A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE)
Abstract The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP...
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| Language: | English |
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Wiley
2024-08-01
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| Series: | EFSA Journal |
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| Online Access: | https://doi.org/10.2903/j.efsa.2024.8954 |
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| author | European Food Safety Authority (EFSA) Kevin M. Crofton Martin Paparella Anna Price Iris Mangas Laura Martino Andrea Terron Antonio Hernández‐Jerez |
| author_facet | European Food Safety Authority (EFSA) Kevin M. Crofton Martin Paparella Anna Price Iris Mangas Laura Martino Andrea Terron Antonio Hernández‐Jerez |
| author_sort | European Food Safety Authority (EFSA) |
| collection | DOAJ |
| description | Abstract The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence‐based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified. |
| format | Article |
| id | doaj-art-c3b3bb85a2de473da5a703e2851b6664 |
| institution | DOAJ |
| issn | 1831-4732 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | EFSA Journal |
| spelling | doaj-art-c3b3bb85a2de473da5a703e2851b66642025-08-20T03:03:45ZengWileyEFSA Journal1831-47322024-08-01228n/an/a10.2903/j.efsa.2024.8954A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE)European Food Safety Authority (EFSA)Kevin M. CroftonMartin PaparellaAnna PriceIris MangasLaura MartinoAndrea TerronAntonio Hernández‐JerezAbstract The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence‐based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified.https://doi.org/10.2903/j.efsa.2024.8954adverse outcome pathwaydevelopmental neurotoxicitydevelopmental neurotoxicity in vitro batteryDNTpyrethroidssystematic literature review |
| spellingShingle | European Food Safety Authority (EFSA) Kevin M. Crofton Martin Paparella Anna Price Iris Mangas Laura Martino Andrea Terron Antonio Hernández‐Jerez A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) EFSA Journal adverse outcome pathway developmental neurotoxicity developmental neurotoxicity in vitro battery DNT pyrethroids systematic literature review |
| title | A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) |
| title_full | A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) |
| title_fullStr | A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) |
| title_full_unstemmed | A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) |
| title_short | A developmental neurotoxicity adverse outcome pathway (DNT‐AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE) |
| title_sort | developmental neurotoxicity adverse outcome pathway dnt aop with voltage gate sodium channel vgsc inhibition as a molecular initiating event mie |
| topic | adverse outcome pathway developmental neurotoxicity developmental neurotoxicity in vitro battery DNT pyrethroids systematic literature review |
| url | https://doi.org/10.2903/j.efsa.2024.8954 |
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