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

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Abstract

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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The Cellular and Molecular Landscapes of the Developing Human Central Nervous System.

John Silbereis, Sirisha Pochareddy, Ying Zhu … (2016)

The human CNS follows a pattern of development typical of all mammals, but certain neurodevelopmental features are highly derived. Building the human CNS requires the precise orchestration and coordination of myriad molecular and cellular processes across a staggering array of cell types and over a long period of time. Dysregulation of these processes affects the structure and function of the CNS and can lead to neurological or psychiatric disorders. Recent technological advances and increased focus on human neurodevelopment have enabled a more comprehensive characterization of the human CNS and its development in both health and disease. The aim of this review is to highlight recent advancements in our understanding of the molecular and cellular landscapes of the developing human CNS, with focus on the cerebral neocortex, and the insights these findings provide into human neural evolution, function, and dysfunction.

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Normal development of brain circuits.

Gregory Z. Tau, Laurence B. Peterson (2009)

Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that is influenced by genetic predispositions, environmental events, and neuroplastic responses to experiential demand that modulates connectivity and communication among neurons, within individual brain regions and circuits, and across neural pathways. Recent advances in neuroimaging and computational neurobiology, together with traditional investigational approaches such as histological studies and cellular and molecular biology, have been invaluable in improving our understanding of these developmental processes in humans in both health and illness. To contextualize the developmental origins of a wide array of neuropsychiatric illnesses, this review describes the development and maturation of neural circuits from the first synapse through critical periods of vulnerability and opportunity to the emergent capacity for cognitive and behavioral regulation, and finally the dynamic interplay across levels of circuit organization and developmental epochs.

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Is Open Access

Update: use of the benchmark dose approach in risk assessment

Anthony Hardy, Diane Benford, Thorhallur Halldorsson … (2017)

Abstract The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the NOAEL approach for deriving a Reference Point (RP). Most of the modifications made to the SC guidance of 2009 concern the section providing guidance on how to apply the BMD approach. Model averaging is recommended as the preferred method for calculating the BMD confidence interval, while acknowledging that the respective tools are still under development and may not be easily accessible to all. Therefore, selecting or rejecting models is still considered as a suboptimal alternative. The set of default models to be used for BMD analysis has been reviewed, and the Akaike information criterion (AIC) has been introduced instead of the log‐likelihood to characterise the goodness of fit of different mathematical models to a dose–response data set. A flowchart has also been inserted in this update to guide the reader step‐by‐step when performing a BMD analysis, as well as a chapter on the distributional part of dose–response models and a template for reporting a BMD analysis in a complete and transparent manner. Finally, it is recommended to always report the BMD confidence interval rather than the value of the BMD. The lower bound (BMDL) is needed as a potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL per ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re‐evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 SC guidance was used, in particular when the exposure is clearly smaller (e.g. more than one order of magnitude) than the health‐based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the expected wide application of the BMD approach.

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Engi Abdelhady Algharably: URI : https://loop.frontiersin.org/people/1314277/overview

Emma Di Consiglio: URI : https://loop.frontiersin.org/people/1853542/overview

Emanuela Testai: URI : https://loop.frontiersin.org/people/1853565/overview

Francesca Pistollato: URI : https://loop.frontiersin.org/people/856521/overview

Abdulkarim Najjar: URI : https://loop.frontiersin.org/people/1456571/overview

Reinhold Kreutz: URI : https://loop.frontiersin.org/people/1280506/overview

Ursula Gundert-Remy: URI : https://loop.frontiersin.org/people/12913/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 07 March 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 1136174

Affiliations

[1] ¹ Institute of Clinical Pharmacology and Toxicology , Charité—Universitätsmedizin Berlin , Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin , Berlin, Germany

[2] ² Mechanisms, Biomarkers and Models Unit , Environment and Health Department , Istituto Superiore di Sanità , Rome, Italy

[3] ³ European Commission , Joint Research Center (JRC) , Ispra, Italy

[4] ⁴ Beiersdorf AG , Hamburg, Germany

Author notes

Edited by: Ted W. Simon, TedSimon LLC, United States

Reviewed by: Harvey Clewell, ScitoVation, United States

Hisham El-Masri, United States Environmental Protection Agency (EPA), United States

Miguel A. Sogorb, Miguel Hernández University of Elche, Spain

*Correspondence: Engi Abdelhady Algharably, engi.algharably@ 123456charite.de

This article was submitted to Predictive Toxicology, a section of the journal Frontiers in Pharmacology

Article

Publisher ID: 1136174

DOI: 10.3389/fphar.2023.1136174

PMC ID: 10027916

PubMed ID: 36959852

SO-VID: 1248d6fb-d251-4658-8002-9f6dd07a239e

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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

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Herbal Medicines Journal (Herb Med J)

Most cited references 56

The Cellular and Molecular Landscapes of the Developing Human Central Nervous System.

Normal development of brain circuits.

Update: use of the benchmark dose approach in risk assessment

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