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

International audienceBackgroundPyrethroids 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.ObjectiveThe 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.MethodsA 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.ResultsThe 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.ConclusionsA 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

Prenatal exposure to chlorpyrifos of French children from the Elfe cohort

International audienceBackground: The organophosphate pesticide chlorpyrifos was widely used in the European Union before its ban in 2020 and was associated with neurodevelopmental disorders. However, within the concept of Developmental Origins of Health and Disease, in utero exposure to chlorpyrifos can lead to neurodevelopmental effects in developing children.Objective: The aim of this study was to estimate fetal exposure to chlorpyrifos using biomonitoring data measured in Elfe pregnant women and a physiologically based pharmacokinetic (PBPK) approach and compare exposure to toxicological reference values.Methods: A pregnancy-PBPK model was developed based on an existing adult chlorpyrifos model and a new toxicological reference value was proposed for neurodevelopmental effects. The pregnant women exposure was estimated based on dialkylphosphate (DAP) levels in urine assuming constant exposure to chlorpyrifos and compared to both the existing toxicological reference value and the new proposed draft toxicological reference value. Fetal internal concentrations in target tissues were then predicted using the developed pregnancy-PBPK model. Urinary concentrations of the chlorpyrifos-specific metabolite (TCPy) were also predicted for comparison with other biomonitoring data.Results: The median daily exposure to chlorpyrifos for the French pregnant women from the Elfe cohort was estimated at 6.3x10-4 μg/kg body weight/day. The predicted urinary excretion of TCPy, the chlorpyrifos-specific metabolite, is in the same range as observed in other European cohorts (mean: 2.13 μg/L). Predicted brain chlorpyrifos levels were similar in pregnant women and their fetus and were 10-fold higher than the predicted blood chlorpyrifos levels. It was estimated that 6% and 20% of the pregnant women population had been exposed to levels exceeding the general population and draft toxicological reference values, respectively.Conclusions: Prenatal exposure to chlorpyrifos was estimated for the French population based on data from the Elfe cohort. Internal chlorpyrifos concentrations in target tissues (brain and blood) were predicted for fetuses at the end of the pregnancy. Under a conservative assumption, a small percentage of the population was identified as being exposed to levels exceeding the toxicological reference values