Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth.

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T1-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (ß per log10 increase in creatinine adjusted mEP = -10.7, 95%CI: -18.12, -3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (ß for mediated path =-0.31, 95%CI: -0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

Fetal Growth Trajectories Among Small for Gestational Age Babies and Child Neurodevelopment.

BACKGROUND: Being born small for gestational age (SGA, <10th percentile) is a risk factor for worse neurodevelopmental outcomes. However, this group is a heterogeneous mix of healthy and growth-restricted babies, and not all will experience poor outcomes. We sought to determine whether fetal growth trajectories can distinguish who will have the worst neurodevelopmental outcomes in childhood among babies born SGA. METHODS: The present analysis was conducted in Generation R, a population-based cohort in Rotterdam, the Netherlands (N = 5,487). Using group-based trajectory modeling, we identified fetal growth trajectories for weight among babies born SGA. These were based on standard deviation scores of ultrasound measures from mid-pregnancy and late pregnancy in combination with birth weight. We compared child nonverbal intelligence quotient (IQ) and attention deficit hyperactivity disorder (ADHD) symptoms at age 6 between SGA babies within each growth trajectory to babies born non-SGA. RESULTS: Among SGA individuals (n = 656), we identified three distinct fetal growth trajectories for weight. Children who were consistently small from mid-pregnancy (n = 64) had the lowest IQ (7 points lower compared to non-SGA babies, 95% confidence interval [CI] = -11.0, -3.5) and slightly more ADHD symptoms. Children from the trajectory that started larger but were smaller at birth showed no differences in outcomes compared to children born non-SGA. CONCLUSIONS: Among SGA children, those who were smaller beginning in mid-pregnancy exhibited the worst neurodevelopmental outcomes at age 6. Fetal growth trajectories may help identify SGA babies who go on to have poor neurodevelopmental outcomes.

Prenatal Exposure to Nonpersistent Chemical Mixtures and Offspring IQ and Emotional and Behavioral Problems.

Prenatal exposure to nonpersistent chemicals such as phthalates, bisphenols, and organophosphate (OP) pesticides is ubiquitous and occurs in mixtures. So far, epidemiological studies investigating neurodevelopmental consequences of these exposures have mainly been restricted to single-pollutant models. Thus, we studied the association between prenatal exposure to nonpersistent chemical mixtures and child IQ and emotional and behavioral problems. Data came from 782 mother-child pairs. Eleven phthalate, one bisphenol, and five OP pesticide urinary exposure biomarkers were measured three times during pregnancy and averaged. Nonverbal IQ, internalizing and attention problems, aggressive behavior, and autistic traits were assessed at child age 6 years. We used quantile g-computation to estimate the change in each outcome per quartile increase in all chemicals within the mixture. Higher exposure to the mixture was associated with lower nonverbal IQ (-4.0 points (95%CI = -7.0, -1.0), -5.5 points (95%CI = -10.2, -0.9), and -4.6 points (95%CI = -10.8, 1.5) for the second, third, and fourth quartile, respectively, compared to the first quartile). These results were mainly driven by the phthalate mixture. No association was observed with emotional and behavioral problems. Prenatal exposure to nonpersistent chemical mixtures was associated with lower nonverbal IQ in children. Exposure to chemical mixtures during gestation is universal and may impact neurodevelopment.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years. METHOD: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. RESULTS: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. CONCLUSIONS: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Effectiveness of a Multidimensional Randomized Control Intervention to Reduce Quartz Exposure Among Construction Workers.

There is little evidence with respect to the effectiveness of intervention programs that focus on the reduction of occupational quartz exposure in the construction industry. This article evaluates the effectiveness of a multidimensional intervention which was aimed at reducing occupational quartz exposure among construction workers by increasing the use of technical control measures. Eight companies participating in the cluster randomized controlled trial were randomly allocated to the intervention (four companies) or control condition (four companies). The multidimensional intervention included engineering, organizational, and behavioural elements at both organizational and individual level. Full-shift personal quartz exposure measurements and detailed observations were conducted before and after the intervention among bricklayers, carpenters, concrete drillers, demolishers, and tuck pointers (n = 282). About 59% of these workers measured at baseline were reassessed during follow-up. Bayesian hierarchical models were used to evaluate the intervention effect on exposure levels. Concrete drillers in the intervention group used technical control measures, particularly water suppression, for a significantly greater proportion of the time spent on abrasive tasks during follow-up compared to baseline (93 versus 62%; P < 0.05). A similar effect, although not statistically significant, was observed among demolishers. A substantial overall reduction in quartz exposure (73 versus 40% in the intervention and control group respectively; P < 0.001) was observed for concrete drillers, demolishers, and tuck pointers. The decrease in exposure in the intervention group compared to controls was significantly larger for demolishers and tuck pointers, but not for concrete drillers. The observed effect could at least partly be explained by the introduced interventions; the statistically significant increased use of control measures among concrete drillers explains the observed effect to some extent in this job category only. Sensitivity analyses indicated that the observed decrease in exposure may also partly be attributable to changes in work location and abrasiveness of the tasks performed. Despite the difficulties in assessing the exact magnitude of the intervention, this study showed that the structured intervention approach at least partly contributed to a substantial reduction in quartz exposure among high exposed construction workers.

Quartz and respirable dust in the Dutch construction industry: a baseline exposure assessment as part of a multidimensional intervention approach.

Quartz exposure can cause several respiratory health effects. Although quartz exposure has been described in several observational workplace studies, well-designed intervention studies that investigate the effect of control strategies are lacking. This article describes a baseline exposure study that is part of a multidimensional intervention program aiming to reduce quartz exposure among construction workers. In this study, personal respirable dust and quartz exposure was assessed among 116 construction workers (bricklayers, carpenters, concrete drillers, demolishers, and tuck pointers). Possible determinants of exposure, like job, tasks, and work practices, use of control measures, and organizational and psychosocial factors, were explored using exposure models for respirable dust and quartz separately. Stratified analyses by job title were performed to evaluate the effect of control measures on exposure and to explore the association between control measures and psychosocial factors. Overall, 62% of all measurements exceeded the Dutch occupational exposure limit for quartz and 11% for respirable dust. Concrete drillers and tuck pointers had the highest exposures for quartz and respirable dust (0.20 and 3.43mg m(-3), respectively). Significant predictors of elevated quartz exposure were abrasive tasks and type of material worked on. Surprisingly, in a univariate model, an increased knowledge level was associated with an increase in exposure. Although control measures were used infrequently, if used they resulted in approximately 40% reduction in quartz exposure among concrete drillers and tuck pointers. Only among concrete drillers, the use of control measures was associated with a higher score for social influence (factor 1.6); knowledge showed an inverse association with use of control measures for concrete drillers, demolishers, and tuck pointers. In conclusion, the detailed information on determinants of exposure, use of control measures, and constraints to use these control measures can be used for the determination and systematic prioritization of intervention measures used to design and implement our intervention strategy. This study underlines the need for multidisciplinary workplace exposure control strategies although larger study populations are necessary to determine a possible causal association between organizational and psychosocial factors and psychosocial factors and control measures.

Validation and Recalibration of the Asbestos Removal Exposure Assessment Tool (AREAT).

OBJECTIVES: The Asbestos Removal Exposure Assessment Tool (AREAT) was previously developed to estimate exposure to respirable asbestos fibres during abatement processes. The current study describes the validation and recalibration of the AREAT model with external data. During model validation, the AREAT model was expanded to be able to estimate asbestos exposure from an additional source category: 'unspecified asbestos remnants'. METHODS: The validation dataset (n = 281) was derived from exposure measurement studies where for each exposure measurement the AREAT model parameters were coded and estimates were calculated. Pearson correlation coefficients (r) and intra class correlation coefficients (icc) were calculated as an indication of the agreement between the AREAT estimates and measured concentrations. In addition, the bias and the proportion of measurements with higher concentrations than model estimates were calculated. To expand and investigate model performance on exposure from 'unspecified asbestos remnants', a separate dataset was created with measurements collected during working with unspecified asbestos remnants, and similar validation comparisons were performed. Lastly, linear regression techniques were used to investigate possible improvements in model parameters. The model was recalibrated on a combined dataset consisting of the validation dataset and the original calibration dataset to increase model robustness. RESULTS: The validation comparisons showed good relative agreement (r) between AREAT estimates and measurements (r = 0.73) and a moderate absolute agreement (icc = 0.53). The overall relative bias was 108%, indicating an overall overestimation of exposure, and 4% of the estimated concentrations were higher than the actual measured concentrations. For the data subset concerning unspecified asbestos remnants, a moderate correlation between model estimates and measurement outcomes was found (r = 0.63). However, based on the low number of data in this subset, and moderate r, it was decided that cleaning of unspecified asbestos remnants is out of scope until more data are available. The results of this validation study suggested that two input parameters (product type friable material, efficacy of control measure foam) underestimated exposure. The effects of these parameters were updated to improve model performance. Compared to the original model, the recalibrated model resulted in slightly higher explained variance (62% compared to 56%) and lower uncertainty (15 compared to 17.3). CONCLUSION: The original AREAT model provided reliable asbestos exposure estimates with a sufficient level of conservatism taking into account the 90-percentile estimates. The model was further improved via the addition of a new feature and recalibration to predict asbestos exposure during the clean-up of unspecified asbestos remnants.

Fetal Organophosphate Pesticide Exposure and Child Adiposity Measures at 10 Years of Age in the General Dutch Population.

BACKGROUND: Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life. OBJECTIVE: We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age. METHODS: Between 2002 and 2006, we included 642 mother-child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid- and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging. RESULTS: Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y. CONCLUSION: We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied. https://doi.org/10.1289/EHP12267.

A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project.

Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appendix XI of REACH, allowing waiving of repeated dose toxicity studies, reproductive toxicity studies and carcinogenicity studies under a number of conditions if exposure is very low. A decision tree is described that was developed in the European project OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-Test and Test Information) to help decide in what cases EBW can be justified. The decision tree uses specific criteria as well as more general questions. For the latter, guidance on interpretation and resulting conclusions is provided. Criteria and guidance are partly based on an expert elicitation process. Among the specific criteria a number of proposed Thresholds of Toxicological Concern are used. The decision tree, expanded with specific parts on absorption, distribution, metabolism and excretion that are not described in this paper, is implemented in the OSIRIS webtool on integrated testing strategies.

Classification of occupational activities for assessment of inhalation exposure.

There is a large variety of activities in workplaces that can lead to emission of substances. Coding systems based on determinants of emission have so far not been developed. In this paper, a system of Activity Classes and Activity Subclasses is proposed for categorizing activities involving chemical use. Activity Classes share their so-called 'emission generation mechanisms' and physical state of the product handled and the underlying determinants of emission. A number of (industrial) stakeholders actively participated in testing and fine-tuning the system. With the help of these stakeholders, it was found to be relatively easy to allocate a large number of activities to the Activity Classes and Activity Subclasses. The system facilitates a more structured classification of activities in exposure databases, a structured analysis of the analogy of exposure activities, and a transparent quantification of the activity emission potential in (new) exposure assessment models. The first use of the system is in the Advanced REACH Tool.

Prenatal Exposure to Nonpersistent Chemical Mixtures and Fetal Growth: A Population-Based Study.

BACKGROUND: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. OBJECTIVE: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. METHODS: Within the Generation R Study, a population-based cohort in Netherlands (n=776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at <18, 18-25, and >25 weeks of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18-25 and >25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. RESULTS: The average EFW at 18-25 wk and >25wk was 369 and 1,626g, respectively, and the average birth weight was 3,451g. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18-25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2-Q4) had 26g [95% confidence intervals (CI):-38, -13], 35g (95% CI: -55, -15), and 27g (95% CI: -54, 1) lower EFW compared with those in the first quartile (Q1). A similar dose-response pattern was observed at >25wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1-Q2 or Q1-Q3. However, fetuses in Q4 had 91g (95% CI: -258, 76) lower birth weight in comparison with those in Q1. Results observed at 18-25 and >25wk were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference. DISCUSSION: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178.

Prediction of Dermal Exposure to Chemical Substances Using a Fluorescence Method within the SysDEA Project.

Dermal exposure is an important exposure route for occupational exposure and risk assessment. A fluorescence method has been developed to quantify occupational dermal exposure based on a visualization technique, using Tinopal SWN as a fluorescent tracer. The method was developed within the framework of a large experimental study, the SysDEA project. In SysDEA, dermal exposure was measured with different methods for 10 simulated exposure situations by sampling powder and liquid formulations containing Tinopal SWN on coveralls and patches and subsequently chemically analysing them. For the fluorescence method, photographs of exposed volunteers who performed the experiments were taken inside a room which consisted of an optimized arrangement of several UV irradiating tube light brackets, reflective and non-reflective backgrounds for maximum light diffusion and a camera. Image processing analysis software processed these photographs to obtain corresponding light intensity in terms of summed pixel values. To be able to estimate the amount of Tinopal SWN, 25% of the measured data from the SysDEA experiments were used to calibrate by correlating the summed pixel values from the photographs to actual measured exposure values using a second order regression model. For spraying both high and low viscosity liquids, showing uniformly distributed exposure patterns, strong Pearson correlation coefficients (R > 0.77) were observed. In contrast, the correlations were either inconsistently poor (R = -0.17 to 0.28 for pouring, rolling high viscosity liquid, manually handling objects immersed in low viscosity liquid and handling objects contaminated with powder), moderate (R = 0.73 for dumping of powder), or strong (R = 0.83 and 0.77 for rolling low viscosity liquid and manually handling objects immersed in high viscosity liquid). A model for spraying was developed and calibrated using 25% of the available experimental data for spraying and validated using the remaining 75%. Under given experimental conditions, the fluorescence method shows promising results and can be used for the quantification of dermal exposure for different body parts (excluding hands) for spraying-like scenarios that have a more uniform exposure pattern, but more research is needed for exposure scenarios with less uniform exposure patterns. For the estimation of exposure levels, the surface loading limit should be lower than 1.5░µg/cm2 (a lower limit could not be quantified based on experiments conducted in this study) on a large surface, like a coverall, which should be ideally perpendicular to the camera.

Performance of a Single Layer of Clothing or Gloves to Prevent Dermal Exposure to Pesticides.

The suitability, availability, and use of protective clothing are critical factors determining the actual dermal exposure (ADE) of operators and workers to pesticides. A realistic assessment of occupational exposure to pesticides requires information about the performance of protective clothing during everyday use. In this study, the performance of clothing or gloves has been investigated based on available dermal exposure data in order to provide recommendations for default protection factors that can be used in regulatory exposure assessments. Suitable dermal exposure data from available exposure databases were collated and analysed. The data that met the selection criteria for the analysis of the performance of protective clothing comprised studies in which protective clothing like cotton coveralls, cotton clothing, polyester-cotton coveralls, Sontara coveralls, Tyvek coveralls, butyl/neoprene gloves, latex/PE/vinyl/PVC gloves, or nitrile gloves were worn. Based on available potential and ADE levels, the migration of pesticides through this protective clothing was estimated. Evaluation of exposure data showed that on average only 2.3-2.6% of the pesticides present on the outside of the clothing or gloves migrated through the garments, although there was a large variation with migration up to 99%. Forearms, legs, and chest areas of the clothing tended to have the greatest migration of pesticides. Caution is needed in the selection of the appropriate protection offered protective clothing for specific situations. This study gives valuable information on the performance of protective clothing, for use in exposure assessment and for default setting in exposure modelling, taking into account the type of clothing or gloves worn. As new data become available, it may be possible to further refine the protection factors offered by different types of clothing or gloves, particularly where a common protocol has been used.

Experimental Assessment of Inhalation and Dermal Exposure to Chemicals During Industrial or Professional Activities in Relation to the Performance of ECETOC TRA.

For many work situations only insufficient exposure data are available to perform proper risk assessment. Because measuring worker exposure can be time consuming and resource intense, the availability of reliable exposure models is important when performing risk assessments. However, the development and improvement of exposure models are hampered by scarcity of sound exposure data as well as by lack of information on relevant exposure factors and conditions of exposure. This paper describes a study where inhalation and dermal exposure data were collected under defined conditions. Exposure scenarios examined included tasks that have not been investigated in previous validation studies. The results of these measurements were compared with ECETOC TRA model version 3.1 predictions. In this study, five exposure scenarios were selected, namely 'use in a closed batch process' (PROC 4), 'mixing or blending in a partly open batch process' (PROC 5), 'rolling' (PROC 10), 'immersion' (PROC 13), and 'stirring' (PROC 19). These PROCs stem from the descriptors that Registration, Evaluation and Authorization of Chemicals has established to depict the identified uses of chemical substances. These exposure scenarios were selected mainly because little or no data are available for these situations, or ECETOC TRA is likely to underestimate exposure for these situations. Experiments were performed by volunteers for the selected exposure scenarios, in which tasks were performed aiming to represent real workplace situations. In total 70 experiments were performed, during which 70 dermal exposure measurements (5 volunteers × 2 repeats × 7 scenarios) and 32 inhalation exposure measurements (4 volunteers × 2 repeats × 4 scenarios) were collected. Two formulations were used, namely pure Tinopal SWN powder (solid product, a fluorescent tracer) and 0.5% Tinopal SWN dissolved in 1,2-dichloroethane (1,2-DCE). DCE is considered a moderate volatile liquid. For exposure scenarios using the liquid formulation, both inhalation and dermal measurements were performed, while for exposure scenarios using the pure powder only dermal exposure measurements were performed. In addition, photographs were taken under ultraviolet light to qualitatively assess exposure patterns on hands and body. Volunteers repeatedly performed a selection of tasks under standardized conditions in a test chamber for each exposure scenario. Results show that ECETOC TRA overestimated dermal hand exposure for all PROCs included in the study, and was considered to be conservative. Additionally, ECETOC TRA overestimated inhalation exposure for closed and partially closed processes, but underestimated inhalation exposure for rolling and handling of immersed objects. Qualitative assessment of the hands and body showed mainly the hands were exposed for tasks involving closed and partially closed processes and when handling of immersed objects. Exposure to other body segments were also observed for rolling and stirring. In conclusion, this study gave insights into dermal and inhalation exposure levels during selected task scenarios, and showed that ECETOC TRA is conservative when dermal exposure is estimated. Inhalation exposure estimates for PROCs 10 and 13 tasks with the moderate volatility liquid were underestimated in this study. It may be therefore necessary to re-evaluate base model predictions for these scenarios when medium fugacity liquids are involved.

Phthalate and Bisphenol Exposure during Pregnancy and Offspring Nonverbal IQ.

BACKGROUND: Prenatal exposures to phthalates and bisphenols are associated with impaired brain development in animals. However, epidemiological studies investigating the association between prenatal phthalate or bisphenol exposure and cognition have produced mixed findings and mostly had modest sample sizes and measured the exposure during the third trimester. OBJECTIVE: We examined the association between pregnancy maternal urinary biomarkers of phthalate or bisphenol exposure and nonverbal intelligence quotient (IQ) in children 6 years of age. METHOD: The study sample consisted of 1,282 mother-child pairs participating in the Generation R Study, a population-based birth cohort in Rotterdam, Netherlands (enrollment 2002-2006). We measured maternal urinary concentrations of 18 phthalate metabolites and 8 bisphenols at <18, 18-25, and >25 wks of gestation. Child nonverbal IQ was measured at 6 years of age using the Snijders-Oomen Nonverbal Intelligence Test-Revised. Linear regression models were fit for each of the three collection phases separately, the three collection phases jointly, and for the averaged prenatal exposure across pregnancy. RESULTS: Higher urinary concentrations of phthalate metabolites during early pregnancy were associated with lower child nonverbal IQ score [e.g., B per 10-fold increase in summed low-molecular weight phthalates=-1.7 (95% CI: -3.1, -0.3)]. This association remained unchanged when adjusted for mid and late pregnancy exposures. We also observed an inverse association between late pregnancy di-n-octyl phthalate (DNOP) exposure and nonverbal IQ. Maternal urinary concentrations of bisphenols were not associated with child nonverbal IQ. There was no effect estimate modification by sex. CONCLUSIONS: We did not observe that maternal biomarkers of bisphenol exposure are associated with nonverbal IQ. We found that phthalate exposure in early pregnancy and DNOP exposure in late pregnancy are associated with lower nonverbal IQ scores in children. Our results might suggest that particularly early pregnancy is a sensitive window of phthalate exposure, but future studies are needed to replicate our findings. https://doi.org/10.1289/EHP6047.

Comparison of Measurement Methods for Dermal Exposure to Hazardous Chemicals at the Workplace: The SysDEA Project.

There is a principal need for more precise methodology with regard to the determination of occupational dermal exposure. The goal of the Systematic analysis of Dermal Exposure to hazardous chemical Agents at the workplace project was therefore to generate scientific knowledge to improve and standardize measurement methods for dermal exposure to chemicals at the workplace. In addition, the comparability of different measurement methods was investigated. Different methods (body sampling by means of coveralls and patches, hand sampling by means of gloves and washing, and head sampling by means of headbands and wiping) were compared. Volunteers repeatedly performed a selection of tasks under standardized conditions in test chambers to increase the reproducibility and decrease variability. The selected tasks were pouring, rolling, spraying, and handling of objects immersed in liquid formulations, as well as dumping and handling objects contaminated with powder. For the chemical analysis, the surrogate test substance Tinopal SWN was analyzed by means of a high-performance liquid chromatographic method using a fluorescence detector. Tinopal SWN was either applied as a solid product in its pure form, or as a low and high viscosity liquid containing Tinopal SWN in dissolved form. To compare the sampling methods with patches and coveralls, the exposure values as measured on the patches were extrapolated to the surface areas of the respective parts of the coverall. Based on this extrapolation approach, using the patch method resulted in somewhat higher exposure values compared to using a coverall for all exposure situations, but the differences were only statistically significant in case of the liquid exposure situations. Using gloves resulted in significantly higher exposure values compared to hand wash for handling immersed objects, rolling, and handling contaminated objects, and slightly higher (not significant) exposure values during pouring and spraying. In the same context, applying wipe sampling resulted in higher exposure values than using a headband, which was at least partly due to extrapolation of the wipe results to the surface area of the headband. No 'golden standard' with regard to a preferred measurement method for dermal exposure could be identified from the methods as investigated in the current study.

Organophosphate Pesticide Exposure in Pregnancy in Association with Ultrasound and Delivery Measures of Fetal Growth.

BACKGROUND: Perturbations in fetal growth may have adverse consequences for childhood and later life health. Organophosphate pesticide (OP) exposure has been associated with reduced birth weight at delivery but results are not consistent. We investigated this question by utilizing ultrasound measures of size in utero in combination with measures from delivery. METHODS: Within Generation R, a population-based prospective cohort conducted between 2002 and 2006 in Rotterdam, Netherlands, we measured dialkyl phosphates (DAPs), OP metabolites, in urine samples from early, middle, and late pregnancy and created a subject-specific average to estimate OP exposure ([Formula: see text]). Ultrasound measures of head circumference, femur length, and estimated fetal weight from middle and late pregnancy and delivery measures were converted to standard deviation scores (SDS). Associations with DAP average were examined in linear mixed effects models that included an interaction term between gestational age at measurement and DAP average to investigate whether the relationship differed over time. Windows of vulnerability to exposure were assessed by modeling urinary DAPs from each visit in relation to growth measurements. RESULTS: A 10-fold increase in average DAPs was associated with a [Formula: see text] SDS decrease in fetal length (95% [Formula: see text], [Formula: see text]) and a [Formula: see text] SDS decrease in estimated fetal weight (95% [Formula: see text], [Formula: see text]) at 20 weeks of gestation. These differences corresponded to 5% and 6% decreases relative to the mean. Effect estimates were greatest in magnitude for DAP concentrations measured early in pregnancy. Associations between average DAPs and growth measures at delivery were positive but not significant for head circumference and length and were null for weight. CONCLUSIONS: Maternal urinary DAPs were associated with decreased fetal weight and length measured during mid-pregnancy, but not at delivery. https://doi.org/10.1289/EHP4858.

Organophosphate pesticide metabolite concentrations in urine during pregnancy and offspring attention-deficit hyperactivity disorder and autistic traits.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings. OBJECTIVE: The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. METHOD: Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18-25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders. RESULTS: Median DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18-25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected. CONCLUSIONS: In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.

Organophosphate Pesticide Metabolite Concentrations in Urine during Pregnancy and Offspring Nonverbal IQ at Age 6 Years.

BACKGROUND: Susceptibility to organophosphate (OP) pesticide neurotoxicity may be greatest during the prenatal period; however, previous studies have produced mixed findings concerning in utero OP pesticide exposure and child cognition. OBJECTIVES: Our objective was to determine whether maternal urinary concentrations of OP pesticide metabolites are inversely associated with child nonverbal IQ at 6 y of age and to examine potential effect measure modification by the PON1 gene. METHODS: Data came from 708 mother­child pairs participating in the Generation R Study. Maternal urine concentrations of six dialkylphosphates (DAPs), collected at [Formula: see text], 18­25, and [Formula: see text] of gestation, were determined. Child nonverbal IQ was measured at 6 y of age using the Mosaics and Categories subtests from the Snijders-Oomen Nonverbal Intelligence Test-Revised. PON1 was determined in cord blood for 474 infants. Multiple linear regression models were fit to estimate the DAP-IQ associations and PON1 interactions. RESULTS: Overall, associations between child nonverbal IQ and maternal DAP concentrations were small and imprecise, and these associations were inconsistent across urine sampling periods. Howover, for a 10-fold difference in total DAP concentration for the [Formula: see text] of gestation samples, adjusted child nonverbal IQ was 3.9 points lower (95% CI: [Formula: see text], [Formula: see text]). Heterogeneity in the DAP­IQ association by PON1 gene allele status was not observed ([Formula: see text]). CONCLUSIONS: Consistent evidence of an association between higher maternal urinary DAP concentrations and lower child IQ scores at 6 y of age was not observed. There was some evidence for an inverse relation of child nonverbal IQ and late pregnancy urinary DAPs, but the estimated association was imprecise. https://doi.org/10.1289/EHP3024.

Effect of extraction and assay media on analysis of airborne endotoxin.

The measurement of airborne endotoxins is thus far not standardized. Earlier studies reported higher endotoxin yields when Tween 20 was added to the media used for filter extraction and in the Limulus amebocyte lysate (LAL) assay. This study compared four common media and assessed the effects of Tween during extraction and analysis separately. Parallel airborne dust samples from five work environments (n = 250) were used to compare the four media (pyrogen-free water [PFW], PFW-Tween 20, PFW-Tris, and PFW-triethylamine-phosphate [TAP]) and an extraction time of 10 or 60 min. A subset of the extracts in PFW or PFW-Tween (n = 40) were analyzed in parallel LAL assays with PFW or PFW-Tween as the assay medium. The results produced by a shorter extraction time or the presence of Tris were similar to the results for the reference procedure (PFW and 60 min of shaking). The use of PFW-TAP showed overall lower yields and a deviant calibration curve. The presence of Tween in the extraction medium resulted in significantly (P < 0.05) higher endotoxin yields from all dust types, independent of the effect of Tween in the assay. Tween in the LAL assay, however, also strongly inhibited the reactivity of the lipopolysaccharide (LPS) standard, thus shifting the calibration curve to higher values. The inhibition of LPS in test samples was less pronounced and varied between dust sources, resulting in enhanced calculated concentrations. This assay effect could be circumvented by diluting extracts at least 50-fold before the LAL assay. In conclusion, of the media tested, only Tween enhances the efficiency of endotoxin extraction from airborne dust samples in a consistent manner. We recommend extraction in PFW-Tween combined with dilution and LAL analysis in PFW.