Abstract
Animal testing has historically been used to evaluate the human safety of chemical compounds, including cosmetic ingredients. Since 2013, the European Cosmetics Regulation prohibits animal testing for all aspects of cosmetic ingredients and their finished products. However, alternative methods capable of addressing the most complex human endpoints, such as repeated dose systemic toxicity, are still lacking. This doctoral thesis project supports the development of such alternative methods by focussing on key cellular events
in toxicity pathways that could be suitable for inclusion in a testing strategy for the specific case of hepatotoxicity. The first study included in this doctoral thesis screened safety evaluation reports of cosmetic ingredients to identify potential target organ(s). It was found that the liver is the most commonly affected organ following repeated oral administration of cosmetic ingredients to experimental animals. In the second study, an adverse outcome
pathway (AOP) network was derived and analysed to determine key events relevant for the prediction of hepatotoxicity in vitro. This work identified cell injury/death, increased production of reactive oxygen species, mitochondrial dysfunction and fatty acid accumulation as the most important key events. In the third study, human-relevant liverbased cell models were repeatedly exposed to compounds known to induce general and liver-specific toxicities, namely necrosis, steatosis and cholestasis, in order to explore the use of toxicogenomics to derive an in vitro point of departure (POD) for risk assessment purposes. The results indicated that benchmark dose (BMD) modelling of gene coexpression networks recapitulate BMD modelling of genes and may be a good approach for the derivation of in vitro transcriptomics PODs. Overall, this doctoral thesis project has provided a considerable contribution to the development of animal-free methods for risk assessment of chemicals.
in toxicity pathways that could be suitable for inclusion in a testing strategy for the specific case of hepatotoxicity. The first study included in this doctoral thesis screened safety evaluation reports of cosmetic ingredients to identify potential target organ(s). It was found that the liver is the most commonly affected organ following repeated oral administration of cosmetic ingredients to experimental animals. In the second study, an adverse outcome
pathway (AOP) network was derived and analysed to determine key events relevant for the prediction of hepatotoxicity in vitro. This work identified cell injury/death, increased production of reactive oxygen species, mitochondrial dysfunction and fatty acid accumulation as the most important key events. In the third study, human-relevant liverbased cell models were repeatedly exposed to compounds known to induce general and liver-specific toxicities, namely necrosis, steatosis and cholestasis, in order to explore the use of toxicogenomics to derive an in vitro point of departure (POD) for risk assessment purposes. The results indicated that benchmark dose (BMD) modelling of gene coexpression networks recapitulate BMD modelling of genes and may be a good approach for the derivation of in vitro transcriptomics PODs. Overall, this doctoral thesis project has provided a considerable contribution to the development of animal-free methods for risk assessment of chemicals.
| Original language | English |
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| Qualification | Doctor of Pharmaceutical Sciences |
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| Supervisors/Advisors |
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| Award date | 19 May 2022 |
| Publication status | Published - 2022 |
Keywords
- Liver toxicity