To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive.
We investigated the association ...between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs.
Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis.
A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11). Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education.
We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.
Experimental and epidemiological studies suggested that exposure to lead (Pb) may influence the hypothalamic-pituitary-adrenal (HPA) axis. However, previous studies have yielded mixed results. We ...evaluated changes in basal salivary cortisol levels and acute cortisol responsivity to psychological stress in relation with blood Pb levels (BPb), in Caucasian individuals 50–67 years of age. Data were collected through the Study of Genetics, Stress and Cognitive Development (2004–2006). Diurnal basal and stress-reactive salivary cortisol levels were collected and BPb levels were determined using inductively coupled plasma mass spectroscopy. A total of 65 participants were included in the current study. General linear mixed models were used to assess the association between BPb level and change in cortisol secretion over time, for diurnal basal pattern and stress-reactive pattern, respectively. The geometric mean BPb was 2.70μg/dL (± 1.44) and two exposure groups were created based on the median value of 2.48µg/dL. No difference in geometric mean of salivary cortisol (µg/dL) at awakening was observed between High and Low BPb groups (0.23 (± 0.11) vs 0.20 (± 0.11), p = 0.36). The overall pattern of change in both diurnal basal (from the awakening to bedtime) and reactive salivary cortisol (during the stress induction protocol) did not differ between groups. In these middle-aged and older adults, we concluded that Pb exposure, within the range observed in the current study, was associated with neither diurnal nor stress-reactive cortisol secretion. Further investigation with larger datasets are needed to confirm our observations.
•We assessed cortisol secretions (CS) in adults aged 50–67 years.•We reported changes in CS in relation to blood lead levels.•At low-levels, lead does not impact the global trend of salivary CS.
► Studies on human PBDE neurotoxicity are reviewed. ► A scheme is proposed for the incorporation of in vitro benchmark data into human risk assessment. ► The importance of adequate pharmacokinetic ...modeling for exposure assessment is emphasized. ► Uncertainties and limitations in extrapolating in vitro data to the in vivo situation are discussed. ► Research needs and perspectives are highlighted.
Polybrominated diphenyl ethers (PBDEs) are flame retardants routinely detected in samples of cord blood and breast milk. Concerns have been raised with regard to the toxicity of both pre- and postnatal exposures towards the developing nervous system. Although there is an increasing body of literature on the disruption of brain cell functions by certain PBDE congeners in vitro, some challenges have yet to be tackled to enable the translation of in vitro findings into their in vivo counterparts. In this paper, we review findings on the PBDE neurotoxicity in human cells and discuss the research gaps to be addressed. Moreover, we propose a scheme for the incorporation of in vitro data in human risk assessment, namely through (i) the determination of in vitro cell benchmark levels; (ii) the consideration of uncertainties in establishing equivalency between the in vitro and the in vivo tissue benchmark levels (e.g., chronic vs. acute exposure, interactions with other chemicals); and (iii) relating tissue benchmark levels to surrogate levels of internal exposure. Alongside the assessment of brain dosimetry following exposure to PBDEs, in vitro neurotoxicity data provide a unique opportunity to evaluate the risks of prenatal and early life exposures on children neurodevelopment.
Reasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine are multifaceted and poorly understood.
We aimed to determine ...whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene reduces 6-month infant BCG vaccine response.
Data came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical-BCG associations among approximately 500 mother-infant pairs, with adjustment for confounders.
The median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid interquartile range (IQR): 37-248, and 388 ng/g lipid (IQR: 115-847) for DDE. Higher 6-month infant concentrations of PCB-153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB-153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: -42, -32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB-DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone.
The associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown.
Jusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobná B, Kočan A, Fabišiková A, Čonka K, Trnovec T, Hertz-Picciotto I, Lawrence BP. 2016. A birth cohort study of maternal and infant serum PCB-153 and DDE concentrations and responses to infant tuberculosis vaccination. Environ Health Perspect 124:813-821; http://dx.doi.org/10.1289/ehp.1510101.
An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported ...(Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42–51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26–1.40), whereas the reported OR was 1.4 (95% CI 1.1–1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.
•Blood PFAS concentrations increase in menopausal women because of reduced loss in menses.•The PFAS Monte Carlo PBPK model reproduces epidemiological population characteristics.•Pharmacokinetics explain a substantial portion of the associations between serum PFAS and onset of menopause.
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A recent meta-analysis based on data from > 7,000 pregnancies reported an association between prenatal polychlorinated biphenyl (PCB)-153 exposure and reduced birth weight. Gestational weight gain, ...which is associated negatively with PCB levels in maternal and cord blood, and positively with birth weight, could substantially confound this association.
We sought to estimate the influence of gestational weight gain on the association between PCB-153 exposure and birth weight using a pharmacokinetic model.
We modified a recently published pharmacokinetic model and ran Monte Carlo simulations accounting for variability in physiologic parameters and their correlations. We evaluated the pharmacokinetic model by comparing simulated plasma PCB-153 levels during pregnancy to serial measurements in 10 pregnant women from another study population. We estimated the association between simulated plasma PCB-153 levels and birth weight using linear regression models.
The plasma PCB-153 level profiles generated with the pharmacokinetic model were comparable to measured levels in 10 pregnant women. We estimated a 118-g decrease in birth weight (95% CI: -129, -106 g) for each 1-μg/L increase in simulated cord plasma PCB-153, compared with the 150-g decrease estimated based on the previous meta-analysis. The estimated decrease in birth weight was reduced to -6 g (95% CI: -18, 6 g) when adjusted for simulated gestational weight gain.
Our findings suggest that associations previously noted between PCB levels and birth weight may be attributable to confounding by maternal weight gain during pregnancy.
Despite experimental evidence that lactational exposure to persistent organic pollutants (POPs) can impact health, results from epidemiologic studies are inconclusive. Inconsistency across studies ...may reflect the inability of current methods to estimate children's blood levels during specific periods of susceptibility.
We developed a toxicokinetic model to simulate blood POP levels in children from two longitudinal birth cohorts and aimed to validate it against blood levels measured at 6, 16, and 45 months of age.
The model consisted of a maternal and a child lipid compartment connected through placental diffusion and breastfeeding. Simulations were carried out based on individual physiologic parameters; duration of breastfeeding; and levels of POPs measured in maternal blood at delivery, cord blood, or breast milk. Model validity was assessed through regression analyses of simulated against measured blood levels.
Simulated levels explained between 10% and 83% of measured blood levels depending on the cohort, the compound, the sample used to simulate children's blood levels, and child's age when blood levels were measured. Model accuracy was highest for estimated blood POP levels at 6 months based on maternal or cord blood levels. However, loss in model precision between the 6th and the 45th month was small for most compounds.
Our validated toxicokinetic model can be used to estimate children's blood POP levels in early to mid-childhood. Estimates can be used in epidemiologic studies to evaluate the impact of exposure during hypothesized postnatal periods of susceptibility on health.
To date, breast cancer epidemiologic studies have relied on blood or tissue specimens sampled at the time of diagnosis or a few years prior to assess lifetime exposure to polychlorinated biphenyls ...(PCB). In this study, we evaluated whether such PCB measurements are indicative of early-life levels by reconstructing lifetime toxicokinetic profiles for women included in the CECILE case-control study, using a physiologically based pharmacokinetic (PBPK) model.
We simulated lifetime toxicokinetic profiles of PCB-153 for 2,134 French women by incorporating information on body weight history, height, pregnancies, and breast-feeding in the PBPK model. Oral dose was calculated by considering measured blood PCB-153 and the temporal trend of environmental contamination. Area under the concentration versus time curve (AUC) for each decade of life and maximum blood concentration (C(max)) were compiled and compared with measured levels, using Pearson partial correlation analyses adjusting for age at diagnosis.
When considering all individuals, simulated AUCs correlated with measured PCBs, with coefficients ranging from 0.735 to 0.981. The weakest correlations were obtained with AUCs for the first decades of life. Stratified analyses suggested that breast-feeding reduces the reliability of late-life blood levels in representing lifetime exposure.
Results of this study suggest that PCB levels measured at the time of diagnosis do not fully represent early-life exposures.
PBPK-derived estimates of early-life levels circumvent the limitations of current approaches in assessing PCB lifetime exposure and may be used to address hypothesized windows of breast vulnerability (e.g., puberty) in this population.
Children are exposed to p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) through placental and lactational transfer. Some studies have suggested ...that early-life exposure to these compounds could lead to increased body mass index (BMI) during childhood. Our aim was to assess whether children's exposure during the first 2 years of life is associated with BMI z-score in Japanese children at 42 months of age.
We used data from a birth cohort (n = 290) of the Tohoku Study of Child Development. p,p'-DDT and p,p'-DDE levels were measured in breast milk samples collected 1 month after birth, and levels in children were estimated using a toxicokinetic model for three exposure periods (0-6 months, 6-12 months, 12-24 months). Associations between exposure estimates and BMI z-score at 42 months of age were assessed using multivariate linear regression models.
We found no significant association between levels of p,p'-DDT measured in breast milk or estimated in children and BMI z-score. However, we observed associations between estimated p,p'-DDE levels in girls during all postnatal exposure periods and BMI z-score; for each log increase in the estimated p,p'-DDE levels, BMI z-score increased by 0.23 (C.I. 95%: 0.01, 0.45) for the 0-6 months exposure period, 0.26 (C.I. 95%: 0.06, 0.47) for the 6-12 months exposure period, and 0.24 (C.I. 95%: 0.05, 0.43) for the 12-24 months exposure period.
In this study of Japanese children, estimated postnatal p,p'-DDE levels were associated with increased BMI z-score at 42 months of age, mostly in girls. These results are in line with previous studies supporting that early-life exposure to p,p'-DDE may be associated with higher BMI during childhood.
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