Estimating the early-life exposure to perfluorinated compounds using PBPK modeling and biomarker measurements

Reverse dosimetry aims at reconstructing the external exposure using measured biomarkers, a physiologically based pharmacokinetic (PBPK) model accounting for the processes that the chemical undergoes in the human body, and individual characteristics. Such approaches are valuable to simulate exposure between biomarker measurement time points. In this work, we propose to estimate the early-life exposure of children to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Our study involved 1239 mother-child pairs of the HELIX cohort from 6 European countries. The compounds were measured in maternal plasma at the time of pregnancy, and in child plasma at the age of 6-9 years old. A PBPK model including childhood, pregnancy, and lactation periods was parameterized for each woman and child based on their individual characteristics. The PBPK model was run for mothers to provide exposure estimates for the child during the pregnancy and breastfeeding period. These estimates were then used as inputs to the PBPK model for the child together with the biomarkers to reconstruct his/her early-life exposure (i.e., daily intakes). Finally the internal exposure of children was simulated. Our results showed that similar levels at birth and during childhood can correspond to very different exposure scenarios. A 3-factor in the diet exposure leads to a difference of 6 in Cmax. The main determinants of the child exposure were the levels at birth (correlated with the mother’s biomarker), the duration of breastfeeding, and the measured biomarker itself. Actual measurements during pregnancy and at the age of 6 to 9 do not correlate well with the predicted internal exposure during the first years of life (birth to 4 years old). The indicators depend most on the information collected through the questionnaires. Neglecting inter-individual differences and actual exposures can lead to large exposure misclassification problems, reducing the power of subsequent dose-response or association analyses