Background: It has been suggested that pre- and postnatal exposure to persistent organic pollutants (POPs) can promote several adverse effects in children, such as altered neurodevelopment. ...Epidemiologic studies to date have relied on the analysis of biological samples drawn pre- or postnatally for exposure assessment, an approach that might not capture some key events in the toxicokinetics of POPs. Objectives: We aimed to build a generic physiologically based pharmacokinetic (PBPK) modeling framework for neutral POPs to assess infant toxicokinetic profiles and to validate the model using data on POP levels measured in mothers and infants from a Northern Québec Inuit population. Methods: The PBPK model developed herein was based upon a previously published model to which an infant submodel was added. Using the model and maternal blood levels at the time of delivery, exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), 2,2',3,4,4',5'-hexachlorobiphenyl (PCB-138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB-180) in mothers was estimated to subsequently simulate infant blood, breast milk, and cord blood POP concentration. Simulations were then compared with corresponding measured levels through Spearman correlation analyses. Results: Predictions were highly correlated with measured concentrations for PCB-153, PCB-180, PCB-138, HCB, and p,p'-DDE (r = 0.83-0.96). Weaker correlations were observed for p,p'-DDT and β-HCH for which levels were near the limits of detection. Conclusion: This is the first study to validate a PBPK model of POPs in infants on an individual basis. This approach will reduce sampling efforts and enable the use of individualized POP toxicokinetic profiles in the epidemiologic studies of POP adverse effects on child development.
Purpose of Review
We offer here a review of intraindividual variability in urinary biomarkers for assessing exposure to nonpersistent chemicals. We provide thoughts on how to better evaluate exposure ...to nonpersistent chemicals.
Recent Findings
We summarized reported values of intraclass correlation coefficients and found that most values fall into categories that indicate only poor to good reproducibility. Even within the “good” classification, a large percentage of study participants is likely to be misclassified as to their exposure.
Summary
There is sufficient information to support the statement that studies using only one spot measurement of a nonpersistent chemical will be unreliable. It is unequivocal that multiple samples have to be collected over a period of toxicological relevance and with consideration of exposure patterns. Sponsors of research and researchers themselves should be vocal about ensuring that sufficient resources are made available to properly characterize exposures when studying nonpersistent chemicals. Otherwise, we will continue to see an ever-growing body of literature yielding inconsistent and/or uninterpretable results.
Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based ...toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants.
Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs.
First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg PFOA/kg/day for gestational days 1–17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED50) and 1st percentile (HED01) of calculated HEDs were calculated.
Estimated PFOA maternal HED50s ranged from 3.0×10−4 to 1.1×10−3mg/kg/day and HED01s ranged from 4.7×10−5 to 2.1×10−4mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3×10−3mg/kg/day).
Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants.
•We calculated human equivalent doses (HEDs) for PFOA based on fetal/child dosimetry.•Mouse and human pharmacokinetic models were used to calculate HEDs.•Calculated HED values ranged from 8.4×10−5 to 1.1×10−3mg/kg/day.•All calculated HEDs were lower than EPA's HED based on adult dosimetry.•HEDs should be based on fetal/child dosimetry for developmental toxicants.
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), R 2, 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, R 2s 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.
To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and ...perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography–mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike’s information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: −56 to −17%) and 40% lower PFOA (95% CI: −54 to −23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children.
Some experimental and human data suggest that exposure to polychlorinated biphenyls (PCBs) may induce ototoxicity, though results of previous epidemiologic studies are mixed and generally focus on ...either prenatal or postnatal PCB concentrations exclusively.
Our aim was to evaluate the association between pre- and postnatal PCB concentrations in relation to cochlear status, assessed by distortion product otoacoustic emissions (DPOAEs), and to further clarify the critical periods in development where cochlear status may be most susceptible to PCBs.
A total of 351 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 months of age. Maternal pregnancy, cord, and child 6-, 16-, and 45-month blood samples were collected and analyzed for PCB concentrations. At 45 months of age, DPOAEs were assessed at 11 frequencies in both ears. Multivariate, generalized linear models were used to estimate the associations between PCB concentrations at different ages and DPOAEs, adjusting for potential confounders.
Maternal and cord PCB-153 concentrations were not associated with DPOAEs at 45 months. Higher postnatal PCB concentrations at 6-, 16-, and 45-months of age were associated with lower (poorer) DPOAE amplitudes. When all postnatal PCB exposures were considered as an area-under-the-curve metric, an increase in PCB-153 concentration from the 25th to the 75th percentile was associated with a 1.6-dB SPL (sound pressure level) decrease in DPOAE amplitude (95% CI: -2.6, -0.5; p = 0.003).
In this study, postnatal rather than maternal or cord PCB concentrations were associated with poorer performance on otoacoustic tests at age 45 months.
In response to a worldwide increase in production of electronic waste, the e-recycling industry is rapidly rowing. E-recycling workers are exposed to many potentially toxic contaminants, among which ...flame retardants (FRs), mainly suspected of being endocrine disruptors, are thought to be the most prevalent.
To conduct an exposure assessment of four chemical groups of FRs in Canadian e-recycling facilities, and to identify the main cofactors of exposure.
Personal air samples were collected over a workday for 85 workers in six e-recycling facilities, grouped into three facility sizes, and for 15 workers in control commercial waste facilities. Total particulate matter was measured by gravimetry with stationary air samples. FRs were collected on OSHA versatile samplers, which allow particulate and vapor phases collection. Fifteen polybrominated diphenyl ether congeners (PBDEs), nine novel brominated (NBFRs), two chlorinated (ClFRs), and fourteen organophosphate ester (OPEs) flame retardants were analysed by gas chromatography–mass spectrometry. Sociodemographic data, tasks performed and materials processed by participating workers were recorded. Tobit regressions were used to identify cofactors of exposure, and their conclusions were corroborated using semi-parametric reverse Cox regressions.
Thirty-nine of the 40 FRs analysed were detected in at least one air sample in e-recycling, and workers in this industry were exposed on average to 26 (range 12 to 39) different substances. The most detected chemical group of FRs in e-recycling was PBDEs with geometric mean sums of all congeners ranging from 120 to 5100 ng/m3, followed by OPEs with 740 to 1000 ng/m3, NBFRs with 7.6 to 100 ng/m3, and finally ClFRs with 3.9 to 32 mg/m3. The most important cofactor of exposure was the size of the e-recycling facility, with the largest one presenting on average 12 times the concentrations found in the control facility. Among tasks as potential cofactors of exposure, manual dismantling and baler operation exposed workers to some of the highest concentrations of PBDEs and ClFRs. There was a reduction of up to 27% in exposure to FRs associated with a 3-year increase in seniority. Finally, particulate matter concentrations in e-recycling facilities were highly correlated with all chemical classes except OPEs, and were higher in the large facility.
Among the FRs analysed, PBDE exposure was particularly high in e-recycling. Dust and particulate matter reduction strategies in these workplaces, together with training on proper working practices would certainly be important first steps to lower occupational exposures and prevent potential health effects.
•39 flame retardants (FRs) were detected in the air of e-recycling facilities.•The most detected FR chemical class is polybrominated diphenyl ethers (PBDEs).•BDE209 predominates among all FRs, especially in high-volume e-recycling facilities.•Higher exposures are found with dismantling and crushing/bailing tasks.•Cathode ray tubes and computer/TV screens are linked to high exposures of all FRs.
Background and objectiveElectronic waste recycling (e-recycling) exposes workers to several contaminants, including flame retardants that are suspected endocrine disruptors. We aimed to explore the ...association between polybrominated diphenyl ethers (PBDEs) and hormone levels in the serum of Canadian e-recycling workers.MethodsIn a cross-sectional study, blood samples were collected from 85 e-recycling workers (six facilities) and from 15 workers in other types of recycling (two facilities), at the end of a work shift. Socio-demographic information was obtained by questionnaire and body mass index (BMI) was calculated from measured height and weight. Serum concentrations of 13 PBDE congeners were measured as well as thyroid hormones (free and total thyroxine T4, triiodothyronine T3, thyroid stimulating hormone TSH) and testosterone (free and total). Linear regressions were stratified on sex and adjusted for age, BMI, seniority, smoking status, and type of recycling. Ten participants were excluded because of thyroid or testicular problems.ResultsParticipants were 23 women and 77 men (mean 40 years old, SD=12 years). Average hormone levels were within the laboratory normal range. In e-recycling, geometric mean concentrations of the most detected congeners were 11, 11 and 20 ng/g lipids for BDE47, BDE153 and BDE209, respectively. Only BDE209 concentrations were higher in e-recycling than in the control group. A two-fold increase in serum BDE209 was associated with a significant increase of 2.48 nmol/L in total T4 in men (p=0.011), and with a close to significant increase in the free/total testosterone ratio of 6% in men (p=0.053). BDE47 and BDE153 were not associated with hormone levels.ConclusionsThe clinical significance of high exposure to BDE209 in working adults is yet to be established, but endocrine effects were observed in this population. E-recycling workers are highly exposed to PBDEs among other substances, which may make them more vulnerable to hormonal disruption.
•Cord to maternal serum concentration ratios were compiled for 105 chemicals.•We developed 10 QSAR models of placental transfer.•PLS and SuperLearner showed the best precision and predictivity.•PLS ...yielded a cross-validated R2 of 0.72, and an external R2 of 0.73.•Results suggest that QSAR modeling can be used to estimate placental transfer.
The increasing diversity of environmental chemicals in the environment, some of which may be developmental toxicants, is a public health concern. The aim of this work was to contribute to the development of rapid and effective methods to assess prenatal exposure. Quantitative structure–activity relationships (QSAR) modeling has emerged as a promising method in the development of a predictive model for the placental transfer of contaminants. Cord to maternal plasma or serum concentration ratios for 105 chemicals were extracted from the literature, and 214 molecular descriptors were generated for each of these chemicals. Ten predictive models were built using Molecular Operating Environment (MOE) software, and the Python and R programming languages. Training and test datasets were used, respectively, to build and validate the models. The Applicability Domain Tool v1.0 was used to determine the applicability domain. Models developed with the partial least squares regression method in MOE and SuperLearner in R showed the best precision and predictivity, with internal coefficients of determination (R2) of 0.88 and 0.82, cross-validated R2s of 0.72 and 0.57, and external R2s of 0.73 and 0.74, respectively. All test chemicals were within the domain of applicability. The results obtained in this study suggest that QSAR modeling can help estimate the placental transfer of environmental chemicals.
Women are exposed to multiple environmental chemicals, many of which are known to transfer to breast milk during lactation. However, little is known about the influence of the different ...chemical-specific pharmacokinetic parameters on children's lactational dose. Our objective was to develop a generic pharmacokinetic model and subsequently quantify the influence of three chemical-specific parameters (biological half-life, milk:plasma partition coefficient, and volume of distribution) on lactational exposure to chemicals and resulting plasma levels in children. We developed a two-compartment pharmacokinetic model to simulate lifetime maternal exposure, placental transfer, and lactational exposure to the child. We performed 10,000 Monte Carlo simulations where half-life, milk:plasma partition coefficient, and volume of distribution were varied. Children's dose and plasma levels were compared to their mother's by calculating child:mother dose ratios and plasma level ratios. We then evaluated the association between the three chemical-specific pharmacokinetic parameters and child:mother dose and level ratios through linear regression and decision trees. Our analyses revealed that half-life was the most influential parameter on children's lactational dose and plasma concentrations, followed by milk:plasma partition coefficient and volume of distribution. In bivariate regression analyses, half-life explained 72% of child:mother dose ratios and 53% of child:mother level ratios. Decision trees aiming to identify chemicals with high potential for lactational exposure (ratio>1) had an accuracy of 89% for child:mother dose ratios and 84% for child:mother level ratios. Our study showed the relative importance of half-life, milk:plasma partition coefficient, and volume of distribution on children's lactational exposure. Developed equations and decision trees will enable the rapid identification of chemicals with a high potential for lactational exposure.
•We used a pharmacokinetic model to estimate children's lactational exposure.•We developed decision trees to evaluate the potential for lactational exposure.•We derived equations to estimate lactational exposure and children's levels.•Biological half-life greatly influences the lactational exposure to a chemical.
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