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
Introduction: 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 ester...
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| Format: | Article |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1136174/full |
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| author | Engi Abdelhady Algharably Emma Di Consiglio Emanuela Testai Francesca Pistollato Anna Bal-Price Abdulkarim Najjar Reinhold Kreutz Ursula Gundert-Remy |
| author_facet | Engi Abdelhady Algharably Emma Di Consiglio Emanuela Testai Francesca Pistollato Anna Bal-Price Abdulkarim Najjar Reinhold Kreutz Ursula Gundert-Remy |
| author_sort | Engi Abdelhady Algharably |
| collection | DOAJ |
| description | Introduction: 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.Methods: 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 obtained in human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia exposed to CPF for 14 days. The in vitro concentration and effect data were used to perform BMD modelling.Results: 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.Discussion: The effective daily intake doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies to induce developmental non-cholinergic neurotoxic responses, which were captured by the analyzed in vitro test battery. These were also higher than the in vivo LOEC for cholinergic effects. Therefore, the quantitative predictive value of the investigated non-choline esterase-dependent effects, although possibly relevant for other chemicals, may not adequately represent potential key events in the MoA for CPF-associated DNT. |
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| format | Article |
| id | doaj.art-e726f4d4360f4d9ca215a1a43ad63add |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T05:32:53Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e726f4d4360f4d9ca215a1a43ad63add2023-03-07T05:30:03ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.11361741136174Prediction of in vivo prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on in vitro toxicity data by quantitative in vitro–in vivo extrapolationEngi Abdelhady Algharably0Emma Di Consiglio1Emanuela Testai2Francesca Pistollato3Anna Bal-Price4Abdulkarim Najjar5Reinhold Kreutz6Ursula Gundert-Remy7Institute of Clinical Pharmacology and Toxicology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyMechanisms, Biomarkers and Models Unit, Environment and Health Department, Istituto Superiore di Sanità, Rome, ItalyMechanisms, Biomarkers and Models Unit, Environment and Health Department, Istituto Superiore di Sanità, Rome, ItalyEuropean Commission, Joint Research Center (JRC), Ispra, ItalyEuropean Commission, Joint Research Center (JRC), Ispra, ItalyBeiersdorf AG, Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyInstitute of Clinical Pharmacology and Toxicology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyIntroduction: 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.Methods: 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 obtained in human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia exposed to CPF for 14 days. The in vitro concentration and effect data were used to perform BMD modelling.Results: 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.Discussion: The effective daily intake doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies to induce developmental non-cholinergic neurotoxic responses, which were captured by the analyzed in vitro test battery. These were also higher than the in vivo LOEC for cholinergic effects. Therefore, the quantitative predictive value of the investigated non-choline esterase-dependent effects, although possibly relevant for other chemicals, may not adequately represent potential key events in the MoA for CPF-associated DNT.https://www.frontiersin.org/articles/10.3389/fphar.2023.1136174/fullPBK modellingreverse dosimetryanimal alternativedose-response modelingorganophosphorus pesticidesnew approach methodologies (NAMs) |
| spellingShingle | Engi Abdelhady Algharably Emma Di Consiglio Emanuela Testai Francesca Pistollato Anna Bal-Price Abdulkarim Najjar Reinhold Kreutz Ursula Gundert-Remy 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 Frontiers in Pharmacology PBK modelling reverse dosimetry animal alternative dose-response modeling organophosphorus pesticides new approach methodologies (NAMs) |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | PBK modelling reverse dosimetry animal alternative dose-response modeling organophosphorus pesticides new approach methodologies (NAMs) |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1136174/full |
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