234; http://dx.doi.org/10.1289/ehp.1206399
doi:10.1289/ehp.1206399
PMCID: PMC3948024  PMID: 24398113
3.  Associations between Extreme Precipitation and Gastrointestinal-Related Hospital Admissions in Chennai, India 
Environmental Health Perspectives  2013;122(3):249-254.
Background: Understanding the potential links between extreme weather events and human health in India is important in the context of vulnerability and adaptation to climate change. Research exploring such linkages in India is sparse.
Objectives: We evaluated the association between extreme precipitation and gastrointestinal (GI) illness-related hospital admissions in Chennai, India, from 2004 to 2007.
Methods: Daily hospital admissions were extracted from two government hospitals in Chennai, India, and meteorological data were retrieved from the Chennai International Airport. We evaluated the association between extreme precipitation (≥ 90th percentile) and hospital admissions using generalized additive models. Both single-day and distributed lag models were explored over a 15-day period, controlling for apparent temperature, day of week, and long-term time trends. We used a stratified analysis to explore the association across age and season.
Results: Extreme precipitation was consistently associated with GI-related hospital admissions. The cumulative summary of risk ratios estimated for a 15-day period corresponding to an extreme event (relative to no precipitation) was 1.60 (95% CI: 1.29, 1.98) among all ages, 2.72 (95% CI: 1.25, 5.92) among the young (≤ 5 years of age), and 1.62 (95% CI: 0.97, 2.70) among the old (≥ 65 years of age). The association was stronger during the pre-monsoon season (March–May), with a cumulative risk ratio of 6.50 (95% CI: 2.22, 19.04) for all ages combined compared with other seasons.
Conclusions: Hospital admissions related to GI illness were positively associated with extreme precipitation in Chennai, India, with positive cumulative risk ratios for a 15-day period following an extreme event in all age groups. Projected changes in precipitation and extreme weather events suggest that climate change will have important implications for human health in India, where health disparities already exist.
Citation: Bush KF, O’Neill MS, Li S, Mukherjee B, Hu H, Ghosh S, Balakrishnan K. 2014. Associations between extreme precipitation and gastrointestinal-related hospital admissions in Chennai, India. Environ Health Perspect 122:249–254; http://dx.doi.org/10.1289/ehp.1306807
doi:10.1289/ehp.1306807
PMCID: PMC3948034  PMID: 24345350
4.  How Cumulative Risks Warrant A Shift In Our Approach To Racial Health Disparities: The Case of Lead, Stress, and Hypertension 
Health affairs (Project Hope)  2011;30(10):1895-1901.
Blacks have persistently higher rates of high blood pressure, or hypertension, compared to whites, resulting in higher health costs and greater mortality. Recent research has shown that social and environmental factors – such as high levels of stress and exposure to lead – may explain racial disparities in hypertension. Based on these findings, we recommend a fundamental shift in approaches to health disparities to focus on these sorts of cumulative risks and health effects. Federal and state agencies and research institutions should develop strategic plans to learn more about these connections and apply the broader findings to policies to improve health disparities.
doi:10.1377/hlthaff.2010.1241
PMCID: PMC3915245  PMID: 21976332
5.  Cumulative exposure to lead and cognition in persons with Parkinson’s disease 
Background
Dementia is an important consequence of Parkinson’s disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition.
Methods
Among 101 persons with PD (“cases”) and, separately, 50 persons without PD (“controls”), we evaluated cumulative lead exposure, gauged via tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status.
Results
After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analogue of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P=0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study who were about seven years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (Pdifference=0.06). Patella bone lead concentration was not consistently associated with performance on the tests.
Conclusions
These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.
doi:10.1002/mds.25247
PMCID: PMC3581753  PMID: 23143985
lead exposure; cognitive function; Parkinson’s disease
6.  A safe strategy to decrease fetal lead exposure in a woman with chronic intoxication 
During pregnancy skeletal lead is mobilized by maternal bone turnover and can threaten fetal development. The exact strategy suggested to women of childbearing age, who were chronically exposed to lead, and, thus, have high bone lead burden, is not well established. We describe 4 years of follow-up of a 29-year-old woman with chronic lead intoxication. We (a) advised her to delay conception until ‘toxicological clearance’, (b) treated her with multiple courses of lead chelator, DMSA, and (c) prescribed oral calcium. Patient had low blood lead and protoporphyrin level during pregnancy until delivery. Delaying conception, lead chelation, and calcium supplementation can decrease fetal exposure.
doi:10.3109/14767050903317708
PMCID: PMC3904658  PMID: 20459344
Lead; chelation; DMSA
7.  Maternal Blood, Plasma, and Breast Milk Lead: Lactational Transfer and Contribution to Infant Exposure 
Background: Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood.
Objectives: We explored the dose–response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant.
Methods: We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose–response relationships between blood, plasma, and milk lead levels.
Results: Maternal lead levels (mean ± SD) were as follows: blood: 7.7 ± 4.0 μg/dL; plasma: 0.1 ± 0.1 μg/L; milk: 0.8 ± 0.7 μg/L. The average M/P lead ratio was 7.7 (range, 0.6–39.8) with 97% of the ratios being > 1. The dose–response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function = 6.5, p = 0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 μg/L of plasma lead, respectively, below and above 0.1 μg/L plasma lead. Infant blood lead level (3.4 ± 2.2 μg/dL) increased by 1.8 μg/dL per 1 μg/L milk lead (p < 0.0001, R2 = 0.3).
Conclusions: The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.
Citation: Ettinger AS, Roy A, Amarasiriwardena CJ, Smith DR, Lupoli N, Mercado-García A, Lamadrid-Figueroa H, Tellez-Rojo MM, Hu H, Hernández-Avila M. 2014. Maternal blood, plasma, and breast milk lead: lactational transfer and contribution to infant exposure. Environ Health Perspect 122:87–92; http://dx.doi.org/10.1289/ehp.1307187
doi:10.1289/ehp.1307187
PMCID: PMC3888576  PMID: 24184948
8.  A Novel Look at Racial Health Disparities: The Interaction Between Social Disadvantage and Environmental Health 
American journal of public health  2012;102(12):10.2105/AJPH.2012.300774.
Objectives
We explored the notion that social disadvantage increases vulnerability to the health effects of environmental hazards. Specifically, we examined (1) whether race modifies the association between blood lead and blood pressure and (2) whether socioeconomic status (SES) plays a role in this modifying effect.
Methods
Using the National Health and Nutrition Examination Survey (2001–2008) and linear regression, we estimated the association between blood lead and blood pressure. Using interactions among race, SES, and lead, we estimated this association by levels of social disadvantage.
Results
Black men and women showed a 2.8 (P < .001) and 4.0 (P < .001) millimeters mercury increase in SBP, respectively, for each doubling of blood lead. White adults showed no association. This lead–SBP association exhibited by Blacks was primarily isolated to Blacks of low SES. For example, poor but not nonpoor Black men showed a 4.8 millimeters mercury (P < .001) increase in SBP for each doubling of blood lead.
Conclusions
Our results suggest that social disadvantage exacerbates the deleterious health effects of lead. Our work provides evidence that social and environmental factors must be addressed together to eliminate health disparities.
doi:10.2105/AJPH.2012.300774
PMCID: PMC3519308  PMID: 23078461
9.  Bone Lead and Endogenous Exposure in an Environmentally Exposed Elderly Population: the Normative Aging Study 
Objective
The objective of this study is to investigate the mobilization of lead from bone to blood (endogenous exposure) in a large epidemiologic population.
Methods
Study subjects were 776 participants in the Normative Aging Study. The subjects had their tibia lead, patella lead, blood lead, and/or urinary N-telopeptide (NTx) levels measured 1-4 times from 1991 to 2002. Regression models were estimated to quantify the association between tibia and patella lead and blood lead. We studied nonlinearity of the association, and explored possible factors that may modify it, including age and NTx levels.
Results and conclusions
There is significant association between bone lead and blood lead, and the association is non-linear. The non-linear associations between blood lead and bone lead are not significantly modified by age and NTx.
doi:10.1097/JOM.0b013e3181aa0106
PMCID: PMC3800179  PMID: 19528829
10.  Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children 
Neurotoxicology  2012;33(5):1040-1047.
Background
The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.
Objective
To draw inferences about windows of susceptibility using the pattern of associations between serial childhood blood lead (BPb) concentrations and children’s cognitive abilities at 4 years of age among 1035 mother–child pairs enrolled in 4 prospective birth cohorts from Mexico City.
Methods
Multiple longitudinally collected BPb measurements were obtained from children (1, 2, 3, and 4 years) between 1994 and 2007. Child cognitive abilities were assessed at 4 years using the general cognitive index (GCI) of the McCarthy Scales of Children’s Abilities. We used multivariable linear regression to estimate the change in cognitive abilities at 4 years of age with a 10 μg/dL increase in childhood BPb concentrations adjusting for maternal IQ, education, marital status, child sex, breastfeeding duration, and cohort.
Results
In separate models for each BPb measurement, 2 year BPb concentrations were most strongly associated with reduced GCI scores at 4 years after adjusting for confounders (β: −3.8; 95% confidence interval CI: −6.3, −1.4). Mutual adjustment for other BPb concentrations in a single model resulted in larger, but less precise estimate between 2 year BPb concentrations and GCI scores at 4 years of age (β: −7.1; 95% CI: −12, −2.0). The association between 2 year BPb and GCI was not heterogeneous (p = 0.89), but some BPb and GCI associations varied in magnitude and direction across the cohorts. Additional adjustment for child hemoglobin, birth weight, gestational age, gestational BPb concentrations, or test examiner did not change the pattern of associations.
Conclusions
Higher BPb concentrations at 2 years of age were most predictive of decreased cognitive abilities among these Mexico City children; however, the observed pattern may be due to exposure, outcome, or cohort related factors. These results may help developing countries more efficiently implement childhood Pb prevention strategies.
doi:10.1016/j.neuro.2012.04.022
PMCID: PMC3576696  PMID: 22579785
Lead; Children; Epidemiology; Cognitive abilities; Windows of development
11.  Forced Expiratory Volume in 1 Second and Cognitive Aging in Men 
OBJECTIVES
To evaluate forced expiratory volume in 1 second (FEV1, a measure of overall lung function), long-term average FEV1, and rate of decline in FEV1 in relation to cognition and cognitive decline in older men.
DESIGN
Prospective observational study.
SETTING
Community-based population.
PARTICIPANTS
Eight hundred sixty-four older men from the Normative Aging Study.
MEASUREMENTS
Starting in 1984, participants underwent triennial clinical evaluations. Lung function assessments provided estimates of FEV1. Cognitive assessments entailing tests of several cognitive abilities began in 1993. FEV1 measured approximately 12 years before baseline cognitive testing, average FEV1 over the 12-year period, and rate of change in FEV1 were all evaluated in relation to baseline and change in performance on the cognitive tests.
RESULTS
In multivariable-adjusted analyses, associations between FEV1 and baseline cognitive scores were mixed, although average FEV1 predicted significantly better performance on tests of visuospatial ability (P =.04) and general cognition (P =.03). Higher FEV1 was more consistently associated with slower cognitive decline, but only the association between historical FEV1 and attention was significant (difference per standard deviation in FEV1 = 0.056, P =.05). Rate of FEV1 decline was not consistently associated with cognitive function or decline. Findings were generally similar or stronger in men who had never smoked. To account for potential bias due to selective attrition, inverse probability of censoring weights were applied to the cognitive decline analyses, yielding slightly larger estimates; the inadequate prognostic power of the censoring models limited this approach.
CONCLUSION
Overall, the data provide limited evidence of an inverse association between FEV1 and cognitive aging.
doi:10.1111/j.1532-5415.2011.03487.x
PMCID: PMC3758858  PMID: 21718272
lung function; cognition; cognitive decline; epidemiology; aging
12.  Cadmium exposure and cardiovascular disease in the 2005 Korea National Health and Nutrition Examination Survey☆,☆☆ 
Environmental research  2010;111(1):171-176.
Background
Limited epidemiologic data are available concerning the cardiovascular effects of cadmium exposure, although recent studies suggest associations with myocardial infarction and peripheral arterial disease. We examined the associations of cadmium exposure with cardiovascular disease in nationally representative general Korean adults.
Methods
We used cross-sectional data on blood cadmium and self-reported diagnoses of ischemic heart disease (IHD), stroke, and hypertension in a sub-sample of 1908 adults, aged 20 years and older, who participated in the 2005 Korea National Health and Nutrition Examination Survey (KNHANES). We used survey logistic regression models accounting for the complex sampling design to estimate the odds ratios (OR), adjusting for age, education, income, alcohol, smoking, body mass index, waist circumference, family history of hypertension, blood pressure, and blood lead.
Results
The geometric mean of blood cadmium was 1.53 μg/L. After adjusting for potential confounders, an interquartile range (IQR) increase in blood cadmium (0.91 μg/L) was found to be associated with an increased risk for IHD (OR 2.1, 95% confidence interval (CI) 1.3–3.4). An IQR increase in blood cadmium was found to be associated with an elevated risk for hypertension only among men (OR 1.4, 95% CI 1.1–1.8) but not among women. No association was observed with stroke in both genders.
Conclusions
These findings suggest that cadmium in blood may be associated with an increased risk for IHD and hypertension in the general Korean adult population.
doi:10.1016/j.envres.2010.10.006
PMCID: PMC3683977  PMID: 21055738
Blood cadmium; Cardiovascular disease; Ischemic heart disease; Hypertension; KNHANES
13.  Windows of lead exposure sensitivity, attained height, and BMI at 48 months 
The Journal of Pediatrics  2012;160(6):1044-1049.
Objectives
To examine longitudinal association of prenatal, infancy, and early childhood lead exposure during sensitive periods with height and BMI.
Study design
The 773 participants were recruited between 1994 and 2005 in Mexico City. We constructed lead exposure history categories for prenatal (maternal patella lead), infancy and childhood periods (mean child blood lead between birth to 24 months and 30 to 48 months, respectively). Linear regression models were used to study lead exposure history with height and BMI at 48 months.
Results
Children with blood lead levels higher than the median during infancy attained a mean height at 48 months that was significantly shorter (−0.84 cm, 95% CI= −1.42 to −0.25) than children with levels lower than the median. Prenatal lead exposure was not associated with height at 48 months. Results for attained BMI were in general in the same direction as for height.
Conclusion
Our study suggests an effect of early life lead exposure on height attainment at 48 months with an exposure window of greatest sensitivity occurring in infancy.
doi:10.1016/j.jpeds.2011.12.022
PMCID: PMC3360798  PMID: 22284921
15.  An efficient sampling and inference procedure for studies with a continuous outcome 
Epidemiology (Cambridge, Mass.)  2007;18(4):461-468.
To characterize the relation between an exposure and a continuous outcome, the sampling of subjects can be done much as it is in a case-control study, such that the sample is enriched with subjects who are especially informative. In an outcome dependent sampling (ODS) design, observations made on a judiciously chosen subset of the base population can provide nearly the same statistical efficiency as observing the entire base population. Reaping the benefits of such sampling, however, requires use of an analysis that accounts for the ODS design. In this report, the authors examined the statistical efficiency of a plain random sample analyzed with standard methods, compared with that of data collected with an ODS design and analyzed by either of two appropriate methods. In addition, three real datasets were analyzed using an ODS approach. The results demonstrate the improved statistical efficiency obtained by using an ODS approach and its applicability in a wide range of settings. An ODS design, coupled with an appropriate analysis, can offer a cost-efficient approach to studying the determinants of a continuous outcome.
doi:10.1097/EDE.0b013e31806462d3
PMCID: PMC3664946  PMID: 17568219
biased sampling; continuous outcome; empirical likelihood; epidemiologic methods; epidemiologic research design; semiparametric
16.  Interaction of the δ-aminolevulinic acid dehydratase (ALAD) polymorphism and lead burden on cognitive function: the VA Normative Aging Study 
Objective
We evaluated the modifying influence of a δ-aminolevulinic acid dehydratase (ALAD) polymorphism on the relation between lead burden and cognition among older men.
Methods
Information on ALAD genotype, lead measurements, potential confounders, and cognitive testing was collected from 982 participants. For each cognitive test and lead biomarker, we fit separate multiple linear regression models which included an interaction term for ALAD genotype and the lead biomarker, and adjusted for potential confounders.
Results
With higher levels of tibia lead, ALAD 1-2/2-2 carriers exhibited worse performance on a spatial copying test in comparison with ALAD 1-1 carriers (pinteraction=0.03). However, there was no consistent pattern of an ALAD genotype-lead interaction for the other tests.
Conclusions
The results provide some evidence that ALAD genotype modifies the relation between lead burden and cognition among older men with low lead burden, particularly for cognitive domains sensitive to the effects of cumulative lead burden.
doi:10.1097/JOM.0b013e3181792463
PMCID: PMC3664949  PMID: 18784554
blood; bone and blood; lead; environmental; polymorphism; genetic; cognition; neuropsychological tests
17.  Genome-Wide DNA Methylation Differences Between Late-Onset Alzheimer’s Disease and Cognitively Normal Controls in Human Frontal Cortex 
Journal of Alzheimer's disease : JAD  2012;29(3):10.3233/JAD-2012-111223.
Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer’s disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-β protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets.
doi:10.3233/JAD-2012-111223
PMCID: PMC3652332  PMID: 22451312
DNA methylation; epigenetics; late onset Alzheimer’s disease; prefrontal cortex
18.  Association between urinary 3, 5, 6-trichloro-2-pyridinol, a metabolite of chlorpyrifos and chlorpyrifos-methyl, and serum T4 and TSH in NHANES 1999–2002 
Thyroid hormones are vital to a host of human physiological functions in both children and adults. Exposures to chemicals, including chlorpyrifos, have been found to modify thyroid signaling at environmentally relevant levels in animal studies. The aim of this study was to examine circulating T4 and TSH levels in relation to urinary concentrations of 3, 5, 6-trichloro-2-pyridinol (TCPY), a metabolite of the organophosphorus insecticides chlorpyrifos and chlorpyrifos-methyl, using data from individuals 12 years and older from the U.S. National Health and Nutrition Examination Surveys (NHANES). NHANES datasets from 1999–2000 and 2001–2002 were combined, and individuals with thyroid disease, those taking thyroid medications, and pregnant women were excluded (N=3249). Multivariable linear regression models for relationships between log-transformed urinary TCPY and serum total T4 or log (TSH) were constructed adjusting for important covariates. Models were stratified by sex and a categorical age variable (12–18, 18–40, 40–60, and >60 years). In male participants, an interquartile range (IQR) increase in urinary TCPY was associated with statistically significant increases in serum T4 of 3.8% (95th CI 0.75 to 7.0)among those 12–18 years of age and 3.5% (95th CI 0.13 to 7.0) in the 18–40 year age group., relative to median T4 levels using unweighted models. An IQR increase in TCPY was also associated with decreases in TSH of 10.7% (−18.7–2.05) among men 18–40 years old and 20.0% (95th CI −28.9 to −9.86) among men >60 years old. Conversely, urinary TCPY was positively associated with TSH in females >60 years of age. Further research to confirm these findings, elucidate mechanisms of action, and explore the clinical and public health significance of such alterations in thyroid hormones is needed.
doi:10.1016/j.scitotenv.2012.02.039
PMCID: PMC3327766  PMID: 22425279
Biomarker; Endocrine Disruption; Exposure; Pesticides; Human
19.  Alzheimer’s Disease and Environmental Exposure to Lead: The Epidemiologic Evidence and Potential Role of Epigenetics 
Current Alzheimer research  2012;9(5):563-573.
Several lines of evidence indicate that the etiology of late-onset Alzheimer’s disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer’s disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.
PMCID: PMC3567843  PMID: 22272628
DNA methylation; epigenetics; epidemiology; Late-onset Alzheimer’s disease; lead exposure; Pb
20.  Black–White Blood Pressure Disparities: Depressive Symptoms and Differential Vulnerability to Blood Lead 
Environmental Health Perspectives  2012;121(2):205-209.
Background: Blacks have higher hypertension rates than whites, but the reasons for these disparities are unknown. Differential vulnerability, through which stress alters vulnerability to the effects of environmental hazards, is an emergent notion in environmental health that may contribute to these disparities.
Objectives: We examined whether blacks and whites exhibit different associations between blood lead (BPb) and blood pressure (BP) and whether depressive symptoms may play a role.
Methods: Using the National Health and Nutrition Examination Survey 2005–2008, we regressed BP on the three-way interaction among race/ethnicity, BPb, and depressive symptoms in blacks and whites ≥ 20 years of age.
Results: Blacks but not whites showed a positive association between BPb and systolic blood pressure (SBP). The disparity in this association between blacks and whites appeared to be specific to the high depressive symptoms group. In the low depressive symptoms group, there was no significant black–white disparity (βinteraction = 0.9 mmHg; 95% CI: –0.9, 2.7). However, of those with high depressive symptoms, blacks and whites had 5.6 mmHg (95% CI: 2.0, 9.2) and 1.2 mmHg (95% CI: –0.5, 2.9) increases in SBP, respectively, in association with each doubling of BPb (βinteraction = 4.4 mmHg; 95% CI: 0.5, 8.3). The pattern of results was similar for diastolic blood pressure.
Conclusions: Our results suggest that depressive symptoms may contribute to the black–white disparity in the association between BPb and BP. Depressive symptoms may result, in part, from psychosocial stress. Our results support the notion that stress increases vulnerability to the health effects of environmental hazards and suggest that stress-related vulnerability may be an important determinant of racial/ethnic health disparities.
doi:10.1289/ehp.1104517
PMCID: PMC3569674  PMID: 23127977
African Americans; depressive symptoms; health status disparities; hypertension; lead; psychosocial stress
22.  Personal characteristics related to the risk of adolescent internet addiction: a survey in Shanghai, China 
BMC Public Health  2012;12:1106.
Background
Paralleling the rapid growth in computers and internet connections, adolescent internet addiction (AIA) is becoming an increasingly serious problem, especially in developing countries. This study aims to explore the prevalence of AIA and associated symptoms in a large population-based sample in Shanghai and identify potential predictors related to personal characteristics.
Methods
In 2007, 5,122 adolescents were randomly chosen from 16 high schools of different school types (junior, senior key, senior ordinary and senior vocational) in Shanghai with stratified-random sampling. Each student completed a self-administered and anonymous questionnaire that included DRM 52 Scale of Internet-use. The DRM 52 Scale was adapted for use in Shanghai from Young’s Internet Addiction Scale and contained 7 subscales related to psychological symptoms of AIA. Multiple linear regression and logistic regression were both used to analyze the data.
Results
Of the 5,122 students, 449 (8.8%) were identified as internet addicts. Although adolescents who had bad (vs. good) academic achievement had lower levels of internet-use (p < 0.0001), they were more likely to develop AIA (odds ratio 4.79, 95% CI: 2.51-9.73, p < 0.0001) and have psychological symptoms in 6 of the 7 subscales (not in Time-consuming subscale). The likelihood of AIA was higher among those adolescents who were male, senior high school students, or had monthly spending >100 RMB (all p-values <0.05). Adolescents tended to develop AIA and show symptoms in all subscales when they spent more hours online weekly (however, more internet addicts overused internet on weekends than on weekdays, p < 0.0001) or when they used the internet mainly for playing games or real-time chatting.
Conclusions
This study provides evidence that adolescent personal factors play key roles in inducing AIA. Adolescents having aforementioned personal characteristics and online behaviors are at high-risk of developing AIA that may compound different psychological symptoms associated with AIA. Spending excessive time online is not in itself a defining symptom of AIA. More attention is needed on adolescent excessive weekend internet-use in prevention of potential internet addicts.
doi:10.1186/1471-2458-12-1106
PMCID: PMC3563549  PMID: 23259906
Adolescent; Internet addiction; Risk factors; China
23.  Childhood and Adult Socioeconomic Position, Cumulative Lead Levels, and Pessimism in Later Life 
American Journal of Epidemiology  2011;174(12):1345-1353.
Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age.
doi:10.1093/aje/kwr269
PMCID: PMC3276297  PMID: 22071587
depression; lead; metals; orientation; psychology; socioeconomic factors
24.  Environmental Cadmium and Lead Exposures and Hearing Loss in U.S. Adults: The National Health and Nutrition Examination Survey, 1999 to 2004 
Environmental Health Perspectives  2012;120(11):1544-1550.
Background: Although cadmium and lead are known risk factors for hearing loss in animal models, few epidemiologic studies have been conducted on their associations with hearing ability in the general population.
Objectives: We investigated the associations between blood cadmium and lead exposure and hearing loss in the U.S. general population while controlling for noise and other major risk factors contributing to hearing loss.
Methods: We analyzed data from 3,698 U.S. adults 20–69 years of age who had been randomly assigned to the National Health and Nutrition Examination Survey (NHANES) 1999–2004 Audiometry Examination Component. Pure-tone averages (PTA) of hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz were computed, and hearing loss was defined as a PTA > 25 dB in either ear.
Results: The weighted geometric means of blood cadmium and lead were 0.40 [95% confidence interval (CI): 0.39. 0.42] µg/L and 1.54 (95% CI: 1.49, 1.60) µg/dL, respectively. After adjusting for sociodemographic and clinical risk factors and exposure to occupational and nonoccupational noise, the highest (vs. lowest) quintiles of cadmium and lead were associated with 13.8% (95% CI: 4.6%, 23.8%) and 18.6% (95% CI: 7.4%, 31.1%) increases in PTA, respectively (p-trends < 0.05).
Conclusions: Our results suggest that low-level exposure to cadmium and lead found in the general U.S. population may be important risk factors for hearing loss. The findings support efforts to reduce environmental cadmium and lead exposures.
doi:10.1289/ehp.1104863
PMCID: PMC3556613  PMID: 22851306
cadmium; epidemiology; hearing; lead; NHANES
25.  A dopamine receptor (DRD2) but not dopamine transporter (DAT1) gene polymorphism is associated with neurocognitive development of Mexican preschool children with lead exposure 
The Journal of pediatrics  2011;159(4):638-643.
Objective
To investigate the effects of pre- and postnatal lead exposure and polymorphisms in dopamine metabolism genes on neurocognitive development of Mexican children at 24 (n=220) and 48 months (n=186) of age.
Study design
We genotyped the dopamine transporter gene (DAT1; SLC6A3) variable nucleotide tandem repeat, and the dopamine receptor D2 (DRD2) Taq 1A single nucleotide polymorphism. Children were assessed at 24 mo with Bayley Scales of Infant Development (MDI, PDI) and at 48 mo with McCarthy Scales of Children’s Abilities.
Results
Lead concentration (BLL) in umbilical cord was 6.6±3.3 μg/dL (measured in 1995-96), 8.1±4.4 μg/dL at 24, and 8.1±3.6 μg/dL at 48 months. Cord BLL was negatively associated with MDI (p<0.01) and PDI (p<0.1) but not McCarthy scores. The 48- but not 24-month BLL was negatively associated with children’s scores. Children with DRD2 TT genotype (variant) scored higher than those with CC genotype (wild type) on MDI and McCarthy memory scale. Neither polymorphism modified the relationship between BLL (either pre or post-natal) and neurocognitive development.
Conclusion
Lead exposure was adversely, whereas the DRD2 Taq 1A TT variant was positively associated with neurocognitive measures. We found no evidence of gene-environment interactions on developmental outcomes in early childhood.
doi:10.1016/j.jpeds.2011.03.043
PMCID: PMC3158955  PMID: 21592505
Cord blood lead; postnatal lead exposure; DAT1; DRD2; gene polymorphisms; Mexico; child development

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