Promotieonderzoek Kirsten Veltman over het verbeteren van de veiligheidsbeoordeling van niet-genotoxische carcinogenen met behulp van new approach methodologies

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Mirjam Luijten; Kirsten Veltman; Jeroen Pennings, 2026, "Promotieonderzoek Kirsten Veltman over het verbeteren van de veiligheidsbeoordeling van niet-genotoxische carcinogenen met behulp van new approach methodologies", https://doi.org/10.21945/D6EE4F55-CD6D-43B2-B9FB-9EB55710F730, RIVM, V1
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Description
RISK-HUNT3R is een Europees initiatief om een nieuw modulair kader te ontwikkelen voor dierproefvrije next generation risk assessment. De visie van RISK-HUNT3R is het combineren van menselijke blootstellingsscenario’s, in vitro hazard assessment en new approach methodology-gebaseerde toxicokinetische en toxicodynamische testen, gevolgd door integratieve risicobeoordeling via computationele methoden en besluitvorming op basis van de weging van het bewijsmateriaal. De eindpunten die in RISK-HUNT3R aan bod komen zijn ontwikkelingsneurotoxiciteit, niet-genotoxische carcinogenese en specifieke doelorgaantoxiciteit. Dit promotieproject maakt deel uit van RISK-HUNT3R en richt zich op niet-genotoxische carcinogenese, specifiek op de inductie van oxidatieve stress die leidt tot regeneratieve proliferatie, een welbekend werkingsmechanisme van niet-genotoxische carcinogenen. Het project omvatte de ontwikkeling van een voor de mens relevant netwerk van adverse outcome pathways (AOP’s) dat dit werkingsmechanisme beschrijft. Ten tweede hebben we een op transcriptomics gebaseerde screeningsmethode ontwikkeld en gevalideerd voor het identificeren van chemicaliën die oxidatieve stress induceren. Ten derde zijn bestaande gegevens uit knaagdierstudies gebruikt om een voorlopige kwantitatieve AOP te ontwikkelen. Als eerste stap richting het onderscheiden van adaptatie en schadelijke effecten, zijn meerdere chemicaliën getest in drie voor de mens relevante blootstellingsscenario’s. Tot slot zijn twee verschillende modelsystemen (HepG2-cellen en zebravisembryo’s) met elkaar vergeleken op hun toepassingsgebied en prestaties. Deze modelsystemen zijn met elkaar verbonden via kinetische modellering. Uiteindelijk dient het AOP-netwerk als een kader voor de ontwikkeling van een testbatterij voor hazard assessment, die wordt toegepast in de vorm van een casestudy.
Theme Health
Keyword NAM, NGRA, adverse outcome pathway, non-genotoxic carcinogenesis, oxidative stress
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