Prenatal exposure to per- and polyfluoroalkyl substances and child behavioral problems.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may adversely affect child behaviors; however, findings of epidemiologic studies are inconsistent. We examined prenatal PFAS exposure in association with child behavioral problems. METHODS: Participants were 177 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). We quantified nine PFAS in maternal serum (1-3 samples per mother) collected from the 1st to 3rd trimesters of pregnancy. Child behavioral problems were assessed at 3 years of age using the Child Behavior Checklist (CBCL), developed to test for various behavioral problems of children. We examined associations of the CBCL scores with individual PFAS concentrations and with their mixture using negative binomial regression and weighted quantile sum regression models. RESULTS: Higher prenatal perfluorononanoate (PFNA) concentrations were associated with higher scores of externalizing problems [ß = 0.16, 95% CI (0.01, 0.32)] and aggressive behavior [ß = 0.17 (0.01, 0.32)]. Higher PFNA, perfluorooctane sulfonate (PFOS), and perfluorodecanoate (PFDA) were associated with higher scores of sleep problems [ß = 0.34 (0.15, 0.54) for PFNA, ß = 0.20 (0.02, 0.37) for PFOS, and ß = 0.19 (0.00, 0.37) for PFDA]. No significant associations observed for typically developing children, whereas PFOS, PFNA, and PFDA were associated with several behavioral problems among children diagnosed with ASD or other neurodevelopmental concerns. Exposure to a mixture of PFAS was associated with higher scores of sleep problems and aggressive behavior, mostly contributed by PFNA and PFDA. CONCLUSIONS: Our study showed that prenatal exposure to some PFAS could increase child behavioral problems at 3 years of age. However, our results should be interpreted with caution because we relied on data from a cohort with increased familial likelihood of ASD and thereby had more behavioral problems.

Toxicokinetic analyses of naphthalene, fluorene, phenanthrene, and pyrene in humans after single oral administration.

Polycyclic aromatic hydrocarbons (PAHs) are generated by incomplete combustion of organic matter. They have health effects in multiple organs and can cause lung, skin, and bladder cancers in humans. Although data regarding their toxicity is available, information on the absorption, distribution, metabolism, and excretion of PAHs in humans is very limited. In the present study, deuterium-labeled naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), and pyrene (Pyr) were orally administered as a single dose (0.02-0.04 mg/kg) to eight healthy adults. Both serum and urine samples were monitored for 72 h after the exposure. Parent compounds and PAH metabolites (monohydroxy-PAHs; OH-PAHs) were measured by headspace-solid phase microextraction coupled with gas chromatography-mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry, respectively. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment models were constructed and validated for each PAH. Subsequently, all of the parent compounds were rapidly absorbed (Tmax: 0.25 to 1.50 h) after oral administration and excreted in urine with a biological half-life (T1/2) of 1.01 to 2.99 h. The fractional urinary excretion (Fue) of OH-PAHs ranged from 0.07 % to 11.3 %; their T1/2 values ranged from 3.4 to 11.0 h. The two-compartment models successfully described the toxicokinetic characteristics of each PAH and its metabolites. Fue and the two-compartment models could be useful tools for exposure simulation or dose-reconstruction of PAHs. The results of this study will provide useful information for interpreting biomonitoring data of PAHs.

Pharmacokinetics of transdermal methyl-, ethyl-, and propylparaben in humans following single dermal administration.

Parabens are common chemicals used as preservatives in foods, cosmetics, and personal care products. Although transdermal exposure to parabens occurs, studies on human pharmacokinetics (PK) following dermal exposure to parabens are scarce. In this study, the PK following dermal exposure to parabens was determined and compared with our previous findings on oral exposure. A paraben mixture cream containing 0.8% deuterated methyl-, ethyl-, and propylparaben (MeP-d4 0.26%; EtP-d4 0.26%, and PrP-d4 0.28%) was dermally applied to the whole arm of five male volunteers at a dose of 24 g/person over 30 min. Blood and urine samples were collected at several intervals over the course of 48 h to measure the levels of MeP-d4, EtP-d4, and PrP-d4 and their conjugated metabolites using HPLC-MS/MS. As a result of non-compartmental analysis, the average peak values of total (sum of conjugated and unconjugated metabolites) MeP-d4, EtP-d4, and PrP-d4 were reached at 7.8 h, 10.5 h, and 5.3 h, indicating a slower absorption rate compared to that of oral exposure (<2 h). The terminal elimination half-lives of MeP-d4, EtP-d4, and PrP-d4 were 12.2 h, 12.0 h, and 9.3 h, respectively. Fractional urinary excretion (Fue) of total MeP-d4, EtP-d4, and PrP-d4 was 1.7%, 2.3%, and 1.9%, respectively. The Fue of total and unconjugated PrP-d4 following dermal exposure was five times lower and three times higher, respectively, compared with those after oral exposure, suggesting that PrP is relatively less metabolized to the conjugated form after dermal exposure. Taken together, dermal exposure to paraben leads to a longer apparent half-life and results in higher proportions of biologically active unconjugated parabens in the systemic circulation as compared to oral exposure. This study provides insights into the kinetic properties of parabens and their metabolites in humans.

Concentrations of blood and urinary arsenic species and their characteristics in general Korean population.

Arsenic (As) exposure has been extensively studied by investigating As species (e.g., inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)) in urine, yet recent research suggests that blood could be a possible biomarker of As exposure. These investigations, however, were conducted on iAs-contaminated areas, and evidence on populations exposed to low levels of iAs is limited. This study aimed to describe the levels and distributions of As species in urine and blood, as well as to estimate methylation efficiency and related factors in the Korean population. Biological samples were obtained by the Korean Ministry of Food and Drug Safety. A total of 2025 urine samples and 598 blood samples were utilized in this study. Six As species were measured using ultra-high-performance liquid chromatography with inductively coupled plasma mass spectrometry (UPLC-ICP-MS): As(V), As(III), MMA, DMA, arsenobetaine (AsB), and arsenocholine (AsC). Multiple linear regression models were used to examine the relationship between As species (concentrations and proportions) and covariates. AsB was the most prevalent species in urine and blood. The relative composition of iAs, MMA, DMA, and AsC in urine and blood differed significantly. Consumption of blue-backed fish was linked to higher levels of AsB in urine and blood. Type of drinking water and multigrain rice consumption were associated with increased iAs concentration in urine. Except for iAs, every species had correlations in urine and blood in both univariate and multivariate analyses. Adolescents and smokers presented a lower methylation efficiency (higher %MMA and lower %DMA in urine) and females presented a higher methylation efficiency (lower %iAs, %MMA, and higher %DMA in urine). In conclusion, blood iAs concentration cannot represent urinary iAs; nonetheless, different compositions of urine and blood might reflect distinct information about iAs exposure. Further investigations on exposure factors and health are needed using low-exposure groups.

Pharmacokinetic profile of propyl paraben in humans after oral administration.

Parabens are commonly used as antimicrobial preservatives in consumer products. Because of their possible endocrine-disrupting activities, their safety has become a public concern. Although pharmacokinetic studies on parabens have been conducted in animals, limited information exists on their pharmacokinetic profiles in humans. In the present study, we determined the pharmacokinetic characteristics of propyl paraben (PP) in humans following a single oral administration of 0.6 mg/kg bw of deuterium labeled-PP. We also conducted experiment with similar design but different exposure amount (2.5 mg/kg bw) to verify the validity of the model to be developed. Blood and urine were collected at several intervals over the course of 48 h to measure levels of PP and its metabolites (conjugates and hydrolysates) in 12 male volunteers. The unconjugated parent compound (free PP), glucuronide and sulfate conjugates, p-hydroxybenzoic acid, and p-hydroxyhippuric acid were measured using HPLC-MS/MS. It was found that PP was rapidly absorbed via ingestion within 2 h and quickly eliminated (terminal half-life, 2.9 h). The fraction of administered dose excreted in the urine was 0.05% for free PP, 8.6% for total PP (free + conjugates), 23.2% for p-hydroxyhippuric acid, and 7.0% for p-hydroxybenzoic acid. Utilizing this pharmacokinetic profile, we successfully constructed a multi-compartment model where the disposition of PP was well described with two compartments and that of its metabolites was explained with first-order reactions. The present pharmacokinetic model provides insights into the kinetic properties of the disposition of PP and its metabolites in humans, and it can be used for risk assessment with biomonitoring of PP.

Pharmacokinetics of bisphenol S in humans after single oral administration.

Bisphenol S (BPS) has been introduced as a substitute for bisphenol A (BPA), and widely used in the manufacture of polycarbonate plastics, epoxy resins and thermal papers. Despite its adverse health outcomes and widespread exposure, pharmacokinetic data of BPS are not available for either animals or humans. The objective of the study is to describe pharmacokinetic characteristics of BPS in human body after a single oral administration with a compartmental pharmacokinetic model. Seven healthy young adults were orally exposed to 8.75µg/bw of d4-BPS, and serum and urine samples were collected for 48h. The concentrations of total and unconjugated d4-BPS in samples were measured using HPLC-MS/MS. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment model was constructed and validated. As a result of non-compartmental analysis, total d4-BPS was rapidly absorbed within 1h (0.7±0.3h) after oral administration, and excreted in urine with terminal half-life of <7h (6.8±0.7h). Fractional urinary excretion (Fue) of total d4-BPS for 48h was 92±17% (67-104%) for men and 70±36% (59-77%) for women. The two-compartment model well described pharmacokinetic properties of BPS, and its parameter estimates were consistent with those from non-compartmental analysis. This study provides information on absorption, distribution, metabolism and elimination of BPS in human body, and the pharmacokinetic model can be utilized for estimating exposure dose of BPS, contributing to more realistic exposure assessment.