22 - 23 May 2023
DOHaD Canada
Oral communications and virtual poster

Elisa Thepaut, Yourdasmine Alidaoud and Aude Ratier  have presented their work at the DOHaD Canada in Montebello (https://dohad.utoronto.ca/).

• Elisa Thepaut (3rd year PhD student) has presented: "Fetal exposure to pyrethroids using p-PBPK modeling (toxicokinetics based on the physiology of pregnant women)".

Abstract: Pregnancy is a particularly vulnerable time for chemical exposure for both the mother and the developing fetus. Like the general population, pregnant women are exposed to pollutants that can affect both maternal and fetal health. The impact of these in utero exposures on the longer-term development of children is increasingly being demonstrated. Pyrethroids are among the most widely used pesticides, leading to exposure via food and domestic environment. Several studies have shown associations between in utero exposure to pyrethroids and neurodevelopmental disorders in children. To estimate maternal and fetal internal concentrations, toxicokinetic models based on physiology applied to pregnancy (p-PBPK) can be developed.

A p-PBPK model was developed for three pyrethroids (permethrin, cypermethrin, deltamethrin). The model is composed of 23 maternal compartments and 19 fetal compartments and was evaluated with data from the literature. It describes the behavior of the 3 pyrethroids (cis- and trans- isomers) including transplacental transfer and considers 4 urinary metabolites that are common pyrethroids biomarkers measured in human biomonitoring studies. This p-PBPK model was used to estimate maternal and fetal exposures to pyrethroids throughout pregnancy based on biomonitoring data from the French cohort Elfe (French longitudinal study of children).

Maternal exposure estimates are in similar range as previous studies concerning the French population. Pyrethroids concentrations estimates in fetal blood are up to 100 times lower than those simulated in maternal blood. After a unique exposure, pyrethroids remain longer in fetal brain (half-life: 10 hours) than in maternal brain (half-life: 5 hours), while pyrethroids' half-life in maternal and fetal blood are respectfully 3 hours and 7 hours. Moreover, the major pyrethroid estimated in the fetal brain (deltamethrin) is different from the one in the maternal brain (cis permethrin).  The next step will be to relate these internal exposures (fetal brain) to neurodevelopmental effects.

• Yourdasmine Alidaoud (3rd year PhD student) has presented: "Development of a pregnancy physiologically based pharmacokinetic (p-PBPK) model for lead: estimation of the prenatal internal exposure of a French cohort".

Abstract: Epidemiological studies have shown associations between prenatal exposure to lead and neurodevelopmental effects in young children. Prenatal exposure is generally characterised by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess the internal exposure to lead during the prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model to simulate the lead levels in blood and target tissues in the fetus, especially during critical periods for brain development.

An existing lead PBPK model was adapted to pregnant women and fetuses. Using literature data, two processes were estimated by Bayesian inference: the maternal bone remodeling that leads to a lead release into the blood during the second trimester, and the placental transfers that deliver lead to the fetus. Once calibrated, the PBPK model was applied to the French Elfe cohort to simulate the internal fetal exposure to lead during pregnancy. The PBPK model was individualized to each mother-newborn pair using available anthropometric data and BLLs in the umbilical cord measured at delivery.

Maternal bone remodeling was estimated to start at 22 weeks and then was linearly correlated with the age of the pregnancy. The placental exchanges were highly variable within the population and were estimated between 4.9 and 355 mg.day-1. The prenatal internal exposure was simulated for the Elfe newborns. The internal exposure greatly varies over the pregnancy with two peaks in blood at the end of the first and third trimesters. The lead levels in the brain follow the same trend, but the peak in the first trimester is reached sooner.

Our p-PBPK model provides insight into the lead kinetics during prenatal life. 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.

• Aude Ratier  has presented in a virtual poster: "Estimating the early-life exposure to two perfluorinated compounds (PFOS and PFOA) using PBPK modeling and biomarker measurements". https://www.scienceopen.com/hosted-document?doi=10.14293/P2199-8442.1.SOP-.PQDEVT.v1 

Abstract: Children exposure to per- and polyfluoroalkyl acids substances (PFAS) is a major concern in health risk assessment as early-life exposures are suspected to induce adverse effects such as cardiometabolic, neurodevelopmental, or impact on immune response. Our work aims to estimate children exposure to PFOA and PFOS using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach.

A lifetime model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and to include individual characteristics and exposure scenarios. Our approach was applied on the HELIX cohort, involving 1,239 mother-child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: during pregnancy and in childhood (6 to 10 y.o).

Our model predicted an increase of the plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher PFOA plasma concentrations than PFOS ones were predicted until 2 y.o, and then PFOS levels gradually became higher than PFOA ones. From 2 to 8 y.o, mean concentrations decrease from 3.09 to 1.88 µg/L (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 (0-4 months), breastfeeding (5 months – 2 (PFOA) or 5 (PFOS) y.o), and food intake (after 3 (PFOA) or 6 (PFOS) y.o). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the child exposure over the early life to improve exposure classification of the child. The simulated internal concentrations in several infants and toddlers exceeded the HBM-I value threshold compared to the ones in older children, especially for PFOA.

Our approach based on PBPK modelling and HBM data demonstrates the possibility to simulate individualized internal exposures, that could be accounted to refine risk assessment in early life.