Birgit Claus Henn

Pesticides and their Metabolites in the Homes and Urine of Farmworker Children Living in the Salinas Valley, CA

In support of planning efforts for the National Childrens Study, we conducted a study to test field methods for characterizing pesticide exposures to 20 farmworker children aged 5–27 months old living in the Salinas Valley of Monterey County, California. We tested methods for collecting house dust, indoor and outdoor air, dislodgeable residues from surfaces and toys, residues on clothing (sock and union suits), food, as well as spot and overnight diaper urine samples. We measured 29 common agricultural and home use pesticides in multiple exposure media samples. A subset of organophosphorus (OP), organochlorine (OC) and pyrethroid pesticides were measured in food. We also analyzed urine samples for OP pesticide metabolites. Finally, we administered four field-based exposure assessment instruments: a questionnaire; food diary; home inspection; and a self-administered child activity timeline. Pesticides were detected more frequently in house dust, surface wipes, and clothing than other media, with chlorpyrifos, diazinon, chlorthal-dimethyl, and cis- and trans-permethrin detected in 90% to 100% of samples. Levels of four of these five pesticides were positively correlated among the house dust, sock, and union suit samples (Spearmans ρ=0.18–0.76). Pesticide loading on socks and union suits was higher for the group of 10 toddlers compared to the 10 younger crawling children. Several OP pesticides, as well as 4,4′-DDE, atrazine, and dieldrin were detected in the food samples. The child activity timeline, a novel, low-literacy instrument based on pictures, was successfully used by our participants. Future uses of these data include the development of pesticide exposure models and risk assessment.

Associations of Early Childhood Manganese and Lead Coexposure with Neurodevelopment

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.

Perinatal and Childhood Exposure to Cadmium, Manganese, and Metal Mixtures and Effects on Cognition and Behavior: A Review of Recent Literature

Lead (Pb) and mercury (Hg) neurotoxicity is well established. In recent years, a growing body of evidence suggests that environmental exposure to other metals including arsenic (As), cadmium (Cd), and manganese (Mn) and their mixtures also poses public health threats. In this paper, we summarize the recent literature examining the relationship of prenatal and childhood environmental metal exposures with cognitive and behavioral outcomes in children. We conducted a literature search to identify epidemiologic studies that examined the relationship of Cd, Mn, and metal mixtures with children’s neurodevelopmental/cognitive and behavioral outcomes. We restricted the search to peer-reviewed studies published in English between January 2009 and March 2015. We identified a total of 31 articles of which 16, 17, and 16 studies examined the effects of Cd, Mn, or metal mixtures, respectively. Based on our review, there is suggestive evidence that prenatal/childhood Cd exposure may be associated with poorer cognition, but additional research is clearly needed. We found little evidence of behavioral effects of early life Cd exposure, and no studies found a significant relationship with attention deficit hyperactivity disorder. Studies of early life Mn exposure consistently reported negative impacts on both cognition and behavior. There is also growing evidence that co-exposure to multiple metals can result in increased neurotoxicity compared to single-metal exposure, in particular during early life. Few studies have evaluated behavioral effects related to metal co-exposure.

Chemical Mixtures and Children’s Health

Purpose of review Humans are routinely exposed to multiple chemicals simultaneously or sequentially. There is evidence that the toxicity of individual chemicals may depend on the presence of other chemicals. Studies on chemical mixtures are limited, however, because of the lack of sufficient exposure data, limited statistical power, and difficulty in the interpretation of multidimensional interactions. This review summarizes the recent literature examining chemical mixtures and pediatric health outcomes, with an emphasis on metal mixtures. Recent findings Several studies report significant interactions between metals in relation to pediatric health outcomes. Two prospective studies found interactive effects of early-life lead and manganese exposures on cognition. In two different cohorts, interactions between lead and cadmium exposures were reported on reproductive hormone levels and on neurodevelopment. Effects of lead exposure on impulsive behavior and cognition were modified by mercury exposure in studies from Canada and Denmark. However, there is little consistency related to exposure indicators and statistical approaches for evaluating interaction. Summary Several studies suggest that metals interact to cause health effects that are different from exposure to each metal alone. Despite the nearly infinite number of possible chemical combinations, mixtures research represents real-life exposure scenarios and warrants more attention, particularly in the context of uniquely vulnerable children.

Associations between urinary diphenyl phosphate and thyroid function

Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer with widespread human exposure. Data on health effects of TPHP are limited. Recent toxicological studies suggest TPHP may alter thyroid function. We used repeated measures to assess the temporal variability in urinary concentrations of the TPHP metabolite, diphenyl phosphate (DPHP), and to examine relationships between DPHP concentrations and thyroid hormones. We sampled 51 adults at months 1, 6, and 12 from 2010 to 2011. Urine samples were analyzed for DPHP. Serum samples were analyzed for free and total thyroxine (fT4, TT4), total triiodothyronine (TT3), and thyroid stimulating hormone (TSH). We assessed variability in DPHP using intraclass correlation coefficients (ICCs) and kappa statistics. We used linear mixed-effects models to examine associations between DPHP and thyroid hormones. DPHP was detected in 95% of urine samples. Mean DPHP concentrations were 43% higher in women than men. DPHP showed high within-subject variability (ICC range, 0.13-0.39; kappa range, 0.16-0.39). High versus low (≥2.65 vs. <2.65ng/mL) DPHP in all participants was associated with a 0.43μg/dL (95% confidence interval: 0.15, 0.72) increase in mean TT4 levels. In sex-stratified analyses, high versus low DPHP was associated with a 0.91μg/dL (95% CI: 0.47, 1.36) increase in mean TT4 in women. The association was attenuated in men (βeta=0.19; 95% CI: -0.15, 0.52). We found no significant associations between DPHP and fT4, TT3, or TSH. We found evidence that TPHP exposure may be associated with increased TT4 levels, especially in women.

Prenatal Arsenic Exposure and Birth Outcomes among a Population Residing near a Mining-Related Superfund Site

Background: Limited epidemiologic data exist on prenatal arsenic exposure and fetal growth, particularly in the context of co-exposure to other toxic metals. Objective: We examined whether prenatal arsenic exposure predicts birth outcomes among a rural U.S. population, while adjusting for exposure to lead and manganese. Methods: We collected maternal and umbilical cord blood samples at delivery from 622 mother–infant pairs residing near a mining-related Superfund site in Northeast Oklahoma. Whole blood arsenic, lead, and manganese were measured using inductively coupled plasma mass spectrometry. We modeled associations between arsenic concentrations and birth weight, gestational age, head circumference, and birth weight for gestational age. Results: Median (25th–75th percentile) maternal and umbilical cord blood metal concentrations, respectively, were as follows: arsenic, 1.4 (1.0–2.3) and 2.4 (1.8–3.3) μg/L; lead, 0.6 (0.4–0.9) and 0.4 (0.3–0.6) μg/dL; manganese, 22.7 (18.8–29.3) and 41.7 (32.2–50.4) μg/L. We estimated negative associations between maternal blood arsenic concentrations and birth outcomes. In multivariable regression models adjusted for lead and manganese, an interquartile range increase in maternal blood arsenic was associated with –77.5 g (95% CI: –127.8, –27.3) birth weight, –0.13 weeks (95% CI: –0.27, 0.01) gestation, –0.22 cm (95% CI: –0.42, –0.03) head circumference, and –0.14 (95% CI: –0.24, –0.04) birth weight for gestational age z-score units. Interactions between arsenic concentrations and lead or manganese were not statistically significant. Conclusions: In a population with environmental exposure levels similar to the U.S. general population, maternal blood arsenic was negatively associated with fetal growth. Given the potential for relatively common fetal and early childhood arsenic exposures, our finding that prenatal arsenic can adversely affect birth outcomes is of considerable public health importance. Citation: Claus Henn B, Ettinger AS, Hopkins MR, Jim R, Amarasiriwardena C, Christiani DC, Coull BA, Bellinger DC, Wright RO. 2016. Prenatal arsenic exposure and birth outcomes among a population residing near a mining-related Superfund site. Environ Health Perspect 124:1308–1315; http://dx.doi.org/10.1289/ehp.1510070

Association of prenatal urinary phthalate metabolite concentrations and childhood bmi and obesity.

BackgroundAlthough experiments in animals suggest that phthalates may have obesogenic effects, studies on prenatal exposure in children show inconsistent results.MethodsWe measured urinary concentrations of 11 phthalate metabolites collected twice during pregnancy from mothers participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study (N=345). Height, weight, waist circumference, and percent body fat were assessed in their children between 5 and 12 years of age. We used generalized estimating equations to examine associations at each age and tested for interaction by sex.ResultsMetabolites of diethyl phthalate (DEP), di-n-butyl phthalate (DBP), butyl benzyl phthalate, and di(2-ethylhexyl) phthalate (DEHP) were positively associated with BMI z-score, waist circumference z-score, and percent body fat at multiple ages. At age 12, we observed increased odds of being overweight/obese with each doubling of prenatal concentrations of DEP (odds ratio=1.3; 95% confidence intervals: 1.1, 1.4), DBP (1.2; 1.0, 1.4), and DEHP (1.3; 1.0, 1.6) metabolites. Results were similar in boys and girls except for DBP metabolites and the non-specific metabolite mono-(3-carboxypropyl) phthalate, which showed positive associations only in boys.ConclusionIn utero exposure to certain phthalates is associated with increased BMI and risk for overweight/obesity in childhood.

The Joint Effect of Prenatal Exposure to Metal Mixtures on Neurodevelopmental Outcomes at 20–40 Months of Age: Evidence from Rural Bangladesh

Background: Exposure to chemical mixtures is recognized as the real-life scenario in all populations, needing new statistical methods that can assess their complex effects. Objectives: We aimed to assess the joint effect of in utero exposure to arsenic, manganese, and lead on children’s neurodevelopment. Methods: We employed a novel statistical approach, Bayesian kernel machine regression (BKMR), to study the joint effect of coexposure to arsenic, manganese, and lead on neurodevelopment using an adapted Bayley Scale of Infant and Toddler Development™. Third Edition, in 825 mother–child pairs recruited into a prospective birth cohort from two clinics in the Pabna and Sirajdikhan districts of Bangladesh. Metals were measured in cord blood using inductively coupled plasma-mass spectrometry. Results: Analyses were stratified by clinic due to differences in exposure profiles. In the Pabna district, which displayed high manganese levels [interquartile range (IQR): 4.8, 18μg/dl], we found a statistically significant negative effect of the mixture of arsenic, lead, and manganese on cognitive score when cord blood metals concentrations were all above the 60th percentile (As≥0.7μg/dl, Mn≥6.6μg/dl, Pb≥4.2μg/dl) compared to the median (As=0.5μg/dl, Mn=5.8μg/dl, Pb=3.1μg/dl). Evidence of a nonlinear effect of manganese was found. A change in log manganese from the 25th to the 75th percentile when arsenic and manganese were at the median was associated with a decrease in cognitive score of −0.3 (−0.5, −0.1) standard deviations. Our study suggests that arsenic might be a potentiator of manganese toxicity. Conclusions: Employing a novel statistical method for the study of the health effects of chemical mixtures, we found evidence of neurotoxicity of the mixture, as well as potential synergism between arsenic and manganese. https://doi.org/10.1289/EHP614

Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures

The impact of neurotoxic chemical mixtures on childrens health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents

Introduction: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school‐age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. Methods: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right‐handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11–14 years old. We examined the relationships of tooth Mn (ln‐transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. Results: We found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn × sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye‐hand coordination in boys compared to girls in sex‐stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right‐hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). Conclusions: This study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex‐specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex‐specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period. HighlightsLiterature on perinatal Mn exposure and motor function in adolescents is limited.We used a novel tooth biomarker to reconstruct prenatal and childhood Mn exposure.Sex‐specific association between Mn exposure and neuromotor functions was observed.Prenatal Mn was associated with better body stability in boys but instability in girls.