PBPK modeling to support risk assessment for prenatal exposure to pyrethroids and chlorpyrifos of the French children 

Dr Elisa Thépaut1, Dr Michèle Bisson1, Ms Cleo Tebby1, Dr Céline Brochot2, Dr Aude Ratier1, Dr Stéphane Personne3, Dr Brice Appenzeller4, Dr Cecile Zaros5, Pr Karen Chardon3, Dr Florence Zeman1

1 Ineris, PhD student, Verneuil-en-Halatte, France. 

2 Certara UK, researcher, Sheffield, United Kingdom. 

3 UPJV, Amiens, France. 

4 LIH, researcher, Luxembourg, Luxembourg. 

5 Ined, coordinator, Aubervilliers, France.

Abstract

Pyrethroids and chlorpyrifos are widely used pesticides that are suspected to affect children's neurodevelopment. Characterization of their exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of their potential effects within the concept of Developmental Origins of Health and Disease. 

The aim of this study was first to estimate maternal exposure to 3 pyrethroids (permethrin, cypermethrin and deltamethrin) of French pregnant women and to predict fetal internal concentrations using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. In a second step, maternal exposure to chlorpyrifos was estimated. Both pregnancy-PBPK models were developed based on existing models for adults. Maternal exposure to each parent compound was estimated by reverse dosimetry based on urinary biomonitoring data measured in pregnant women in the Elfe (French Longitudinal Study since Childhood) cohort. 

Estimated maternal exposures to pyrethroids and to chlorpyrifos were compared to a newly proposed children specific toxicological reference values (TRVs) to assess the risk in case of exposure to each of the 3 pyrethroids or chlorpyrifos during pregnancy i.e. during the in utero exposure period. 

For each pyrethroid considered independently, only the estimated exposures for 2.5% of the population exceeded the permethrin proposed children specific TRV. For chlorpyrifos, under conservative assumptions, a small percentage of the population was identified as being exposed to levels that exceeded the proposed TRV.

Estimating the early life exposure to PFAS using PBPK modelling and Human biomarker data

Dr. Aude Ratier1, Dr. Ophélia Gestin1, Prof. Martine Vrijheid2, Dr. Céline Brochot3, Dr. Florence Zeman1

1 INERIS (Institut National de l'Environnement Industriel et des Risques), Research engineer toxicokinetic modelling, 60550 Verneuil en Halatte, France.
2 ISGlobal, Research Professor environment and child health, Barcelona, Spain.
3 Certara UK Ltd, Simcyp Division, Senior Principal Scientist, Sheffield, United Kingdom. 

DOI: 10.14293/P2199-8442.1.SOP-.PHUNH2.v1 

Abstract

In 2020, EFSA established a tolerable weekly intake (TWI) of 4.4 ng/kg bw/week for PFOA, PFNA, PFHxS and PFOS based on a sum value approach. 

Our work aims to estimate the exposure of children to these compounds using a physiologically based pharmacokinetic (PBPK) modelling approach and to determine the contribution of each exposure source (in utero, breastfeeding and diet). A PFAS lifetime model was updated to simulate internal PFAS exposures during prenatal and childhood and to include individual characteristics and exposure scenarios. Our approach was applied to the HELIX cohort which contains more than a thousand mother-child pairs from six European countries with measured plasma concentrations of the four PFAS at two sampling times: during pregnancy and in childhood (6 to 10 years).

Our first results show that the model predicted an increase in plasma concentrations during fetal development and childhood up to the age of 2 years, when maximum concentrations are reached. The estimated total daily intakes (DI) of several infants aged of one year exposed to the four PFAS exceed the EFSA threshold, although the average for all children remains below. The highest DI appear to be found in children from France and Norway for PFOS and in France, England and Norway for PFOA.

Furthermore, we observed that similar measured biomarker levels can correspond to large differences in simulated internal exposures, highlighting the importance of studying the child's exposure in early life to refine early life risk assessment.