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1.  Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function 
Neurotoxicology  2013;0:10.1016/j.neuro.2013.08.002.
Background
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.
Methods
We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.
Results
A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.
Conclusion
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
doi:10.1016/j.neuro.2013.08.002
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
2.  Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study 
Environmental Health  2014;13(1):77.
Background
Given the relationship between iron metabolism and lead toxicokinetics, we hypothesized that polymorphisms in iron metabolism genes might modify maternal-fetal lead transfer. The objective of this study was to determine whether maternal and/or infant transferrin (TF) and hemochromatosis (HFE) gene missense variants modify the association between maternal blood lead (MBL) and umbilical cord blood lead (UCBL).
Methods
We studied 476 mother-infant pairs whose archived blood specimens were genotyped for TF P570S, HFE H63D and HFE C282Y. MBL and UCBL were collected within 12 hours of delivery. Linear regression models were used to examine the association between log-transformed MBL and UCBL, examine for confounding and collinearity, and explore gene-environment interactions.
Results
The geometric mean MBL was 0.61 μg/dL (range 0.03, 3.2) and UCBL 0.42 (<0.02, 3.9). Gene variants were common with carrier frequencies ranging from 12-31%; all were in Hardy-Weinberg equilibrium. In an adjusted linear regression model, log MBL was associated with log UCBL (β = 0.92, 95% CI: 0.82, 1.03; p < 0.01) such that a 1% increase in MBL was associated with a 0.92% increase in UCBL among infants born to wild-type mothers. In infants born to C282Y variants, however, a 1% increase in MBL is predicted to increase UCBL 0.65% (βMain Effect = −0.002, 95% CI: −0.09, −0.09; p = 0.97; βInteraction = −0.27, 95% CI: −0.52, −0.01; p = 0.04), representing a 35% lower placental lead transfer among women with MBL 5 μg/dL.
Conclusions
Maternal HFE C282Y gene variant status is associated with greater reductions in placental transfer of lead as MBL increases. The inclusion of gene-environment interaction in risk assessment models may improve efforts to safeguard vulnerable populations.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-77) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-069X-13-77
PMCID: PMC4271345  PMID: 25287020
Hemochromatosis gene; C282Y; H63D; Lead; Pediatric; Polymorphism; Prenatal; P570S; Transferrin gene
3.  Lead Exposure, B Vitamins, and Plasma Homocysteine in Men 55 Years of Age and Older: The VA Normative Aging Study 
Environmental Health Perspectives  2014;122(10):1066-1074.
Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors.
Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism.
Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12.
Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: –0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes.
Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.
Citation: Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A III, Vokonas PS, Nie LH, Hu H, Weuve J. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA Normative Aging Study. Environ Health Perspect 122:1066–1074; http://dx.doi.org/10.1289/ehp.1306931
doi:10.1289/ehp.1306931
PMCID: PMC4181916  PMID: 24905780
4.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 
Lim, Stephen S | Vos, Theo | Flaxman, Abraham D | Danaei, Goodarz | Shibuya, Kenji | Adair-Rohani, Heather | Amann, Markus | Anderson, H Ross | Andrews, Kathryn G | Aryee, Martin | Atkinson, Charles | Bacchus, Loraine J | Bahalim, Adil N | Balakrishnan, Kalpana | Balmes, John | Barker-Collo, Suzanne | Baxter, Amanda | Bell, Michelle L | Blore, Jed D | Blyth, Fiona | Bonner, Carissa | Borges, Guilherme | Bourne, Rupert | Boussinesq, Michel | Brauer, Michael | Brooks, Peter | Bruce, Nigel G | Brunekreef, Bert | Bryan-Hancock, Claire | Bucello, Chiara | Buchbinder, Rachelle | Bull, Fiona | Burnett, Richard T | Byers, Tim E | Calabria, Bianca | Carapetis, Jonathan | Carnahan, Emily | Chafe, Zoe | Charlson, Fiona | Chen, Honglei | Chen, Jian Shen | Cheng, Andrew Tai-Ann | Child, Jennifer Christine | Cohen, Aaron | Colson, K Ellicott | Cowie, Benjamin C | Darby, Sarah | Darling, Susan | Davis, Adrian | Degenhardt, Louisa | Dentener, Frank | Des Jarlais, Don C | Devries, Karen | Dherani, Mukesh | Ding, Eric L | Dorsey, E Ray | Driscoll, Tim | Edmond, Karen | Ali, Suad Eltahir | Engell, Rebecca E | Erwin, Patricia J | Fahimi, Saman | Falder, Gail | Farzadfar, Farshad | Ferrari, Alize | Finucane, Mariel M | Flaxman, Seth | Fowkes, Francis Gerry R | Freedman, Greg | Freeman, Michael K | Gakidou, Emmanuela | Ghosh, Santu | Giovannucci, Edward | Gmel, Gerhard | Graham, Kathryn | Grainger, Rebecca | Grant, Bridget | Gunnell, David | Gutierrez, Hialy R | Hall, Wayne | Hoek, Hans W | Hogan, Anthony | Hosgood, H Dean | Hoy, Damian | Hu, Howard | Hubbell, Bryan J | Hutchings, Sally J | Ibeanusi, Sydney E | Jacklyn, Gemma L | Jasrasaria, Rashmi | Jonas, Jost B | Kan, Haidong | Kanis, John A | Kassebaum, Nicholas | Kawakami, Norito | Khang, Young-Ho | Khatibzadeh, Shahab | Khoo, Jon-Paul | Kok, Cindy | Laden, Francine | Lalloo, Ratilal | Lan, Qing | Lathlean, Tim | Leasher, Janet L | Leigh, James | Li, Yang | Lin, John Kent | Lipshultz, Steven E | London, Stephanie | Lozano, Rafael | Lu, Yuan | Mak, Joelle | Malekzadeh, Reza | Mallinger, Leslie | Marcenes, Wagner | March, Lyn | Marks, Robin | Martin, Randall | McGale, Paul | McGrath, John | Mehta, Sumi | Mensah, George A | Merriman, Tony R | Micha, Renata | Michaud, Catherine | Mishra, Vinod | Hanafiah, Khayriyyah Mohd | Mokdad, Ali A | Morawska, Lidia | Mozaff arian, Dariush | Murphy, Tasha | Naghavi, Mohsen | Neal, Bruce | Nelson, Paul K | Nolla, Joan Miquel | Norman, Rosana | Olives, Casey | Omer, Saad B | Orchard, Jessica | Osborne, Richard | Ostro, Bart | Page, Andrew | Pandey, Kiran D | Parry, Charles D H | Passmore, Erin | Patra, Jayadeep | Pearce, Neil | Pelizzari, Pamela M | Petzold, Max | Phillips, Michael R | Pope, Dan | Pope III, C Arden | Powles, John | Rao, Mayuree | Razavi, Homie | Rehfuess, Eva A | Rehm, Jürgen T | Ritz, Beate | Rivara, Frederick P | Roberts, Thomas | Robinson, Carolyn | Rodriguez-Portales, Jose A | Romieu, Isabelle | Room, Robin | Rosenfeld, Lisa C | Roy, Ananya | Rushton, Lesley | Salomon, Joshua A | Sampson, Uchechukwu | Sanchez-Riera, Lidia | Sanman, Ella | Sapkota, Amir | Seedat, Soraya | Shi, Peilin | Shield, Kevin | Shivakoti, Rupak | Singh, Gitanjali M | Sleet, David A | Smith, Emma | Smith, Kirk R | Stapelberg, Nicolas J C | Steenland, Kyle | Stöckl, Heidi | Stovner, Lars Jacob | Straif, Kurt | Straney, Lahn | Thurston, George D | Tran, Jimmy H | Van Dingenen, Rita | van Donkelaar, Aaron | Veerman, J Lennert | Vijayakumar, Lakshmi | Weintraub, Robert | Weissman, Myrna M | White, Richard A | Whiteford, Harvey | Wiersma, Steven T | Wilkinson, James D | Williams, Hywel C | Williams, Warwick | Wilson, Nicholas | Woolf, Anthony D | Yip, Paul | Zielinski, Jan M | Lopez, Alan D | Murray, Christopher J L | Ezzati, Majid
Lancet  2012;380(9859):2224-2260.
Summary
Background
Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.
Methods
We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.
Findings
In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.
Interpretation
Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(12)61766-8
PMCID: PMC4156511  PMID: 23245609
5.  Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age 
Background
Previous studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life.
Objectives
To evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24-36 months of age.
Methods
This analysis was conducted on the first three years of life among a subsample of 136 mother-child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di-2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36 months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level.
Results
No significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (β = −2.11 [95% CI: −3.73, −0.49]), MEHHP (β = −1.89 [95% CI: −3.64, −0.15]), MEOHP (β = −1.80 [95% CI: −3.58, −0.03]) MECPP (β = −2.52 [95% CI: −4.44, −0.61]), and DEHP (β = −3.41 [95% CI: −5.26, −1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (β = 1.79 [95% CI: 0.14, 3.45]) and MCPP (β = 1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls.
Conclusion
This study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment.
doi:10.1016/j.scitotenv.2013.05.021
PMCID: PMC3735862  PMID: 23747553
Prenatal Exposure; Biomarkers; Phthalates; Child Development; Longitudinal Study
6.  Effect modification by Transferrin C2 polymorphism on lead exposure, hemoglobin levels, and IQ 
Neurotoxicology  2013;38:17-22.
Background
Iron deficiency and lead exposure remain significant public health issues in many parts of the world and are both independently associated with neurocognitive deficits. Polymorphisms in iron transport pathways have been shown to modify the absorption and toxicity of lead.
Objective
We hypothesized that the transferrin (TF) C2 polymorphism modifies the effects of lead and hemoglobin on intelligence.
Methods
Children aged 3–7 years (N=708) were enrolled from 12 primary schools in Chennai, India. The Binet-Kamat Scale of Intelligence were administered to ascertain intelligence quotient (IQ). Venous blood was analyzed for lead and hemoglobin levels. Genotyping for the TF C2 polymorphism (rs1049296) was carried out using a MassARRAY iPLEXTM platform. Stratified analyses and interaction models, using generalized estimating equations, were examined to explore interactions between lead, hemoglobin, and TF C2 categories.
Results
A one-unit increase in log blood lead and 1 g/dl higher hemoglobin was associated with −7.7 (95% CI: −13.6, −1.8) and 1.7 (95% CI 1.4, 2.1) IQ points, respectively, among children carrying the C2 variant. In comparison, among children who had the homozygous wildtype allele, the same increment of lead and hemoglobin were associated with -−2.1(95% CI: −6.5, 2.4) and 2.8(95% CI:1.5, 4.0) IQ points, respectively. There was a significant interaction between lead (p=0.04) and hemoglobin (p=0.07) with the C2 variant.
Conclusion
Children who carry the TF C2 variant may be more susceptible to the neurotoxic effects of lead exposure and less protected by higher levels of hemoglobin.
doi:10.1016/j.neuro.2013.05.005
PMCID: PMC3770761  PMID: 23732512
lead; hemoglobin; iron; transferrin; intelligence quotient (IQ); genotype
7.  Lead Exposure and Fear-Potentiated Startle in the VA Normative Aging Study: A Pilot Study of a Novel Physiological Approach to Investigating Neurotoxicant Effects 
Background
Physiologically-based indicators of neural plasticity in humans could provide mechanistic insights into toxicant actions on learning in the brain, and perhaps prove more objective and sensitive measures of such effects than other methods.
Objectives
We explored the association between lead exposure and classical conditioning of the acoustic startle reflex (ASR)—a simple form of associative learning in the brain—in a population of elderly men. Fifty-one men from the VA Normative Aging Study with cumulative bone lead exposure measurements made with K-X-Ray-Fluorescence participated in a fear-conditioning protocol.
Results
The mean age of the men was 75.5 years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.7μg/g bone (sd=15.9). Baseline ASR eyeblink response decreased with age, but was not associated with subsequent conditioning. Among 37 men with valid responses at the end of the protocol, higher patella lead was associated with decreased awareness of the conditioning contingency (declarative learning; adjusted odds ratio [OR] per 20 μg/g patella lead=0.91, 95% confidence interval [CI]: 0.84, 0.99, p=0.03). Eyeblink conditioning (non-declarative learning) was 0.44sd less (95% CI:−0.91, 0.02; p=0.06) per 20 μg/g patella lead after adjustment. Each result was stronger when correcting for the interval between lead measurement and startle testing (awareness: OR=0.88, 95% CI: 0.78, 0.99, p = 0.04; conditioning: −0.79sd less, 95% CI: −1.56, 0.03, p = 0.04).
Conclusions
This initial exploration suggests that lead exposure interferes with specific neural mechanisms of learning and offers the possibility that the ASR may provide a new approach to physiologically explore the effects of neurotoxicant exposures on neural mechanisms of learning in humans with a paradigm that is directly comparable to animal models.
doi:10.1016/j.ntt.2013.04.003
PMCID: PMC3774537  PMID: 23603705
lead; aging; acoustic startle response; psychophysiology; behavioral toxicology
8.  Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study 
Environmental Health  2014;13:50.
Background
Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City.
Methods
From 2007–11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers’ tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14–35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope.
Results
After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: −13%; Confidence Interval [CI]: −24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: −2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC.
Conclusions
Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy.
doi:10.1186/1476-069X-13-50
PMCID: PMC4068833  PMID: 24916609
Lead; Cortisol; Epidemiology; Pregnancy
9.  Determining Prenatal, Early Childhood and Cumulative Long-Term Lead Exposure Using Micro-Spatial Deciduous Dentine Levels 
PLoS ONE  2014;9(5):e97805.
The aim of this study was to assess the validity of micro-spatial dentine lead (Pb) levels as a biomarker for accurately estimating exposure timing over the prenatal and early childhood periods and long-term cumulative exposure to Pb. In a prospective pregnancy cohort sub-sample of 85 subjects, we compared dentine Pb levels measured using laser ablation-inductively coupled plasma mass spectrometry with Pb concentrations in maternal blood collected in the second and third trimesters, maternal bone, umbilical cord blood, and childhood serial blood samples collected from the ages of 3 months to ≥6 years. We found that Pb levels (as 208Pb:43Ca) in dentine formed at birth were significantly associated with cord blood Pb (Spearman ρ = 0.69; n = 27; p<0.0001). The association of prenatal dentine Pb with maternal patella Pb (Spearman ρ = 0.48; n = 59; p<0.0001) was stronger than that observed for tibia Pb levels (Spearman ρ = 0.35; n = 41; p<0.03). When assessing postnatal exposure, we found that Pb levels in dentine formed at 3 months were significantly associated with Pb concentrations in children’s blood collected concurrently (Spearman ρ = 0.64; n = 55; p<0.0001). We also found that mean Pb concentrations in secondary dentine (that is formed from root completion to tooth shedding) correlated positively with cumulative blood lead index (Spearman ρ = 0.38; n = 75; p<0.0007). Overall, our results support that micro-spatial measurements of Pb in dentine can be reliably used to reconstruct Pb exposure timing over the prenatal and early childhood periods, and secondary dentine holds the potential to estimate long-term exposure up to the time the tooth is shed.
doi:10.1371/journal.pone.0097805
PMCID: PMC4026445  PMID: 24841926
10.  Comparison of digestion procedures and methods for quantification of trace lead in breast milk by isotope dilution inductively coupled plasma mass spectrometry 
Measurement of lead in breast milk is an important public health consideration and can be technically quite challenging. The reliable and accurate determination of trace lead in human breast milk is difficult for several reasons including: potential for contamination during sample collection, storage, and analysis; complexities related to the high fat content of human milk; and poor analytic sensitivity at low concentrations. Breast milk lead levels from previous published studies should therefore be reviewed with caution. Due to the difficulty in identifying a method that would successfully digest samples with 100% efficiency, we evaluated three different digestion procedures including: (1) dry ashing in a muffle furnace, (2) microwave oven digestion, and (3) digestion in high pressure asher. High temperature, high pressure asher digestion was selected as the procedure of choice for the breast milk samples. Trace lead analysis was performed using isotope dilution (ID) inductively coupled plasma mass spectrometry (ICP-MS). Measured lead concentrations in breast milk samples (n = 200) from Mexico ranged from 0.2 to 6.7 ng ml−1. The precision for these measurements ranged from 0.27–7.8% RSD. Use of strict contamination control techniques and of a very powerful digestion procedure, along with an ID-ICP-MS method for lead determination, enables us to measure trace lead levels as low as 0.2 ng ml−1 in milk (instrument detection limit = 0.01 ng ml−1).
doi:10.1039/C3AY26321E
PMCID: PMC4010228  PMID: 24808927
11.  Parent-adolescent interaction and risk of adolescent internet addiction: a population-based study in Shanghai 
BMC Psychiatry  2014;14:112.
Background
Family-based intervention is essential for adolescents with behavioral problems. However, limited data are available on the relationship between family-based factors and adolescent internet addiction (AIA). We aimed to examine this relationship using a representative sample of Shanghai adolescents.
Methods
In October 2007, a total of 5122 adolescents were investigated from 16 high schools via stratified-random sampling in Shanghai. Self-reported and anonymous questionnaires were used to assess parent-adolescent interaction and family environments. AIA was assessed by DRM-52 Scale, developed from Young’s Internet-addiction Scale, using seven subscales to evaluate psychological symptoms of AIA.
Results
Adjusting for adolescents’ ages, genders, socio-economic status, school performances and levels of the consumption expenditure, strong parental disapproval of internet-use was associated with AIA (vs. parental approval, OR = 2.20, 95% CI: 1.24-3.91). Worse mother-adolescent relationships were more significantly associated with AIA (OR = 3.79, 95% CI: 2.22-6.48) than worse father-adolescent relationships (OR = 1.76, 95% CI: 1.10-2.80). Marital status of “married-but-separated” and family structure of “left-behind adolescents” were associated with symptoms of some subscales. When having high monthly allowance, resident students tended to develop AIA but commuter students did not. Family social-economic status was not associated with the development of AIA.
Conclusions
The quality of parent-adolescent relationship/communication was closely associated with the development of AIA, and maternal factors were more significantly associated with development of AIA than paternal factors. Family social-economic status moderated adolescent internet-use levels but not the development of AIA.
doi:10.1186/1471-244X-14-112
PMCID: PMC3999889  PMID: 24731648
Adolescents; Internet addiction; Mother-child relations; Father-child relations; China; Marital status; Family structure
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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

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