Estimating the dynamic early life exposure to PFOA and PFOS of the HELIX children: Emerging profiles via prenatal exposure, breastfeeding, and diet.

In utero and children's exposure to per- and polyfluoroalkyl substances (PFAS) is a major concern in health risk assessment as early life exposures are suspected to induce adverse health effects. Our work aims to estimate children's exposure (from birth to 12 years old) to PFOA and PFOS, using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach. A model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and including individual characteristics and exposure scenarios (e.g., duration of breastfeeding, weight at birth, etc.). Our approach was applied to the HELIX cohort, involving 1,239 mother-child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: maternal and child plasma concentrations (6 to 12 y.o). Our model predicted an increase in plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher plasma concentrations of PFOA than PFOS were predicted until 2 y.o, and then PFOS concentrations gradually became higher than PFOA concentrations. From 2 to 8 y.o, mean concentrations decreased from 3.1 to 1.88 µg/L or ng/mL (PFOA) and from 4.77 to 3.56 µg/L (PFOS). The concentration-time profiles vary with the age and were mostly influenced by in utero exposure (on the first 4 months after birth), breastfeeding (from 5 months to 2 (PFOA) or 5 (PFOS) y.o of the children), and food intake (after 3 (PFOA) or 6 (PFOS) y.o of the children). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the children's exposure over the early life to improve exposure classification. Our approach demonstrates the possibility to simulate individual internal exposures using PBPK models when measured biomarkers are scarce, helping risk assessors in gaining insight into internal exposure during critical windows, such as early life.

PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women.

BACKGROUND: Pyrethroids are widely used pesticides and are suspected to affect children's neurodevelopment. The characterization of pyrethroid exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of pyrethroids potential effects within the concept of Developmental Origins of Health and Disease. OBJECTIVE: The aim of this study was to estimate maternal exposure of French pregnant women from biomonitoring data and simulate maternal and fetal internal concentrations of 3 pyrethroids (permethrin, cypermethrin and deltamethrin) using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. The estimated maternal exposures were compared to newly proposed toxicological reference values (TRV) children specific also called draft child-specific reference value to assess pyrethroid exposure risk during pregnancy i.e. during the in utero exposure period. METHODS: A pregnancy-PBPK model was developed based on an existing adult pyrethroids model. The maternal exposure to each parent compound of pregnant women of the Elfe (French Longitudinal Study since Childhood) cohort was estimated by reverse dosimetry based on urinary biomonitoring data. To identify permethrin and cypermethrin contribution to their common urinary biomarkers of exposure, an exposure ratio based on biomarkers in hair was tested. Finally, exposure estimates were compared to current and draft child-specific reference values derived from rodent prenatal and postnatal exposure studies. RESULTS: The main contributor to maternal pyrethroid diet intake is cis-permethrin. In blood, total internal concentrations main contributor is deltamethrin. In brain, the major contributors to internal pyrethroid exposure are deltamethrin for fetuses and cis-permethrin for mothers. Risk is identified only for permethrin when referring to the draft child-specific reference value. 2.5% of the population exceeded permethrin draft child-specific reference value. CONCLUSIONS: A new reverse dosimetry approach using PBPK model combined with human biomonitoring data in urine and hair was proposed to estimate Elfe pregnant population exposure to a pyrethroids mixture with common metabolites.

Development of a physiologically based toxicokinetic model for lead in pregnant women: The role of bone tissue in the maternal and fetal internal exposure.

Epidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6 and 283 L.day-1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment.

PBTK modeled perfluoroalkyl acid kinetics in zebrafish eleutheroembryos suggests impacts on bioconcentrations by chorion porosity dynamics.

The zebrafish eleutheroembryo (zfe) is widely used as a model to characterize the toxicity of chemicals. However, analytical methods are still missing to measure organ concentrations. Therefore, physiologically-based toxicokinetic (PBTK) modeling may overcome current limitations to help understand the relationship between toxic effects and internal exposure in various organs. A previous PBTK model has been updated to include the chorionic transport barrier and its permeabilization, hatching dynamics within a zfe population over development, and active mediated transport mechanisms. The zfe PBTK model has been calibrated using measured time-dependent internal concentrations of PFBA, PFHxS, PFOA, and PFOS in a zfe population and evaluated using external datasets from the literature. Calibration was successful with 96% of the predictions falling within a 2-fold range of the observed concentrations. The external dataset was correctly estimated with about 50% of the predictions falling within a factor of 3 of the observed data and 10% of the predictions are out of the 10-fold error. The calibrated model suggested that active mediated transport differs between PFAS with a sulfonic and carboxylic acid functional end groups. This PBTK model predicts well the fate of PFAS with various physicochemical properties in zfe. Therefore, this model may improve the use of zfe as an alternative model in toxicokinetic-toxicodynamic studies and help to refine and reduce zfe-based experiments, while giving insights into the internal kinetics of chemicals.

A PBPK model to evaluate zebrafish eleutheroembryos' actual exposure: bisphenol A and analogs' (AF, F, and S) case studies.

The zebrafish eleutheroembryo model is increasingly used to assess the toxicity and developmental adverse effects of xenobiotics. However, the actual exposure is seldom measured (poorly accessible), while a predictive model could estimate these concentrations. The predictions with a new eleutheroembryo physiologically based pharmacokinetic (PBPK) model have been evaluated using datasets obtained from literature data for several bisphenols. The model simulated the toxicokinetics of bisphenols A (BPA), AF, F, and S through the eleutheroembryo tissues while considering the body and organ growth. We further improved the predictions by adding dynamic flows through the embryo and/or its chorion, impact of experimental temperature, metabolic clearance, and saturation of the absorption by Bayesian calibration. The model structure was determined using the BPA dataset and generalized to the other bisphenols. This model revealed the central role of the chorion in the compound uptake in the first 48 h post-fertilization. The predictions for the BPA substitutes estimated by our PBPK model were compared to available toxicokinetics data for zebrafish embryos, and 63% and 88% of them were within a twofold and fivefold error intervals of the corresponding experimental values, respectively. This model provides a tool to design new eleutheroembryo assays and evaluate the actual exposure.

PBPK Modeling to Simulate the Fate of Compounds in Living Organisms.

Pharmacokinetics study the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software.

Mapping blood lead levels in French children due to environmental contamination using a modeling approach.

The decrease in levels of lead in air and drinking water over the last 40 years has resulted in an overall decrease in blood lead levels (BLLs). However, there is no known safe level of lead regarding developmental effects in children. This paper maps predicted BLLs of children in France, resulting from a simulated chronic exposure in two steps, with the aim of identifying areas with environmentally overexposed populations. Probabilistic estimates of BLLs based on environmental contamination were obtained and compared to biomonitoring data. First, the contribution of various environmental exposure pathways was estimated using a multimedia exposure model: spatialized data on soil, drinking water and air contamination, together with data on food contamination and ingestion, was joined using geostatistical approaches. In a second step, a Physiologically Based Toxicokinetic (PBTK) model provided estimates of BLLs. Probabilistic estimates of BLLs were obtained by simulating uncertainty and variability of exposure levels, physiological characteristics and lead-specific parameters in the PBTK model. The median and 95th percentile of predicted BLLs in children aged 1 to 11 were compared to recent biomonitoring data obtained in France in young children (SATURNINF study): median predictions were overestimated in infants and in agreement with median observed BLLs in children aged 3 to 6. Upper bounds of predicted BLLs were protective due to uncertainties in exposure estimates. The main source of exposure appeared to be drinking water in children over 2 years old, and vegetal food and milk in children under 2 years old. Although elevated drinking water lead levels were not related to large geographical areas, the relatively fine resolution map also pinpointed geographical areas of concern due to elevated soil lead levels.

Spatio-temporal assessment of pregnant women exposure to chlorpyrifos at a regional scale.

BACKGROUND: The aim of this study was to use an integrated exposure assessment approach, combining spatiotemporal modeling of environmental exposure and fate of the chemical to assess the exposure of vulnerable populations. In this study, chlorpyrifos exposure of pregnant women in Picardy was evaluated at a regional scale during 1 year. This approach provided a mapping of exposure indicators of pregnant women to chlorpyrifos over fine spatial and temporal resolutions using a GIS environment. METHODS: Fate and transport models (emission, atmospheric dispersion, multimedia exposure, PBPK) were combined with environmental databases in a GIS environment. Quantities spread over agricultural fields were simulated and integrated into a modeling chain coupling models. The fate and transport of chlorpyrifos was characterized by an atmospheric dispersion statistical metamodel and the dynamiCROP model. Then, the multimedia model Modul'ERS was used to predict chlorpyrifos daily exposure doses which were integrated in a PBPK model to compute biomarker of exposure (TCPy urinary concentrations). For the concentration predictions, two scenarios (lower bound and upper bound) were built. RESULTS: At fine spatio-temporal resolutions, the cartography of biomarkers in the lower bound scenario clearly highlights agricultural areas. In these maps, some specific areas and hotspots appear as potentially more exposed specifically during application period. Overall, predictions were close to biomonitoring data and ingestion route was the main contributor to chlorpyrifos exposure. CONCLUSIONS: This study demonstrated the feasibility of an integrated approach for the evaluation of chlorpyrifos exposure which allows the comparison between modeled predictions and biomonitoring data.

Evaluation of Placental Transfer and Tissue Distribution of cis- and Trans-Permethrin in Pregnant Rats and Fetuses Using a Physiological-Based Pharmacokinetic Model.

Biomonitoring studies have highlighted the exposure of pregnant women to pyrethroids based on the measurement of their metabolites in urine. Pyrethroids can cross the placental barrier and be distributed in the fetus as some pyrethroids were also measured in the meconium of newborns. Prenatal exposure to pyrethroids is suspected to alter the neurodevelopment of children, and animal studies have shown that early life exposure to permethrin, one of the most commonly used pyrethroid in household applications, can alter the brain development. This study aimed to characterize the fetal permethrin exposure throughout gestation in rats. We developed a pregnancy physiologically based pharmacokinetic (pPBPK) model that describes the maternal and fetal kinetics of the cis- and trans- isomers of permethrin during the whole gestation period. Pregnant Sprague-Dawley rats were exposed daily to permethrin (50 mg/kg) by oral route from the start of gestation to day 20. Permethrin isomers were quantified in the feces, kidney, mammary gland, fat, and placenta in dams and in both maternal and fetal blood, brain, and liver. Cis- and trans-permethrin were quantified in fetal blood and tissues, with higher concentrations for the cis-isomer. The pPBPK model was fitted to the toxicokinetic maternal and fetal data in a Bayesian framework. Several parameters were adjusted, such as hepatic clearances, partition coefficients, and intestinal absorption. Our work allowed to estimate the prenatal exposure to permethrin in rats, especially in the fetal brain, and to quantitatively estimate the placental transfer. These transfers could be extrapolated to humans and be incorporated in a human pPBPK model to estimate the fetal exposure to permethrin from biomonitoring data.

Characterizing environmental geographic inequalities using an integrated exposure assessment.

BACKGROUND: At a regional or continental scale, the characterization of environmental health inequities (EHI) expresses the idea that populations are not equal in the face of pollution. It implies an analysis be conducted in order to identify and manage the areas at risk of overexposure where an increasing risk to human health is suspected. The development of methods is a prerequisite for implementing public health activities aimed at protecting populations. METHODS: This paper presents the methodological framework developed by INERIS (French National Institute for Industrial Environment and Risks) to identify a common framework for a structured and operationalized assessment of human exposure. An integrated exposure assessment approach has been developed to integrate the multiplicity of exposure pathways from various sources, through a series of models enabling the final exposure of a population to be defined. RESULTS: Measured data from environmental networks reflecting the actual contamination of the environment are used to gauge the population's exposure. Sophisticated methods of spatial analysis are applied to include additional information and take benefit of spatial and inter-variable correlation to improve data representativeness and characterize the associated uncertainty. Integrated approaches bring together all the information available for assessing the source-to-human-dose continuum using a Geographic Information System, multimedia exposure and toxicokinetic model. DISCUSSION: One of the objectives of the integrated approach was to demonstrate the feasibility of building complex realistic exposure scenarios satisfying the needs of stakeholders and the accuracy of the modelling predictions at a fine spatial-temporal resolution. A case study is presented to provide a specific application of the proposed framework and how the results could be used to identify an overexposed population. CONCLUSION: This framework could be used for many purposes, such as mapping EHI, identifying vulnerable populations and providing determinants of exposure to manage and plan remedial actions and to assess the spatial relationships between health and the environment to identify factors that influence the variability of disease patterns.

Estimating human exposure to pyrethroids' mixtures from biomonitoring data using physiologically based pharmacokinetic modeling.

Human biomonitoring data provide evidence to exposure of environmental chemicals. Physiologically based pharmacokinetic (PBPK) modelling together with an adequate exposure scenario allows to transpose measured concentrations of chemicals or their metabolites into exposure levels, as daily intakes. In France, high levels of urinary pyrethroids metabolites have been measured in populations. Our work aims at estimating the exposure of the French ENNS cohort to mixtures of four pyrethroids (deltamethrin, permethrin, cypermethrin, and cyfluthrin) from the urinary concentrations of five pyrethroids' metabolites commonly measured in biomonitoring studies. We developed a modelling approach based on a global toxicokinetic model that accounts for the cumulative exposure to pyrethroids as some of the metabolites can be shared by several parent compounds and for human inter-individual variability in metabolism. The median of the individual daily intakes was estimated to 8.1 ng/kg bw/day for permethrin, 17.7 ng/kg bw/day for cypermethrin, 20.4 ng/kg bw/day for cyfluthrin and 34.3 ng/kg bw/day for deltamethrin leading to similar weights for the pair permethrin and cypermethrin (36%), cyfluthrin (31%) and deltamethrin (33%) to the cumulative exposure. Accounting for human variability enabled to explain some of the variations in the metabolites' levels within the cohort. The cumulative exposure was then weighted by their toxicities towards three neurotoxic effects to calculate margins of exposure (MOE). Low MOE values were always associated with high measured concentrations of metabolites in urine and the lowest MOEs were observed for the autonomic division. No risks associated with reconstructed mixtures of pyrethroids were expected for the ENNS cohort. Our approach is an asset to analyse the biomarkers of exposure to pyrethroids simultaneously and could be easily adapted to any local or national specificities in pyrethroids' exposure or populations.

Assessing the impacts on fetal dosimetry of the modelling of the placental transfers of xenobiotics in a pregnancy physiologically based pharmacokinetic model.

The developmental origin of health and diseases theory supports the critical role of the fetal exposure to children's health. We developed a physiologically based pharmacokinetic model for human pregnancy (pPBPK) to simulate the maternal and fetal dosimetry throughout pregnancy. Four models of the placental exchanges of chemicals were assessed on ten chemicals for which maternal and fetal data were available. These models were calibrated using non-animal methods: in vitro (InV) or ex vivo (ExV) data, a semi-empirical relationship (SE), or the limitation by the placental perfusion (PL). They did not impact the maternal pharmacokinetics but provided different profiles in the fetus. The PL and InV models performed well even if the PL model overpredicted the fetal exposure for some substances. The SE and ExV models showed the lowest global performance and the SE model a tendency to underprediction. The comparison of the profiles showed that the PL model predicted an increase in the fetal exposure with the pregnancy age, whereas the ExV model predicted a decrease. For the SE and InV models, a small decrease was predicted during the second trimester. All models but the ExV one, presented the highest fetal exposure at the end of the third trimester. Global sensitivity analyses highlighted the predominant influence of the placental transfers on the fetal exposure, as well as the metabolic clearance and the fraction unbound. Finally, the four transfer models could be considered depending on the framework of the use of the pPBPK model and the availability of data or resources to inform their parametrization.

Aggregate and cumulative chronic risk assessment for pyrethroids in the French adult population.

Pyrethroids are commonly used as insecticides in households, in agriculture or in veterinary and medicinal products. This study aimed to assess cumulative aggregate exposure to cyfluthrin, cypermethrin, deltamethrin and permethrin in adults in France and the associated health risk, and to identify major contributions of exposure sources and routes. External chronic exposures were estimated from dietary and several environmental sources for the oral, inhalation and dermal routes. Internal concentrations of five associated metabolites were simulated with a physiologically-based pharmacokinetic model. The predicted urinary concentrations were in same order of magnitude as those of the French ENNS biomonitoring survey. Dietary exposure, especially from cereals and animal products, was the major source of exposure. For the 1% of adults most highly exposed, dermal exposure to permethrin through medicinal and veterinary products was an important source of exposure. Considering alterations of motor, sensory and autonomic division, all individual margins of exposure were higher than 100, suggesting that no neurotoxic risk associated with the cumulative aggregate exposure to these four pyrethroids is expected for the French adult population.

A generic PBTK model implemented in the MCRA platform: Predictive performance and uses in risk assessment of chemicals.

Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last stage, elimination or absorption parameters were calibrated based on available in vivo kinetic data. The results illustrate that parametrization plays a capital role in the output of the PBTK model, as it can change how chemicals are prioritized based on internal concentration factors. In data-poor situations, estimates can be far from observed values. In many cases of chronic exposure, the PBTK model can be summarized by an external to internal dose factor, and interspecies concentration factors can be used to perform interspecies extrapolation. We finally discuss the implementation and use of the model in the MCRA risk assessment platform.

Integrative Strategy of Testing Systems for Identification of Endocrine Disruptors Inducing Metabolic Disorders-An Introduction to the OBERON Project.

Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

The MCRA toolbox of models and data to support chemical mixture risk assessment.

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.

Determination of maternal and foetal distribution of cis- and trans-permethrin isomers and their metabolites in pregnant rats by liquid chromatography tandem mass spectrometry (LC-MS/MS).

We developed a method to quantify cis-permethrin and trans-permethrin and their metabolites in several biological matrices in pregnant rats and foetuses using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The objective was to quantify cis-permethrin and trans-permethrin in faeces, kidney, mammary gland, fat and placenta in mothers and in both maternal and foetal blood, brain and liver. The metabolites cis-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis-DCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (trans-DCCA) and 3-phenoxybenzoic acid (3-PBA) were measured in blood, liver and urine. Sample preparation was performed by liquid-liquid extraction. A purification step was not carried out except for the more complex biological samples (fat, mammary glands and faeces). Validation parameters including specificity, linearity, matrix effect, limits of quantification (LOQs), accuracy and precision were evaluated. The recoveries of target compounds ranged from 47 to 136%. LOQs were in the range 4 to 80 ng/mL for permethrin isomers and 4 to 800 ng/mL for their respective metabolites. Intra- and inter-batch precision and accuracy in matrix were better than 15%. The validated method was applied in a preliminary toxicokinetic study in pregnant rats with oral dosing of 50 mg/kg permethrin. In pregnant rats, permethrin isomers and their metabolites were quantified in all requested matrices except maternal liver and blood for trans-permethrin and cis-DCCA respectively. In foetuses, cis- and trans-permethrin were also quantified, demonstrating that the method is suitable for the analysis of foetal distribution of permethrin in toxicokinetic studies.

Prediction of maternal and foetal exposures to perfluoroalkyl compounds in a Spanish birth cohort using toxicokinetic modelling.

Prenatal exposures to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been associated with child health outcomes, but many of these associations remain poorly characterized. The aim of this work was to provide new indicators of foetal exposure for the Spanish INMA birth cohort. First, a pregnancy and lactation physiologically based pharmacokinetic (PBPK) model was calibrated in a population framework to provide quantitative estimates for the PFOA and PFOS placental transfers in humans. The estimated distributions indicated that PFOA crosses the placental barrier at a rate three times higher than PFOS and shows a higher variability between mothers. The PBPK model was then used to back-calculate the time-varying daily intakes of the INMA mothers corrected for their individual history from a spot maternal concentration. We showed the importance of accounting for the mothers' history as different dietary intakes can result in similar measured concentrations at one time point. Finally, the foetal exposure was simulated in target organs over pregnancy using the PBPK model and the estimated maternal intakes. We showed that the pattern of PFOA and PFOS exposures varies greatly among the foetuses. About a third has levels of either one compound always higher than the levels of the other compound. The other two thirds showed different ranking of PFOA and PFOS in terms of concentrations in the target organs. Our simulated foetal exposures bring additional information to the measured maternal spot concentrations and can help to better characterize the prenatal exposure in target organs during windows of susceptibility.

Estimating the cumulative human exposures to pyrethroids by combined multi-route PBPK models: Application to the French population.

Human biomarkers of exposure to pyrethroid insecticides are usually urinary concentrations of metabolites that can be specific to a pyrethroid or common to several compounds. We developed a global toxicokinetic model that links the external exposure to four widely-used pyrethroids and their isomers (deltamethrin and cis and trans isomers of permethrin, cypermethrin, and cyfluthrin) to the urinary concentrations of metabolites (cis- and trans-DCCA, 3-PBA, F-PBA and DBCA). This global model includes physiologically based pharmacokinetic models for each parent compound and one-compartment models for the metabolites. Existing in vivo, in vitro and in silico data were used for model calibration, and human toxicokinetic data for model evaluation. Overall, the global model reproduced the data accurately as about 90% of predictions were inside the 3-fold error interval. A sensitivity analysis showed that the most influent parameter for each urinary metabolite concentration was the fraction of parent compound that is transformed into that metabolite. The global model was then tested with realistic exposures for the French population: the predictions were consistent with biomonitoring data. The global model is a tool that will improve the interpretation of biomonitoring data for pyrethroids.