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.

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.

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats.

Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4'OH-phenoxybenzoic acid (4'-OH-PBA). In vivo experiments performed in Sprague-Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4'-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine.

Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: a case study with acetaminophen.

In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods.

Interpreting PCB levels in breast milk using a physiologically based pharmacokinetic model to reconstruct the dynamic exposure of Italian women.

Polychlorinated biphenyls (PCBs) are persistent contaminants suspected to cause adverse health effects in humans. As PCBs levels in food have not been monitored frequently in the past, modeling approaches based on environmental data have been proposed to predict the human dietary intake. In this work, we propose to improve these approaches by taking into account internal levels of PCBs in humans. This methodology is based on the analysis of biomonitoring data using exposure and physiologically based pharmacokinetic (PBPK) modeling to determine the most probable scenario of exposure. Breast milk concentrations were measured in Italian women for PCB-138, PCB-153 and PCB-180. For each congener, three exposure scenarios were derived and a PBPK model was used to relate the lifetime exposure to the breast milk levels. For the three PCBs, we determined the most probable scenario of exposure. Our results support the adequacy of the exposure and the PBPK models for PCB-180 and PCB-153, whereas we observed discrepancies between the models and the biomonitoring data for PCB-138. Our intake estimates are in good agreement with previous exposure assessments based solely on food contamination demonstrating the relevance of our approach to reconstruct accurately the exposure and to fill in data gaps on exposure.

Individual sensitivity distribution evaluation from survival data using a mechanistic model: implications for ecotoxicological risk assessment.

Two main alternatives are typically used to model mechanistically dose-survival relationship in ecotoxicity tests. Effects are related to a concentration of concern, for instance body concentration, and, to account for their differences relative to time-to-death, individuals have either different concentration thresholds for death ("individual tolerance approach"), or equal probability to die, with death occurring randomly ("stochastic death approach"). A general framework to unify both approaches has recently been proposed. We derived a model from this framework to analyse five datasets (daphnids exposed to selenium, guppies exposed to dieldrin and second, third and fourth instars chironomids exposed to copper), by extending the standard stochastic death approach. We showed the possibility to estimate properly the toxicity parameters together with inter-organisms differences of sensitivity for at least one of these parameters (here the threshold for effect). For the daphnids, there was no improvement of using the extended model, which confirms the expected low variability among genetically identical individuals. For all the other datasets, our model outperformed the standard approach without accounting for differences of sensitivity. We estimated coefficients of variations in the distribution of the logarithm of the threshold from 44% to 4% and showed, for chironomids, a decrease of inter-individual differences of sensitivity with the age of the larvae. All standard threshold estimates were close but above the medium value of the distribution in the new approach, which means that a concentration equal to the standard threshold would ultimately result in the death of more than half of the exposed organisms. A more relevant parameter, such as the concentration protecting 95% of the population, would be 2-4 times inferior to the standard threshold.