Prediction of in vivo prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on in vitro toxicity data by quantitative in vitro–in vivo extrapolation

Epidemiological studies in children suggested that in utero exposure to chlorpyrifos (CPF), an organophosphate insecticide, may cause developmental neurotoxicity (DNT). We applied quantitative in vitro–in vivo extrapolation (QIVIVE) based on in vitro concentration and non-choline esterase-dependent effects data combined with Benchmark dose (BMD) modelling to predict oral maternal CPF exposure during pregnancy leading to fetal brain effect concentration. By comparing the results with data from epidemiological studies, we evaluated the contribution of the in vitro endpoints to the mode of action (MoA) for CPF-induced DNT. A maternal-fetal PBK model built in PK-Sim® was used to perform QIVIVE predicting CPF concentrations in a pregnant women population at 15 weeks of gestation from cell lysate concentrations of human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia and exposed to CPF for 14 days. The in vitro concentration and effect data were used to perform BMD modelling. The upper BMD was converted into maternal doses which ranged from 3.21 to 271 mg/kg bw/day. Maternal CPF blood levels from epidemiological studies reporting DNT findings in their children were used to estimate oral CPF exposure during pregnancy using the PBK model. It ranged from 0.11 to 140 µg/kg bw/day. The effective doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies.

ABDELHADY ALGHARABLY Engi;  DI CONSIGLIO Emma;  TESTAI Emanuela;  PISTOLLATO Francesca;  PRICE Anna;  NAJJAR Abdulkarim;  KREUTZ Reinhold;  GUNDERT-REMY Ursula; 

2023-03-13

HINDAWI PUBLISHING CORPORATION

JRC132468

1663-9812 (online),   

https://www.frontiersin.org/articles/10.3389/fphar.2023.1136174,    https://publications.jrc.ec.europa.eu/repository/handle/JRC132468,   

10.3389/fphar.2023.1136174 (online),