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Lead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy.To assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles.We measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally.Mothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity.Weekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Background: Exposure to lead (Pb) during the early life stages has been associated with the development of metabolic syndrome (MetS). Longitudinal studies of Pb exposure in critical developmental windows in children are limited.Methods: Our study included 601 mother–child dyads from the PROGRESS (Programming Research in Obesity, Growth, Environment and Social Stressors) birth cohort. Blood lead levels (BLLs) were assessed during the second and third gestational trimesters, in cord blood at delivery, and at ages 1, 2, and 4 years. Bone lead levels in the patella and tibia were assessed at 1 month postpartum and evaluated in separate models. To account for cumulative exposure (prenatal, postnatal, and cumulative), we dichotomized the BLLs at each stage visit and determined the following: “higher” if a BLL was at least once above the median (HPb) and “lower” if all BLLs were below the median (LPb). We analyzed fasting glucose, HbA1c, triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (cHDL), low-density lipoprotein cholesterol (cLDL), body mass index, waist circumference (WC), body fat percentage, and systolic (SBP) and diastolic blood pressure (DBP) at two study visits between 6 and 12 years of age and created cutoff points based on the clinical guidelines for each indicator. Mixed effects models were used to analyze each outcome longitudinally for each BLL score, adjusting for child's sex, size for gestational age, child's age, maternal parity, mother's age, and socioeconomic status.Results: We observed associations for HPb exposure and TC in all stages (OR = 0.53, 95%CI = 0.32–0.86) and postnatally (OR = 0.59, 95%CI = 0.36–0.94) and for prenatal HPb and TGs (OR = 0.65, 95%CI = 0.44–0.95). HPb at all stages was associated with WC (OR = 0.27, 95%CI = 0.08–0.86), BMI (OR = 0.33, 95%CI = 0.11–0.99), SBP (OR = 0.53, 95%CI = 0.32–0.85), and DBP (OR = 0.57, 95%CI = 0.34–0.95). Pb levels in the patella were associated with cHDL (OR = 1.03, 95%CI = 1.00–1.07) and those in the tibia with TGs (OR = 0.95, 95%CI = 0.91–0.99).Conclusion: Early life exposure to Pb may alter early indicators of MetS. A follow-up of these children will allow for more definition on the impact of longer-term exposures.

Background: Previous studies have examined the association between blood lead levels and pubertal timing in adolescent girls; however, the evidence is lacking on the role of lead exposure during sensitive developmental periods on sexual maturation. Objectives: To examine the association of prenatal and early childhood lead exposure with pubertal stages among 264 boys and 283 girls aged 9.8–18.0 years in Mexico City. Methods: We measured maternal bone lead (a proxy for cumulative fetal exposure to lead from maternal bone stores mobilized during pregnancy) at 1 month postpartum. Blood lead was measured annually from 1 to 4 years. Pubertal stage was assessed by a pediatrician. We examined the association between lead and pubertal stages of breast, pubic hair and genitalia using ordinal regression. Age at menarche was evaluated using Cox proportional-hazard models. Results: Multivariate models showed that maternal patella lead and early childhood blood lead were inversely associated with breast growth (patella OR = 0.72, 95% CI: 0.51–1.00; blood OR = 0.70, 95% CI: 0.53–0.93) in girls. Girls with maternal patella lead in the 3rd tertile and child blood lead in the 2nd tertile had a later age at menarche compared with girls in the 1st tertile (patella HR = 0.60, 95% CI: 0.41–0.88; blood HR = 0.65, 95% CI 0.46–0.91). Additionally, early childhood blood lead was negatively associated with pubic hair growth (OR = 0.68, 95% CI: 0.51–0.90) in girls. No associations were found in boys. Conclusions: These data suggest that higher prenatal and early childhood exposure to lead may be associated with delayed pubertal development in girls but not boys. Our findings are consistent with previous analyses and reinforce the reproductive effects of lead for girls. Keywords: Bone lead, Blood lead, Pregnancy, Early childhood, Puberty, Age at menarche

Background: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles. Objective: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11–18 years of age. Methods: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n=144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction. Results: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43±5.16μg/dL in Trimester 1 (T1), 5.66±5.21μg/dL in Trimester 2 (T2), and 5.86±4.34μg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean±standard deviation(SD), 2.08±4.18%), NINJ2 (G/C: 2.01±5.95; GG: 0.90±3.97), RAB5A (0.66±0.80%), and TPPP (1.11±6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3±9.63%), NINJ2 (heterozygotes: 38.6±7.39%; GG homozygotes: 67.3±9.83%), RAB5A (1.41±1.21%), and TPPP (92.5±8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (β=−0.37, p=0.03) and 5hmC in NINJ2 (β=0.49, p=0.003); T2 BLLs with 5mC in HCN2 (β=0.37, p=0.03) and 5hmC in NINJ2 (β=0.27, p=0.008); and T3 BLLs with 5mC in HCN2 (β=0.50, p=0.01) and NINJ2 (β=−0.35, p=0.004) and 5hmC in NINJ2 (β=0.45, p

Background: Lead is a neurotoxic metal potentially affecting the developing brain. Children are particularly susceptible since they can absorb between 50% and 100% of ingested lead. There is no safe level for lead, therefore preventing exposure is crucial. We previously reported a positive association between lead concentrations found in candy and concurrent blood lead levels in Mexican children. This first report garnered media and the general public’s attention. Objective: To conduct a follow-up study to assess lead concentrations in candy brands that we previously reported with concentrations ≥0.1ppm the U.S. Food and Drug Administration’s recommended maximum lead level in candy likely to be consumed frequently by small children. Methods: In 2018 we analyzed 50 additional candy samples. Lead concentrations were analyzed by an inductively coupled plasma mass spectrometer and lead content per candy unit was calculated. Findings: We found concentrations were typically low, with a marked decrease from prior levels (2008). Nevertheless two candy units had concentrations of 0.1 ppm of lead. Conclusions: Candy may have lead concentrations up to 0.1 ppm and 1.2 μg per unit. This is a concern because candies are exported and consumed in many countries worldwide potentially resulting in human exposure. Continued public health surveillance is needed to protect populations especially vulnerable to lead exposure, especially children.

Background: As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth. Objectives: To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth. Methods: We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders. Results: While linear regression showed a negative association between maternal BLL and BWGA z-score (β = −0.06 z-score units per log2 BLL increase; 95% CI: −0.13, 0.003; P = 0.06), quantile regression revealed larger magnitudes of this association in the

Lead exposure during pregnancy remains a public health problem with potential lifelong impacts on children's growth and development. Mexico is unique in that stunting and obesity are both major public health concerns in children. This situation might be exacerbated by lead exposure which remains more common in Mexico than in the United States due in part to the use of lead glazed pottery in food preparation and storage. Our objective is to determine how lead exposure during pregnancy is associated with children's growth parameters, including height, weight, body mass index and percentage body fat measured between ages 4-6 years old in a Mexico City pregnancy cohort. Blood lead was collected in the 2nd and 3rd trimester of pregnancy as well as at delivery. Bone lead was assessed in mothers as a long term exposure biomarker. We performed multivariable linear regression analyses to assess the association between each of these lead exposure biomarkers and child anthropometry. We found a significant negative association between maternal 3rd trimester blood lead concentration and offspring height for age (β-0.10; 95% CI -0.19, -0.01), and a negative association between maternal 3rd trimester blood lead concentration and weight for age (β-0.11; 95% CI -0.22,-0.003). Our results in this Mexican population add to previous findings of an association of lead and decreased stature and weight in early childhood. Ongoing follow-up and longitudinal analyses may help elucidate how this impacts growth trajectory and other children's health outcomes.

PurposeThe Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project is a mother–child pregnancy and birth cohort originally initiated in the mid-1990s to explore: (1) whether enhanced mobilisation of lead from maternal bone stores during pregnancy poses a risk to fetal and subsequent offspring neurodevelopment; and (2) whether maternal calcium supplementation during pregnancy and lactation can suppress bone lead mobilisation and mitigate the adverse effects of lead exposure on offspring health and development. Through utilisation of carefully archived biospecimens to measure other prenatal exposures, banking of DNA and rigorous measurement of a diverse array of outcomes, ELEMENT has since evolved into a major resource for research on early life exposures and developmental outcomes.Participantsn=1643 mother–child pairs sequentially recruited (between 1994 and 2003) during pregnancy or at delivery from maternity hospitals in Mexico City, Mexico.Findings to dateMaternal bone (eg, patella, tibia) is an endogenous source for fetal lead exposure due to mobilisation of stored lead into circulation during pregnancy and lactation, leading to increased risk of miscarriage, low birth weight and smaller head circumference, and transfer of lead into breastmilk. Daily supplementation with 1200 mg of elemental calcium during pregnancy and lactation reduces lead resorption from maternal bone and thereby, levels of circulating lead. Beyond perinatal outcomes, early life exposure to lead is associated with neurocognitive deficits, behavioural disorders, higher blood pressure and lower weight in offspring during childhood. Some of these relationships were modified by dietary factors; genetic polymorphisms specific for iron, folate and lipid metabolism; and timing of exposure. Research has also expanded to include findings published on other toxicants such as those associated with personal care products and plastics (eg, phthalates, bisphenol A), other metals (eg, mercury, manganese, cadmium), pesticides (organophosphates) and fluoride; other biomarkers (eg, toxicant levels in plasma, hair and teeth); other outcomes (eg, sexual maturation, metabolic syndrome, dental caries); and identification of novel mechanisms via epigenetic and metabolomics profiling.Future plansAs the ELEMENT mothers and children age, we plan to (1) continue studying the long-term consequences of toxicant exposure during the perinatal period on adolescent and young adult outcomes as well as outcomes related to the original ELEMENT mothers, such as their metabolic and bone health during perimenopause; and (2) follow the third generation of participants (children of the children) to study intergenerational effects of in utero exposures.Trial registration numberNCT00558623.

Background Exposure to environmental toxicants may play a role in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD). Cumulative exposure to lead (Pb) has chronic and permanent effects on liver function. Pediatric populations are vulnerable to the toxic effects of Pb, even at low exposure levels. The purpose of the study was to estimate the association between cumulative Pb exposure during childhood and hepatic steatosis biomarkers in young Mexican adults. Methods A subsample of 93 participants from the ELEMENT cohort were included in this study. Childhood blood samples were collected annually from ages 1–4 years and were used to calculate the Cumulative Childhood Blood Lead Levels (CCBLL). Hepatic steatosis during adulthood was defined as an excessive accumulation of hepatic triglycerides (>5%) determined using Magnetic Resonance Imaging (MRI). Liver enzymes were also measured at this time, and elevated liver enzyme levels were defined as ALT (≥30 IU/L), AST (≥30 IU/L), and GGT (≥40 IU/L). Adjusted linear regression models were fit to examine the association between CCBLL (quartiles) and the hepatic steatosis in young adulthood. Results In adulthood, the mean age was 21.4 years, 55% were male. The overall prevalence of hepatic steatosis by MRI was 19%. Elevate levels of the enzymes ALT, AST, and GGT were present in 25%, 15%, and 17% of the sample, respectively. We found a positive association between the highest quartile of CCBLL with the steatosis biomarkers of hepatic triglycerides (Q4 vs. Q1: β = 6.07, 95% CI: 1.91–10.21), elevated ALT (Q4 vs. Q1: β = 14.5, 95% CI: 1.39–27.61) and elevated AST (Q4 vs. Q1: β = 7.23, 95% CI: 0.64–13.82). No significant associations were found with GGT. Conclusions Chronic Pb exposure during early childhood is associated with a higher levels of hepatic steatosis biomarkers and hepatocellular injury in young adulthood. More actions should be taken to eliminate sources of Pb during the first years of life.

Background Recent studies have shown that lead exposure continues to pose a health risk in Mexico. Children are a vulnerable population for lead effects and Mexican candy has been found to be a source of exposure in children. There are no previous studies that estimates lead concentrations in candy that children living in Mexico City consume and its association with their blood lead level. Objectives To evaluate whether there is an association between reported recent consumption of candies identified to have lead, and blood lead levels among children in Mexico City. Methods A subsample of 171 children ages 2–6 years old, from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort study was assessed between June 2006 and July 2007. The candy reported most frequently were analyzed for lead using ICP-MS. The total weekly intake of lead through the consumption of candy in the previous week was calculated. Capillary blood lead levels (BLL) were measured using LeadCare (anodic stripping voltammetry). Results Lead concentrations ≥0.1 ppm, the FDA permitted level (range: 0.13–0.7 ppm) were found in 6 samples out of 138 samples from 44 different brands of candy. Median BLL in children was 4.5 µg/dl. After adjusting for child’s sex, age, BMI, maternal education & occupation, milk consumption, sucking the candy wrapper, use of lead-glazed pottery, child exposure behavior, living near a lead exposure site and use of folk remedies, an increase of 1 µg of lead ingested through candy per week was associated with 3% change (95% CI: 0.1%, 5.2%) in BLL. Conclusions Although lead concentrations in candy were mostly below the FDA permitted level, high lead concentrations were detected in 4% of the candy samples and 12% of brands analyzed. Although candy intake was modestly associated with children’s BLL, lead should not be found in consumer products, especially in candy that children can consume due to the well documented long-lasting effect of lead exposure.

Aim: Toxic metals including lead and mercury are associated with adverse pregnancy outcomes. This study aimed to assess the association between miRNA expression in the cervix during pregnancy with lead and mercury levels. Materials & methods: We obtained cervical swabs from pregnant women (n = 60) and quantified cervical miRNA expression. Women's blood lead, bone lead and toenail mercury levels were analyzed. We performed linear regression to examine the association between metal levels and expression of 74 miRNAs adjusting for covariates. Results: Seventeen miRNAs were negatively associated with toenail mercury levels, and tibial bone lead levels were associated with decreased expression of miR-575 and miR-4286. Conclusion: The findings highlight miRNAs in the human cervix as novel responders to maternal chemical exposure during pregnancy.

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

Epigenetic perturbations induced by environmental exposures at susceptible lifestages contribute to disease development. Even so, the influence of early life and ongoing exposures on the adolescent epigenome is rarely examined. We examined the association of exposure biomarkers for lead (Pb), bisphenol A (BPA), and nine phthalates metabolites with blood leukocyte DNA methylation at LINE-1 repetitive elements and environmentally responsive genes ( IGF2 , H19 , and HSD11B2 ) in peri-adolescents. Participants ( n = 247) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were followed-up once between the ages of 8 and 14 years, and concurrent exposures were measured in biospecimen collected at that time (blood Pb, urinary BPA, and phthalate metabolites). Prenatal and childhood exposures to Pb were previously approximated using maternal and child samples. BPA and phthalate metabolites were measured in third trimester maternal urine samples. Significant associations ( P

The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.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.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.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.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.

OBJECTIVE: Research on the role of environmental lead exposure in the complex etiology of premature birth has yielded inconsistent results. We assessed the trimester-specific effect of prenatal lead exposure on gestational age and risk of premature delivery. METHODS: We used linear and logistic regression to identify critical windows of susceptibility to lead exposure on gestational length. RESULTS: In single-trimester models decreases in gestational length were most strongly associated with first and second trimester blood lead. In adjusted logistic regression models a one-standard deviation increase in second trimester blood lead was associated with an odds ratio of prematurity of 1.75 (95% CI: 1.02 3.02). CONCLUSIONS: Maternal whole blood lead levels measured during first and second trimesters yielded the most prominent inverse association with length of gestation and increased the risk of prematurity.

Background Fetal lead exposure is associated with adverse pregnancy outcomes and developmental and cognitive deficits; however, the mechanism(s) by which lead-induced toxicity occurs remains unknown. Epigenetic fetal programming via DNA methylation may provide a pathway by which environmental lead exposure can influence disease susceptibility. Objective This study was designed to determine whether prenatal lead exposure is associated with alterations in genomic methylation of leukocyte DNA levels from umbilical cord samples. Methods We measured genomic DNA methylation, as assessed by Alu and LINE-1 (long interspersed nuclear element-1) methylation via pyrosequencing, on 103 umbilical cord blood samples from the biorepository of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study group. Prenatal lead exposure had been assessed by measuring maternal bone lead levels at the mid-tibial shaft and the patella using a spot-source 109Cd K-shell X-ray fluorescence instrument. Results We found an inverse dose–response relationship in which quartiles of patella lead correlated with cord LINE-1 methylation (p for trend = 0.01) and and tibia lead correlated with Alu methylation (p for trend = 0.05). In mixed effects regression models, maternal tibia lead was negatively associated with umbilical cord genomic DNA methylation of Alu (β= −0.027; p = 0.01). We found no associations between cord blood lead and cord genomic DNA methylation. Conclusions Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and disease susceptibility throughout the life course.

Background Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment. Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and/or intestinal absorption of ingested lead. Objective Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy. Methods In a double-blind, randomized, placebo-controlled trial conducted from 2001 through 2003 in Mexico City, we randomly assigned 670 women in their first trimester of pregnancy to ingest calcium (n = 334) or placebo (n = 336). We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead, using an intent-to-treat analysis by a mixed-effects regression model with random intercept, in 557 participants (83%) who completed follow-up. We then conducted as-treated analyses using similar models stratified by treatment compliance. Results Adjusting for baseline lead level, age, trimester of pregnancy, and dietary energy and calcium intake, calcium was associated with an average 11% reduction (0.4 μg/dL) in blood lead level relative to placebo (p = 0.004). This reduction was more evident in the second trimester (−14%, p < 0.001) than in the third (−8%, p = 0.107) and was strongest in women who were most compliant (those who consumed ≥ 75% calcium pills; −24%, p < 0.001), had baseline blood lead > 5 μg/dL (−17%, p < 0.01), or reported use of lead-glazed ceramics and high bone lead (−31%, p < 0.01). Conclusion Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and, consequently, fetal exposure.

Background: Previous studies suggest that blood lead levels are positively associated with attention deficit/hyperactivity disorder (ADHD) and ADHD-symptoms in children. However, the associations between lead exposure and ADHD subtypes are inconsistent and understudied. Objective: The objective of this study was to explore the association of low-level concurrent lead exposure with subtypes of ADHD symptoms in 578 Mexican children 6–13 years of age. Methods: We measured concurrent blood lead levels using inductively coupled plasma mass spectrometry (ICPMS). We administered the Conners’ Rating Scales-Revised (CRS-R) to mothers to evaluate their children’s ADHD symptoms. We used imputation to fill missing values in blood lead levels and used segmented regression models adjusted for relevant covariates to model the nonlinear relationship between blood lead and ADHD symptoms. Results: Mean ± SD blood lead levels were 3.4 ± 2.9 μg/dL. In adjusted models, a 1-μg/dL increase in blood lead was positively associated with Hyperactivity and Restless-Impulsivity scores on the CRS-R scale and Hyperactivity-Impulsivity scores on the CRS-R scale of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, but only in children with blood lead level ≤ 5 μg/dL. Blood lead was not associated with Inattentive symptoms or overall ADHD behavior. Conclusions: In this population of Mexican children, current blood lead level among children with low exposure (≤ 5 μg/dL) was positively associated with hyperactive/impulsive behaviors, but not with inattentiveness. These results add to the existing evidence of lead-associated neurodevelopmental deficits at low levels of exposure. Citation: Huang S, Hu H, Sánchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado-García A, Wright RO, Basu N, Cantonwine DE, Hernández-Avila M, Téllez-Rojo MM. 2016. Childhood blood lead levels and symptoms of attention deficit hyperactivity disorder (ADHD): a cross-sectional study of Mexican children. Environ Health Perspect 124:868–874; http://dx.doi.org/10.1289/ehp.1510067

OBJETIVO: Determinar los efectos de la exposición al plomo relacionados con el tiempo requerido para embarazo. MATERIAL Y MÉTODOS: Entre 1997 y 2001 se realizó un estudio en 142 mujeres residentes en la Ciudad de México, participantes en un estudio de cohorte para evaluar diversos efectos del plomo sobre la salud reproductiva. Se realizaron mediciones de plomo en sangre y en hueso a cada una de las participantes en el momento de ingresar al estudio, y se obtuvo información relativa a la exposición y otras variables de interés a través de un cuestionario. A cada una de las participantes se les siguió hasta el momento en que se embarazaron, o bien, hasta el tiempo de término del estudio, con el propósito de determinar la asociación entre la exposición al plomo y el tiempo requerido para quedar embarazada. El análisis estadístico se llevó a cabo utilizando curvas de Kaplan-Meier y modelos de riesgos proporcionales de Cox. RESULTADOS: Del total de mujeres que iniciaron el estudio se embarazaron 42, de las cuales 34 lo lograron antes del primer año de seguimiento y ocho posteriormente. Las medias de las concentraciones de plomo en sangre fueron de 9.3 µg/dl; en rótula y tibia fueron de 16.0 y 11.0 µg Pb/g de hueso mineral, respectivamente. No se detectaron diferencias en los niveles de plomo en sangre respecto al tiempo que durante el estudio requirió la mujer para embarazarse en el primer año; no obstante, se encontró que en las mujeres con plomo en sangre por encima de 10 µg/dl el riesgo de no embarazo fue cinco veces mayor [IC 95% (1.9-19.1)] después de un año de seguimiento, comparado con aquellas mujeres con plomo en sangre por debajo de 10 µg/dl. CONCLUSIONES: La exposición a concentraciones altas de plomo puede ser un factor de riesgo importante en el tiempo requerido para que una mujer quede embarazada, principalmente en aquellas que siendo fértiles tienen periodos mayores de un año buscando un embarazo.OBJECTIVE: To determine the effects of lead exposure on the time elapsed to become pregnant. MATERIAL AND METHODS: The study population consisted of 142 women residing in Mexico City between 1997 and 2001, who were already participating in a study to evaluate effects of lead exposure on reproductive health. Measurements of lead in bone were performed when women were first admitted to the program. Information on lead exposure and other variables of interest was obtained through a questionnaire. Participants were followed up to assess the relationship between the time required to become pregnant and lead exposure. Statistical analysis consisted of Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: Of the total number of women in the program, 42 got pregnant: 34 before the first year of follow-up, and 8 at a later date. The mean value for lead concentration in blood was 9.3 µg/dl. The mean values for lead concentration in patella and tibia were 16.0 y 11.0 µg Pb/g of bone, respectively. Survival analysis was performed and no differences were detected in blood lead levels and time to pregnancy in the first year. Nevertheless, in women with blood lead levels above 10.0 µg/dl, the likelihood of not achieving pregnancy was five times higher (95% confidence interval [CI] 0.05-0.56) after one year of follow-up compared with women with blood lead levels below 10.0 µg/dl. CONCLUSIONS: Exposure to high lead concentrations may be an important risk factor influencing the time period for a woman to get pregnant, especially in fertile women who have tried to get pregnant for more than a year.

To establish a blood lead quantification correlation from two occupational health laboratories (OHL1V and OHL2DF), and the ABC Hospital (LABC) metals laboratory.A cross-sectional study was performed in 84 workers from a voltage regulators company, where lead is welded; in 54 % (46 of them) a blood sample was taken and analyzed by OHL1V, and in 28.6 % (24) by OHL2DF. All samples were analyzed by atomic absorption spectrophotometry. Pearson correlation (r), coefficient of determination (r2), Lin (rho) concordance test, and Bland-Altman plots were calculated.The blood lead mean: LABC was 5.8 ± 2.4 μg/dL vs. OHL2DF of 4.4 ± 3.6 μg/dL (r = 0.25 [p = 0.24], r2 = 0.06 [p = 0.24], and rho = 0.21 [p = 0.21]). And with LABC, 6.75 ± 3.3 μg/dL vs. OHL1V 5.6 ± 2.9 μg/dL (r = 0.91 [p0.001], r2 = 0.83 [p0001], and rho = 0.85 [p0.001]).Agreement between LABC and OHL1V was poor (0.90), and with OHL2DF was null. An occupational health laboratory certification is needed in order to have reliable biological exposure index measurements in lead occupational exposure.determinar la concordancia de las cuantificaciones del plomo en la sangre de dos laboratorios del Instituto Mexicano del Seguro Social (LST1V y LST2DF), con las del Laboratorio de Metales del Hospital ABC (LABC). MÉTODOS: se realizó un estudio transversal en 84 trabajadores que sueldan con plomo en una empresa de reguladores. Se tomaron muestras de sangre; 100 % fue analizado por el LABC, 54 % (46) por el LST1V y 28.6 % (24) por el LST2DF. Todas las muestras se analizaron por espectrofotometría de absorción atómica. Se calculó la correlación de Pearson (r), el coeficiente de determinación (r2), la concondancia de Lino (rho) y las gráficas de Bland-Altman.las muestras analizadas en el LST2DF indicaron 4.4 ± 3.6 µg/dL de plomo en la sangre y en el LABC, 5.8 ± 2.4 μg/dL (r = 0.25 [p = 0.24], r2 = 0.06 [p = 0.24] y rho = 0.21 [p = 0.21]). Las muestras analizadas en el LST1V indicaron 5.6 ± 2.9 μg/dL y en el LABC, 6.75 ± 3.3 μg/dL (r = 0.91 [p0.001], r2 = 0.83 [p0.001] y rho = 0.85 [p0.001]).los resultados del LABC concordaron pobremente con los del LST1V (0.90) y no lo hicieron con los del LST1-DF. Es necesario certificar a los laboratorios institucionales y acreditar a los técnicos que realizan los análisis, para obtener resultados confiables de los indicadores biológicos de exposición ocupacional.

Background The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure. Objective We studied prenatal lead exposure’s impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels. Methods We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose. Results Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores. Conclusions Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.

OBJECTIVE. Increasing evidence suggests that 10 μg/dL, the current Centers for Disease Control and Prevention screening guideline for children's blood lead level, should not be interpreted as a level at which adverse effects do not occur. Using data from a prospective study conducted in Mexico City, Mexico, we evaluated the dose-effect relationship between blood lead levels and neurodevelopment at 12 and 24 months of age.METHODS. The study population consisted of 294 children whose blood lead levels at both 12 and 24 months of age were RESULTS. Adjusting for covariates, children's blood lead levels at 24 months were significantly associated, in an inverse direction, with both Mental Development Index and Psychomotor Development Index scores at 24 months. Blood lead level at 12 months of age was not associated with concurrent Mental Development Index or Psychomotor Development Index scores or with Mental Development Index at 24 months of age but was significantly associated with Psychomotor Development Index score at 24 months. The relationships were not altered by adjustment for cord blood lead level or, in the analyses of 24-month Mental Development Index and Psychomotor Development Index scores, for the 12-month Mental Development Index and Psychomotor Development Index scores. For both Mental Development Index and Psychomotor Development Index at 24 months of age, the coefficients that were associated with concurrent blood lead level were significantly larger among children with blood lead levels 10 μg/dL.CONCLUSIONS. These analyses indicate that children's neurodevelopment is inversely related to their blood lead levels even in the range of

To determine the effects of lead exposure on the time elapsed to become pregnant.The study population consisted of 142 women residing in Mexico City between 1997 and 2001, who were already participating in a study to evaluate effects of lead exposure on reproductive health. Measurements of lead in bone were performed when women were first admitted to the program. Information on lead exposure and other variables of interest was obtained through a questionnaire. Participants were followed up to assess the relationship between the time required to become pregnant and lead exposure. Statistical analysis consisted of Kaplan-Meier estimates and Cox proportional hazards models.Of the total number of women in the program, 42 got pregnant: 34 before the first year of follow-up, and 8 at a later date. The mean value for lead concentration in blood was 9.3 micrograms/dl. The mean values for lead concentration in patella and tibia were 16.0 y 11.0 micrograms Pb/g of bone, respectively. Survival analysis was performed and no differences were detected in blood lead levels and time to pregnancy in the first year. Nevertheless, in women with blood lead levels above 10.0 micrograms/dl, the likelihood of not achieving pregnancy was five times higher (95% confidence interval [CI] 0.05-0.56) after one year of follow-up compared with women with blood lead levels below 10.0 micrograms/dl.Exposure to high lead concentrations may be an important risk factor influencing the time period for a woman to get pregnant, especially in fertile women who have tried to get pregnant for more than a year. This paper is available too at: http://www.insp.mx/salud/index.html.

Background Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (HFE) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight. Methods We investigated the role of HFE C282Y, HFE H63 D, and transferrin (TF) P570 S gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant HFE or TF genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates. Results 3.1%, 16.8% and 17.5% of infants (N = 390) and 1.9%, 14.5% and 18.9% of mothers (N = 533) carried the HFE C282Y, HFE H63D, and TF P570 S variants, respectively. The presence of infant HFE H63 D variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal HFE H63 D variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant HFE H63 D genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal HFE H63 D variant carriers had a negative association between tibia lead and birthweight. Conclusions These results suggest that the HFE H63 D genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals.

Background Blood lead has been associated with an elevated risk of miscarriage. The plasmatic fraction of lead represents the toxicologically active fraction of lead. Women with a tendency to have a higher plasma/whole blood Pb ratio could tend towards an elevated risk of miscarriage due to a higher plasma Pb for a given whole blood Pb and would consequently have a history of spontaneous abortion. Methods We studied 207 pregnant Mexico City residents during the 1st trimester of pregnancy, originally recruited for two cohorts between 1997 and 2004. Criteria for inclusion in this study were having had at least one previous pregnancy, and having valid plasma and blood Pb measurements. Pb was measured in whole blood and plasma by inductively coupled plasma mass spectrometry using ultra-clean techniques. History of miscarriage in previous pregnancies was obtained by interview. The incidence rate of spontaneous abortion was defined as the proportion of previous pregnancies that resulted in miscarriage. Data were analyzed by means of Poisson regression models featuring the incidence rate of spontaneous abortion as the outcome and continuous or categorized plasma/blood Pb ratios as predictor variables. All models were adjusted for age and schooling. Additionally, logistic regression models featuring inclusion in the study sample as the outcome were fitted to assess potential selection bias. Results The mean number of miscarriages was 0.42 (range 0 to 4); mean Pb concentrations were 62.4 and 0.14 μg/L in whole blood and plasma respectively. Mean plasma/blood Pb ratio was 0.22%. We estimated that a 0.1% increment in the plasma/blood Pb ratio lead was associated to a 12% greater incidence of spontaneous abortion (p = 0.02). Women in the upper tertile of the plasma/blood Pb ratio had twice the incidence rate of those in the lower tertile (p = 0.02). Conditional on recruitment cohort, inclusion in the study sample was unrelated to observable characteristics such as number of abortions, number of pregnancies, blood Pb levels, age schooling, weight and height. Conclusion Women with a large plasma/whole blood Pb ratio may be at higher risk of miscarriage, which could be due to a greater availability of placental barrier-crossing Pb.