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Hypospadias is the ectopic opening of the urethra on the penis or scrotum. Exposure to estrogenic and/or anti-androgenic chemicals in utero may play an etiologic role. DDT and the pyrethroids cypermethrin and deltamethrin, are used to control malaria. DDT is estrogenic and its breakdown product DDE is anti-androgenic; cypermethrin and deltamethrin can also disrupt androgen pathways. We examined the relationship between maternal exposure to these insecticides during pregnancy and hypospadias among boys participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) in Limpopo Province, South Africa. We measured peripartum levels of p,p'-DDT and p,p'-DDE in maternal serum and urinary pyrethroid metabolites. We conducted urogenital examination on 359 one-year-old boys. A total of 291 (81.0 %) had phimosis, which prevented full urogenital examination, leaving a final sample of 68 boys for determination of the presence of hypospadias. Diagnosis was based on concordance of two independent physicians. We identified hypospadias in 23 of the 68 boys (34 %). Maternal urinary concentrations of cis-DCCA and trans-DCCA metabolites of cypermethrin and other pyrethroids, were associated with an increased risk for hypospadias, but the other metabolite 3-PBA was not (adjusted relative risk per 10-fold increase = 1.58, 95 % CI 1.07-2.34; 1.61, 95 % CI 1.09-2.36; and 1.48, 95 % CI 0.78-2.78, respectively). No associations were found between p,p'-DDT, p,p'-DDE, 3-PBA or cis-DBCA and hypospadias. We observed a high prevalence of hypospadias among boys without phymosis. Boys with higher prenatal exposure to pyrethroid insecticides were at higher risk of hypospadias. Our findings may have global implications given that pyrethroid insecticides are widely used for malaria control, in agriculture and for home use.

BackgroundHalf the world's population is at risk for malaria. Indoor residual spraying (IRS) with insecticides has been effective in controlling malaria, yet the potential neurotoxicity of these insecticides is of concern, particularly for infants exposed in utero.ObjectivesTo determine the association of prenatal exposure to DDT/DDE and pyrethroid insecticides and behavioral/emotional problems in two-year-old children.MethodsThe Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) birth cohort in South Africa, measured concentrations of p,p'-DDT and p,p'-DDE in maternal serum and pyrethroid metabolites (cis-DBCA, cis-DCCA, trans-DCCA, and 3-PBA) in maternal urine collected during pregnancy. At 2 years, 683 mothers were interviewed about their children's behavior and emotional development, using the Child Behavior Checklist (CBCL). We examined associations between behavioral or emotional problems and biomarkers of prenatal insecticide exposure.ResultsMaternal serum p,p'-DDT concentrations were associated with heightened withdrawn behavior in 2-year olds, with a 0.24 increase in raw scores (95%CI = 0.00, 0.49) and a 12% increase (95%CI = 1.01, 1.23) in risk of being at or above the borderline-clinical level, per 10-fold increase in concentrations. Ten-fold increases in p,p'-DDT and p,p'-DDE were related to 30% (RR = 1.30; 95%CI = 1.01, 1.67) and 39% (RR = 1.39; 95%CI =1.01, 1.91) higher risks, respectively, for increased oppositional-defiant behavior. p,p'-DDE concentrations were also related to increased risk of ADHD-related problems (RR = 1.30; 95%CI = 0.98, 1.72). Maternal urinary concentrations of cis-DBCA and 3-PBA were associated with increased risk of externalizing behaviors (RR = 1.30; 95%CI = 1.05, 1.62; RR = 1.35, 95%CI = 1.03, 1.78 per 10-fold increase, respectively), with some evidence of an association between cis-DBCA and affective disorders (RR = 1.25; 95%CI = 0.99, 1.56). Some associations with maternal pyrethroid concentrations were stronger in girls than boys.ConclusionsPrenatal exposure to DDT and pyrethroid insecticides may be associated with maternally-reported behavioral problems in two-year-old children. Given their long history and continued use, further investigation is warranted.

BackgroundDichlorodiphenyltrichloroethane (DDT) or pyrethroid insecticides are sprayed inside dwellings for malaria vector control, resulting in high exposure to millions of people, including pregnant women. These chemicals disrupt endocrine function and may affect child growth. To our knowledge, few studies have investigated the potential impact of prenatal exposure to DDT or pyrethroids on growth trajectories.MethodsWe investigated associations between gestational insecticide exposure and child growth trajectories in the Venda Health Examination of Mothers, Babies and their Environment, a birth cohort of 751 children born between 2012 and 2013 in South Africa. Based on child weight measured at follow-up and abstracted from medical records, we modeled weight trajectories from birth to 5 years using SuperImposition, Translation and Rotation, which estimated two child-specific parameters: size (average weight) and tempo (age at peak weight velocity). We estimated associations between peripartum maternal concentrations of serum DDT, dichlorodiphenyldichloroethylene, or urinary pyrethroid metabolites and SuperImposition, Translation and Rotation parameters using marginal structural models.ResultsWe observed that a 10-fold increase in maternal concentrations of the pyrethroid metabolite trans-3-(2,2,-dicholorvinyl)-2,2-dimethyl-cyclopropane carboxylic acid was associated with a 21g (95% confidence interval = -40, -1.6) smaller size among boys but found no association among girls (Pinteraction = 0.07). Estimates suggested that pyrethroids may be associated with earlier tempo but were imprecise. We observed no association with serum DDT or dichlorodiphenyldichloroethylene.ConclusionsInverse associations between pyrethroids and weight trajectory parameters among boys are consistent with hypothesized disruption of androgen pathways and with our previous research in this population, and support the endocrine-disrupting potential of pyrethroids in humans.

Indoor Residual Spraying (IRS), the application of insecticides on the inside walls of dwellings, is used by 84 countries for malaria control. Although effective in preventing malaria, this practice results in elevated insecticide exposure to >100 million people, most of whom are Africans. Pyrethroid insecticides and dichlorodiphenyl trichloroethane (DDT) are currently used for IRS. Animal and in vitro studies suggest that pyrethroids and DDT interfere with thyroid hormone homeostasis but human studies are inconsistent and no prior study has investigated this question in a population residing in an area where IRS is conducted. Our objective was thus to evaluate whether prenatal exposure to pyrethroids, DDT or DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE) is associated with altered thyroid hormone levels among neonates from Limpopo, South Africa, where pyrethroids and DDT are used annually to control malaria. We measured serum DDT/E and urinary pyrethroid metabolite concentrations in maternal peripartum samples from 717 women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study conducted in Limpopo's Vhembe district. We measured total thyroxine (T4) and thyroid-stimulating hormone (TSH) in dried blood spots collected via heel stick. We found that all pyrethroid metabolites were positively associated with TSH; trans-DCCA and 3-PBA showed the strongest associations with a 12.3% (95%CI = 3.0, 22.3) and 14.0% (95%CI = 0.5, 30.2) change for each 10-fold increase in biomarker concentration, respectively. These associations were substantially stronger among children from households below the South African food poverty line. DDT and DDE were associated with lower total T4 among boys only (β = -0.27 μg/dL per 10-fold increase; 95%CI = -0.47, -0.04). Results suggest that prenatal exposure to DDT, DDE and pyrethroid insecticides is associated with changes in neonatal thyroid hormones consistent with hypothyroidism/hypothyroxinemia and that sex and poverty modify associations. Further research is needed to confirm these findings and examine whether they have implications for child development.

Although effective in controlling malaria, indoor residual spraying results in elevated exposure to insecticides such as dichlorodiphenyltrichloroethane (DDT) and pyrethroids. These chemicals cross the placenta, but no studies have examined their associations with birth outcomes in populations residing in indoor residual spraying areas. We investigated this question in the Venda Health Examination of Mothers, Babies and Their Environment (VHEMBE), a birth cohort study of 751 South African children born between 2012 and 2013. We measured maternal peripartum serum DDT and urine pyrethroid metabolite concentrations and collected data on birth weight, length, head circumference, and duration of gestation. We analyzed the data using marginal structural models with inverse-probability-of-treatment weights, generalized propensity scores, and standard conditional linear regression. Using all 3 analytical methods, p,p'-DDT, o,p'-DDT, and to a lesser extent p,p'-dichlorodiphenyldichloroethylene were related to elevated birth weight, birth length, and head circumference among girls. Changes in gestational duration did not mediate this relationship, suggesting that these exposures accelerate fetal growth, which is consistent with the known estrogenic properties of o,p'-DDT and p,p'-DDT. No associations with pyrethroid metabolites were found. Results suggest that prenatal exposure to DDT is related to elevated birth size. Further studies are needed to elucidate the implications of these findings.

BackgroundThe World Health Organization recommends indoor residual spraying (IRS) of insecticides (including dichlorodiphenyltrichloroethane [DDT]) to fight malaria vectors in endemic countries. There is limited information on children's exposure to DDT in sprayed areas, and tools to estimate early-life exposure have not been thoroughly evaluated in this context.ObjectivesTo document serum p,p'-DDT/E levels in 47 mothers and children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a study conducted in an area where IRS insecticides are used annually, and to evaluate the precision and accuracy of a published pharmacokinetic model for the estimation of children's p,p'-DDT/E levels.Methodsp,p'-DDT/E levels were measured in maternal serum at delivery, and in children's serum at 12 and 24 months of age. A pharmacokinetic model of gestational and lactational exposure was used to estimate children's p,p'-DDT/E levels during pregnancy and the first two years of life, and estimated levels were compared to measured levels.ResultsThe geometric means of children's serum p,p'-DDT/E levels at 12 and 24 months were higher than those of maternal serum levels. Regression models of measured children's p,p'-DDT/E levels vs. levels estimated with the pharmacokinetic model (which only accounted for children's exposure through placental transfer and breastfeeding) had coefficients of determination (R2) ranging from 0.75 to 0.82. Estimated p,p'-DDE levels were not significantly different from measured levels, whereas p,p'-DDT levels were overestimated by 36% at 12 months, and 51% at 24 months.ConclusionResults indicate that children living in a sprayed area have serum p,p'-DDT/E levels exceeding their mothers' during the first two years of life. The pharmacokinetic model may be useful to estimate children's levels in the VHEMBE population.

Environmental phenols and parabens are commonly used in personal care products and other consumer products and human exposure to these chemicals is widespread. Although human and animal studies suggest an association between exposure to phenols and parabens and thyroid hormone levels, few studies have investigated the association of in utero exposure to these chemicals and thyroid hormones in pregnant women and their neonates. We measured four environmental phenols (triclosan, benzophenone-3, and 2,4- and 2,5-dichlorophenol), and three parabens (methyl-, propyl-, and butyl paraben) in urine collected from mothers at two time points during pregnancy as part of the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study. We measured free thyroxine (T4), total T4, and thyroid-stimulating hormone (TSH) in serum of the pregnant women (N = 454) and TSH in their neonates (N = 365). We examined potential confounding by a large number of additional chemical exposures and used Bayesian Model Averaging (BMA) to select the most influential chemicals to include in regression models. We observed negative associations of prenatal urinary concentrations of propyl paraben and maternal TSH (β for two-fold increase = -3.26%, 95% CI: -5.55, -0.90) and negative associations of 2,4-dichlorophenol and maternal free T4 (β for two-fold increase = -0.05, 95% CI: -0.08, -0.02), after controlling for other chemical exposures. We observed negative associations of triclosan with maternal total T4 after controlling for demographic variables, but this association became non-significant after controlling for other chemicals (β for two-fold increase = -0.05, 95% CI: -0.11, 0.00). We found evidence that environmental phenols and parabens are associated with lower TSH and free T4 in pregnant women after controlling for related chemical exposures.

BackgroundIndoor residual spraying (IRS) of insecticides, conducted in low- and middle-income countries to control malaria, may result in high exposure to dichlorodiphenyltrichloroethane (DDT), its breakdown product dichlorodiphenyldichloroethylene (DDE), or pyrethroids. Animal studies suggest in utero exposure to these chemicals may increase childhood infection frequency.ObjectivesWe investigated associations between maternal DDT/E and pyrethroid metabolite concentration and child infection associations in an IRS setting in which susceptibility factors are common and infections are leading causes of child morbidity and mortality.MethodsUsing gas chromatography-mass spectrometry, we measured serum DDT/E and urinary pyrethroid metabolite concentrations in peripartum samples from 674 women participating in the Venda Health Examination of Mother, Babies and their Environment (VHEMBE) study. Counts of persistent child fevers, otitis media, and severe sore throat between 1 and 2 y of age were ascertained from maternal interviews. Associations between DDT/E and pyrethroid metabolite concentrations and infections were estimated using zero-inflated Poisson regression. We estimated relative excess risks due to interaction (RERI) with poverty, maternal energy intake, and maternal HIV status.ResultsConcentrations of DDT/E, particularly p,p'-DDE, were associated with higher rates of persistent fevers [IRR=1.21 (95% CI: 1.01, 1.46)], for a 10-fold increase in p,p'-DDE). This association was stronger among children from households below versus above the South African food poverty line [IRR=1.31 (95% CI: 1.08, 1.59) vs. IRR=0.93 (95% CI: 0.69, 1.25), respectively] and for children whose mothers had insufficient versus sufficient caloric intake during pregnancy [IRR=1.30 (95% CI: 1.07, 1.58) vs. IRR=0.96 (95% CI: 0.72, 1.28), respectively].ConclusionsIn utero IRS insecticide exposure may increase childhood infection rates. This was particularly apparent among children from poorer households or whose mothers had low energy intake during pregnancy. https://doi.org/10.1289/EHP2657.

BackgroundAlthough indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment.ObjectivesWe aimed to estimate the effects of maternal insecticide exposure and neurodevelopment of toddlers living in a malaria-endemic region currently using IRS.MethodsThe Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort of 752 mother-child pairs in Limpopo, South Africa. We measured maternal exposure to DDT and its breakdown product, dichlorodiphenyldichloroethylene (DDE), in maternal serum, and measured pyrethroid metabolites in maternal urine. We assessed children's neurodevelopment at 1 and 2 y of age using the Bayley Scales of Infant Development, third edition (BSID-III), and examined associations with maternal exposure.ResultsDDT and DDE were not associated with significantly lower scores for any BSID-III scale. In contrast, each 10-fold increase in cis-DCCA, trans-DCCA, and 3-phenoxybenzoic acid were associated, respectively, with a -0.63 (95% CI: -1.14, -0.12), -0.48 (95% CI: -0.92, -0.05), and -0.58 (-1.11, -0.06) decrement in Social-Emotional scores at 1 y of age. In addition, each 10-fold increase in maternal cis-DBCA levels was associated with significant decrements at 2 y of age in Language Composite scores and Expressive Communication scores [β=-1.74 (95% CI: -3.34, -0.13) and β=-0.40 (95% CI: -0.77, -0.04), respectively, for a 10-fold increase]. Significant differences by sex were estimated for pyrethroid metabolites and motor function scores at 2 y of age, with higher scores for boys and lower scores for girls.ConclusionsPrenatal exposure to pyrethroids may be associated at 1 y of age with poorer social-emotional development. At 2 y of age, poorer language development was observed with higher prenatal pyrethroid levels. Considering the widespread use of pyrethroids, these findings deserve further investigation. https://doi.org/10.1289/EHP2129.

BackgroundPregnant women may be co-exposed to multiple insecticides in regions where both pyrethroids and dichlorodiphenyltrichloroethane (DDT) are used for indoor residual spraying (IRS) for malaria control. Despite the potential for adverse effects on offspring, there are few studies in areas where IRS is currently used and little is known about the effects of pyrethroids on children's health.MethodsWe investigated the relationship between concentrations of four urinary pyrethroid metabolites in urine and organochlorine pesticide concentrations in maternal blood collected near delivery on body weight and body composition among children ≤2 years old participating in the prospective South Africa VHEMBE birth cohort (N = 708). We used measurements of length/height and weight collected at 1 and 2 years of age to calculate body mass index (BMI)-for-age, weight-for-age, and weight-for-height z-scores based on World Health Organization standards. We fit separate single-pollutant mixed effects models for each exposure of interest and also stratified by sex. We also fit all analyte concentrations jointly by using a Bayesian kernel machine regression (BKMR) statistical method to assess variable importance of each analyte and to explore the potential for joint effects of the multiple exposures.ResultsSingle-pollutant linear mixed effects models showed that, among girls only, p,p'-DDT was associated with higher BMI-for-age (adjusted [a]β = 0.22 [95% CI: 0.10, 0.35]; sex interaction p-value = 0.001), weight-for-height (aβ = 0.22 [95% CI: 0.09, 0.34]; sex interaction p-value = 0.002), and weight-for-age (aβ = 0.17 [95% CI: 0.05, 0.29], sex interaction p-value = 0.01). Although single-pollutant models suggested that p,p'-DDT and dichlorodiphenyldichloroethylene (p,p'-DDE) were also associated with these outcomes in girls, p,p'-DDE was no longer associated in multi-pollutant models with BKMR. The pyrethroid metabolites cis-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylicacid (cis-DBCA) and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA) were inversely related to BMI-for-age and weight-for-height overall; however, results suggested that weight-for-age and weight-for-height associations for trans-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for-height = 0.13) and cis-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for-height = 0.08) were strongest and most consistent in boys relative to girls. BKMR also revealed joint effects from the chemical mixture. For instance, with increased concentrations of p,p'-DDE, the negative exposure-response relationship for cis-DBCA on BMI-for-age became steeper.ConclusionsOur single-pollutant and multi-pollutant model results show that maternal serum p,p'-DDT concentration was consistently and positively associated with body composition and body weight in young girls and that maternal urinary pyrethroid metabolite concentrations (particularly cis-DBCA and trans-DCCA) were negatively associated with body weight and body composition in young boys. Joint effects of the insecticide exposure mixture were also apparent, underscoring the importance of using advanced statistical methods to examine the health effects of chemical mixtures.

Indoor Residual Spraying (IRS), the use of insecticides inside residences for malaria control, may cause elevated exposure to insecticides such as dichlorodiphenyl trichloroethane (DDT). Evidence suggests that DDT exposure may increase blood pressure but no study has investigated associations with hypertensive disorders of pregnancy (HDP) in an IRS area. We measured the serum concentration of DDT and its breakdown product dichlorodiphenyl trichloroethylene (DDE) at the time of delivery among 733 rural South African women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE). We also collected data on HDP diagnosis through questionnaires administered to participants and medical record abstraction. We used multiple logistic regression models to examine the relation between DDT/E and HDP. p,p'-DDT and p,p'-DDE serum concentrations were associated with HDP based on self-report (OR = 1.50; 95%CI = 1.10, 2.03 for p,p'-DDT and OR = 1.58; 95%CI = 1.09, 2.28 for p,p'-DDE) and medical records (OR = 1.32; 95%CI = 0.99, 1.75 for p,p'-DDT and OR = 1.47; 95%CI = 1.03, 2.09 for p,p'-DDE). p,p'-DDE was also associated with gestational hypertension (OR = 1.44; 95% CI = 1.00, 2.07). Exposure to DDT and DDE may be associated with elevated risks of HDP in South African women residing in an area sprayed for malaria control.

BackgroundAlthough indoor residual spraying (IRS) is an effective tool for malaria control, its use contributes to high insecticide exposure in sprayed communities and raises concerns about possible unintended health effects.ObjectiveThe Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort study initiated in 2012 to characterize prenatal exposure to IRS insecticides and exposures' impacts on child health and development in rural South Africa.MethodsIn this report, we describe the VHEMBE cohort and dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) serum concentrations measured in VHEMBE mothers when they presented for delivery. In addition, we applied a causal inference framework to estimate the potential reduction in population-level p,p'-DDT and p,p'-DDE serum concentrations under five hypothetical interventions. A total of 751 mothers were enrolled.ResultsSerum concentrations of p,p' isomers of DDT and DDE were above the limit of detection (LOD) in ≥98% of the samples, whereas the o,p' isomers were above the LOD in at least 80% of the samples. Median (interquartile range) p,p'-DDT and p,p'-DDE serum concentrations for VHEMBE cohort participants were 55.3 (19.0-259.3) and 242.2 (91.8-878.7) ng/g-lipid, respectively. Mothers reporting to have lived in a home sprayed with DDT for malaria control had ~5-7 times higher p,p'-DDT and p,p'-DDE serum concentrations than those who never lived in a home sprayed with DDT. Of the five potential interventions tested, we found increasing access to water significantly reduced p,p'-DDT exposure and increasing the frequency of household wet mopping significantly reduced p,p'-DDT and p,p'-DDE exposure.ConclusionOur findings suggest that several intervention approaches may reduce DDT/DDE exposure in pregnant women living in IRS communities. https://doi.org/10.1289/EHP353.

BackgroundPolybrominated diphenyl ether (PBDE) flame retardants are endocrine-disrupting chemicals that exhibit estrogenic and androgenic properties and may affect pubertal timing.MethodsStudy subjects were participants between 1999 and 2013 in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal cohort study of predominantly Mexican origin families in Northern California. We measured serum concentrations of four PBDEs (BDE-47, -99, -100, -153) in blood collected from mothers during pregnancy (N=263) and their children at age 9years (N=522). We determined timing of pubertal onset in 309 boys and 314 girls using clinical Tanner staging every 9months between 9 and 13years of age, and timing of menarche by self-report. We used Poisson regression for relative risk (RR) of earlier puberty and parametric survival analysis for time ratios (TR) of pubertal milestones.ResultsPrenatal concentrations of all 4 congeners and ƩPBDEs were associated with later menarche in girls (RRearlier menarche=0.5, 95% confidence interval (CI): 0.3, 0.9 for ƩPBDEs) but earlier pubic hair development in boys (RRearlier pubarche=2.0, 95% CI: 1.3, 3.3 for ƩPBDEs). No associations were seen between prenatal exposure and girls' breast or pubic hair development or boys' genital development. Childhood PBDE exposure was not associated with any measure of pubertal timing, except for an association of BDE-153 with later menarche.ConclusionsWe found that prenatal PBDE exposure was associated with later menarche in girls but earlier pubarche in boys, suggesting opposite pubertal effects in girls and boys.

Although approximately 123 million people may be exposed to high levels of insecticides through the use of indoor residual spraying (IRS) for malaria control, few studies exist on indoor insecticide contamination due to IRS and its relationship with human exposure. In the present study, we developed a sampling method to collect undisturbed dust from 50 homes in Limpopo, South Africa, a region where dichlorodiphenyltrichloroethane (DDT) has been used in IRS programs to prevent malaria for ~70years. We quantified DDT and its degradation products, dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) in dust samples to determine dust loading levels and compared these levels to paired serum concentrations of p,p'-DDT and p,p'-DDE in women residents. p,p'-DDT and p,p'-DDE had the highest detection frequencies in both dust (58% and 34% detection, respectively) and serum samples (98% and 100% detection, respectively). Significantly higher detection frequencies for o,p'-DDT, p,p'-DDE, and p,p'-DDD were observed in dust samples collected in buildings that had been previously sprayed for malaria control. We also observed a significant, positive association between dust loading and serum concentrations of p,p'-DDT and p,p'-DDE (Spearman's rho=0.68 and 0.54, respectively). Despite the low detection frequency in dust, our results indicate that undisturbed dust may be a good metric to quantify long-term home exposure to DDT-related compounds and that contamination of the home environment may be an important determinant/source of DDT and DDE exposure.

Although banned in most countries, dichlorodiphenyl-trichloroethane (DDT) continues to be used for vector control in some malaria endemic areas. Previous findings from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study found increased prenatal levels of DDT and its breakdown product dichlorodiphenyl-dichloroethylene (DDE) to be associated with altered neurodevelopment in children at 1 and 2years of age. In this study, we combined the measured maternal DDT/E concentrations during pregnancy obtained for the prospective birth cohort with predicted prenatal DDT and DDE levels estimated for a retrospective birth cohort. Using generalized estimating equation (GEE) and linear regression models, we evaluated the relationship of prenatal maternal DDT and DDE serum concentrations with children's cognition at ages 7 and 10.5years as assessed using the Full Scale Intelligence Quotient (IQ) and 4 subtest scores (Working Memory, Perceptual Reasoning, Verbal Comprehension, and Processing Speed) of the Wechsler Intelligence Scale for Children (WISC). In GEE analyses incorporating both age 7 and 10.5 scores (n=619), we found prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales (p-value>0.05). In linear regression analyses assessing each time point separately, prenatal DDT levels were inversely associated with Processing Speed at age 7years (n=316), but prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales at age 10.5years (n=595). We found evidence for effect modification by sex. In girls, but not boys, prenatal DDE levels were inversely associated with Full Scale IQ and Processing Speed at age 7years. We conclude that prenatal DDT levels may be associated with delayed Processing Speed in children at age 7years and the relationship between prenatal DDE levels and children's cognitive development may be modified by sex, with girls being more adversely affected.

BackgroundPolybrominated diphenyl ethers (PBDEs) are lipophilic flame retardants that bioaccumulate in humans. Child serum PBDE concentrations in California are among the highest worldwide. PBDEs may be associated with obesity by disrupting endocrine systems.ObjectiveIn this study, we examined whether pre- and postnatal exposure to the components of pentaBDE mixture was associated with childhood obesity in a population of Latino children participating in a longitudinal birth cohort study in the Salinas Valley, California.MethodsWe measured PBDEs in serum collected from 224 mothers during pregnancy and their children at 7 years of age, and examined associations with body mass index (BMI) at age 7 years.ResultsMaternal PBDE serum levels during pregnancy were associated with higher BMI z-scores in boys (BMI z-score βadjusted = 0.26; 95% CI: -0.19, 0.72) but lower scores in girls (BMI z-score βadjusted = -0.41; 95% CI: -0.87, -0.05) at 7 years of age (pinteraction = 0.04). In addition, child's serum BDE-153 concentration (log10), but not other pentaBDE congeners, demonstrated inverse associations with BMI at age 7 years (BMI z-score βadjusted = -1.15; 95% CI: -1.53, -0.77), but there was no interaction by sex.ConclusionsWe estimated sex-specific associations with maternal PBDE levels during pregnancy and BMI at 7 years of age, finding positive associations in boys and negative associations in girls. Children's serum BDE-153 concentrations were inversely associated with BMI at 7 years with no difference by sex. Future studies should examine the longitudinal trends in obesity with PBDE exposure and changes in hormonal environment as children transition through puberty, as well as evaluate the potential for reverse causality.

Study sample size in prospective birth cohorts of prenatal exposure to persistent organic pollutants (POPs) is limited by costs and logistics of follow-up. Increasing sample size at the time of health assessment would be beneficial if predictive tools could reliably back-extrapolate prenatal levels in newly enrolled children. We evaluated the performance of three approaches to back-extrapolate prenatal levels of p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE) and four polybrominated diphenyl ether (PBDE) congeners from maternal and/or child levels 9 years after delivery: a pharmacokinetic model and predictive models using deletion/substitution/addition or Super Learner algorithms. Model performance was assessed using the root mean squared error (RMSE), R2, and slope and intercept of the back-extrapolated versus measured levels. Super Learner outperformed the other approaches with RMSEs of 0.10 to 0.31, R2s of 0.58 to 0.97, slopes of 0.42 to 0.93 and intercepts of 0.08 to 0.60. Typically, models performed better for p,p'-DDT/E than PBDE congeners. The pharmacokinetic model performed well when back-extrapolating prenatal levels from maternal levels for compounds with longer half-lives like p,p'-DDE and BDE-153. Results demonstrate the ability to reliably back-extrapolate prenatal POP levels from levels 9 years after delivery, with Super Learner performing best based on our fit criteria.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant. Although experimental evidence suggests that TCDD alters thyroid hormone levels in rodents, human data are inconsistent. In 1976, a trichlorophenol plant exploded in Seveso, Italy. Women living in highly exposed areas were followed through the Seveso Women's Health Study. TCDD concentrations were measured in 1976 (n = 981) and 1996 (n = 260), and levels of total thyroxine, free thyroxine, free triiodothyronine, and thyroid-stimulating hormone were measured in 1996 (n = 909) and 2008 (n = 724). We used conditional multiple linear regression and marginal structural models with inverse-probability-of-treatment weights to evaluate associations and causal effects. TCDD concentration in 1976 was inversely associated with total thyroxine level in 1996 but not in 2008. Associations were stronger among women who had been exposed before menarche. Among these women, associations between total thyroxine and concurrent 1996 TCDD were slightly weaker than those with 1976 TCDD. A model including both 1976 and 1996 measurements strengthened the relationship between 1976 TCDD and total thyroxine but drove the association with 1996 TCDD to the null. TCDD exposure was not associated with levels of other thyroid hormones. TCDD exposure, particularly exposure before menarche, may have enduring impacts on women's total thyroxine levels. Initial exposure appears to be more influential than remaining body burden.

BackgroundCalifornia children's exposures to polybrominated diphenyl ether flame retardants (PBDEs) are among the highest worldwide. PBDEs are known endocrine disruptors and neurotoxicants in animals.ObjectiveHere we investigate the relation of in utero and child PBDE exposure to neurobehavioral development among participants in CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a California birth cohort.MethodsWe measured PBDEs in maternal prenatal and child serum samples and examined the association of PBDE concentrations with children's attention, motor functioning, and cognition at 5 (n = 310) and 7 years of age (n = 323).ResultsMaternal prenatal PBDE concentrations were associated with impaired attention as measured by a continuous performance task at 5 years and maternal report at 5 and 7 years of age, with poorer fine motor coordination-particularly in the nondominant-at both age points, and with decrements in Verbal and Full-Scale IQ at 7 years. PBDE concentrations in children 7 years of age were significantly or marginally associated with concurrent teacher reports of attention problems and decrements in Processing Speed, Perceptual Reasoning, Verbal Comprehension, and Full-Scale IQ. These associations were not altered by adjustment for birth weight, gestational age, or maternal thyroid hormone levels.ConclusionsBoth prenatal and childhood PBDE exposures were associated with poorer attention, fine motor coordination, and cognition in the CHAMACOS cohort of school-age children. This study, the largest to date, contributes to growing evidence suggesting that PBDEs have adverse impacts on child neurobehavioral development.

BackgroundBisphenol A (BPA) is widely used in the manufacture of polycarbonate plastic bottles, food and beverage can linings, thermal receipts, and dental sealants. Animal and human studies suggest that BPA may disrupt thyroid function. Although thyroid hormones play a determinant role in human growth and brain development, no studies have investigated relations between BPA exposure and thyroid function in pregnant women or neonates.ObjectiveOur goal was to evaluate whether exposure to BPA during pregnancy is related to thyroid hormone levels in pregnant women and neonates.MethodsWe measured BPA concentration in urine samples collected during the first and second half of pregnancy in 476 women participating in the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study. We also measured free thyroxine (T4), total T4, and thyroid-stimulating hormone (TSH) in women during pregnancy, and TSH in neonates.ResultsAssociations between the average of the two BPA measurements and maternal thyroid hormone levels were not statistically significant. Of the two BPA measurements, only the one taken closest in time to the TH measurement was significantly associated with a reduction in total T4 (β = -0.13 µg/dL per log2 unit; 95% CI: -0.25, 0.00). The average of the maternal BPA concentrations was associated with reduced TSH in boys (-9.9% per log2 unit; 95% CI: -15.9%, -3.5%) but not in girls. Among boys, the relation was stronger when BPA was measured in the third trimester of pregnancy and decreased with time between BPA and TH measurements.ConclusionResults suggest that exposure to BPA during pregnancy is related to reduced total T4 in pregnant women and decreased TSH in male neonates. Findings may have implications for fetal and neonatal development.

ContextOrganophosphate (OP) pesticides are neurotoxic at high doses. Few studies have examined whether chronic exposure at lower levels could adversely affect children's cognitive development.ObjectiveWe examined associations between prenatal and postnatal exposure to OP pesticides and cognitive abilities in school-age children.MethodsWe conducted a birth cohort study (Center for the Health Assessment of Mothers and Children of Salinas study) among predominantly Latino farmworker families from an agricultural community in California. We assessed exposure to OP pesticides by measuring dialkyl phosphate (DAP) metabolites in urine collected during pregnancy and from children at 6 months and 1, 2, 3.5, and 5 years of age. We administered the Wechsler Intelligence Scale for Children, 4th edition, to 329 children 7 years of age. Analyses were adjusted for maternal education and intelligence, Home Observation for Measurement of the Environment score, and language of cognitive assessment.ResultsUrinary DAP concentrations measured during the first and second half of pregnancy had similar relations to cognitive scores, so we used the average of concentrations measured during pregnancy in further analyses. Averaged maternal DAP concentrations were associated with poorer scores for Working Memory, Processing Speed, Verbal Comprehension, Perceptual Reasoning, and Full-Scale intelligence quotient (IQ). Children in the highest quintile of maternal DAP concentrations had an average deficit of 7.0 IQ points compared with those in the lowest quintile. However, children's urinary DAP concentrations were not consistently associated with cognitive scores.ConclusionsPrenatal but not postnatal urinary DAP concentrations were associated with poorer intellectual development in 7-year-old children. Maternal urinary DAP concentrations in the present study were higher but nonetheless within the range of levels measured in the general U.S. population.

Organophosphorus (OP) pesticides are used in agriculture and several are registered for home use. As young children age they may experience different pesticide exposures due to varying diet, behavior, and other factors. We measured six OP dialkylphosphate (DAP) metabolites (three dimethyl alkylphosphates (DMAP) and three diethyl alkylphosphates (DEAP)) in urine samples collected from ~400 children living in an agricultural community when they were 6, 12, and 24 months old. We examined bivariate associations between DAP metabolite levels and determinants such as age, diet, season, and parent occupation. To evaluate independent impacts, we then used generalized linear mixed multivariable models including interaction terms with age. The final models indicated that DMAP metabolite levels increased with age. DMAP levels were also positively associated with daily servings of produce at 6- and 24-months. Among the 6-month olds, DMAP metabolite levels were higher when samples were collected during the summer/spring versus the winter/fall months. Among the 12-month olds, DMAP and DEAP metabolites were higher when children lived ≤ 60 meters from an agricultural field. Among the 24-month-olds, DEAP metabolite levels were higher during the summer/spring months. Our findings suggest that there are multiple determinants of OP pesticide exposures, notably dietary intake and temporal and spatial proximity to agricultural use. The impact of these determinants varied by age and class of DAP metabolite.

BackgroundHuman exposure to polybrominated diphenyl ether (PBDE) flame retardants has increased exponentially over the last three decades. Animal and human studies suggest that PBDEs may disrupt thyroid function. Although thyroid hormone (TH) of maternal origin plays an essential role in normal fetal brain development, there is a paucity of human data regarding associations between exposure to PBDEs and maternal TH levels during pregnancy.ObjectivesOur goal was to determine whether PBDE serum concentrations are associated with TH levels in pregnant women.MethodsWe measured the concentration of 10 PBDE congeners, free thyroxine (T4), total T4, and thyroid-stimulating hormone (TSH) in 270 pregnant women around the 27th week of gestation.ResultsSerum concentrations of individual PBDE congeners with detection frequencies > 50% (BDEs 28, 47, 99, 100, and 153) and their sum (ΣPBDEs) were inversely associated with TSH levels. Decreases in TSH ranged between 10.9% [95% confidence interval (CI), -20.6 to 0.0] and 18.7% (95% CI, -29.2 to -4.5) for every 10-fold increase in the concentration of individual congeners. Odds of subclinical hyperthyroidism (low TSH but normal T4) were also significantly elevated in participants in the highest quartile of ΣPBDEs and BDEs 100 and 153 relative to those in the first quartile. Associations between PBDEs and free and total T4 were not statistically significant. Results were not substantially altered after the removal of outliers and were independent of the method used to adjust for blood lipid levels and to express ΣPBDEs.ConclusionsResults suggest that exposure to PBDEs is associated with lower TSH during pregnancy. Findings may have implications for maternal health and fetal development.

BackgroundExposure to polybrominated diphenyl ether (PBDE) flame retardants is widespread, with 97% of Americans having detectable levels. Although PBDEs have been associated with reproductive and hormonal effects in animals, no human studies have examined their association with fertility.ObjectivesThis study was designed to determine whether maternal concentrations of PBDEs in serum collected during pregnancy are associated with time to pregnancy and menstrual cycle characteristics.MethodsPregnant women (n = 223) living in a low-income, predominantly Mexican-immigrant community in California were interviewed to determine how many months they took to become pregnant. Blood samples were collected and analyzed for PBDEs. PBDE concentrations were lipid adjusted and log10 transformed. Analyses were limited to PBDE congeners detected in > 75% of the population (BDEs 47, 99, 100, 153). Cox proportional hazards models modified for discrete time were used to obtain fecundability odds ratios (fORs) for the association of PBDEs and time to pregnancy.ResultsWe detected all four congeners in > 97% of women. Increasing levels of BDEs 47, 99, 100, 153 and the sum of these four congeners were all associated with longer time to pregnancy. We observed significantly reduced fORs for BDE-100 [adjusted fOR = 0.6; 95% confidence interval (CI), 0.4-0.9], BDE-153 (adjusted fOR = 0.5; 95% CI, 0.3-0.8), and the sum of the four congeners (adjusted fOR = 0.7; 95% CI, 0.5-1.0). PBDEs were not associated with menstrual cycle characteristics.ConclusionsWe found significant decreases in fecundability associated with PBDE exposure in women. Future studies are needed to replicate and confirm this finding.

ObjectivesDichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure.Data sources and extractionWe conducted a PubMed search in October 2008 and retrieved 494 studies.Data synthesisUse restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children.ConclusionsAlthough we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.

Little information has been published about pesticide exposures experienced by pregnant women. We measured six dialkyl phosphate (DAP) urinary metabolites of organophosphate (OP) pesticides in 600 pregnant, low-income women living in the Salinas Valley, California, an agricultural area. A total of 28% were employed as farm fieldworkers during pregnancy, and 81% had at least one household member who worked in agriculture. Samples were collected twice during pregnancy (mean = 13 and 26 weeks' gestation, respectively) and just after delivery (mean = 9 days). As in other studies, dimethyldithiophosphate levels were higher than those of other urinary OP metabolites. Total DAP metabolite levels in samples collected after delivery were higher than in samples collected during pregnancy. Median metabolite levels at the first and second prenatal sampling points and at the postpartum collection were 102.8, 106.8, and 227.2 nmol/L, respectively. Both prenatal and postpartum metabolite levels were higher in these Salinas Valley women than in a sample of women of childbearing age in the general U.S. population (National Health and Nutrition Examination Survey), although the deviation from U.S. reference levels was most pronounced after delivery. Higher DAP metabolite levels in the immediate postpartum period may have implications for estimating dose during pregnancy and for exposure during lactation.