Testing chemical compounds for carcinogenic properties is currently performed in rats. These studies cost a lot of animals, money and time. In addition, these studies are only sometimes predictive for humans. RIVM investigates a novel animal-free approach to improve carcinogenic hazard assessment while using fewer animals.
Short video about RIVM's activities researching next generation carcinogenicity testing
video
Next generation carcinogenicity testing
Speaker: Dr. Mirjam Luijten, senior research scientist
DR. MIRJAM LUIJTEN: Improvement of chemical carcinogenicity testing requires a mechanism-based approach with a reduced use of laboratory animals.
TEXT: Next generation carcinogenicity testing.
VOICE OVER: Carcinogenicity testing of chemical substances currently relies on studies in which rodents are exposed during their entire lifetime. These studies cost a lot of money and animals. From a scientific point of view it is known that these studies not always reliably predict carcinogenic hazard for humans.
DR. MIRJAM LUIJTEN: Mechanisms relevant for carcinogenesis are traditionally divided into two categories: genotoxic and non-genotoxic mechanisms. And this categorisation is based on the ability of a substance to directly interact with genetic material. For the assessment of genotoxic potential, a reliable testing strategy is in place. And this testing strategy includes both in silico and in vitro methods and, where needed, a selected set of in vivo tests. The assessment of carcinogenic potential however still requires lifetime studies using rodents.
VOICE OVER: To conceptualise a novel animal-free approach researchers at RIVM started with charting the underlying mechanisms of chemical carcinogenesis. The approach is firmly rooted in human tumor biology and in-depth knowledge of mechanisms of non-genotoxic carcinogenicity.
DR. MIRJAM LUIJTEN: We identified several mechanisms relevant for non-genotoxic carcinogenesis based on data from OECD guideline studies. These data are publicly available through assessment reports from regulatory agencies. We applied the concept of adverse outcome pathways to build networks of mechanisms relevant for carcinogenesis. And these networks guide the selection of appropriate in silico and in vitro methods, which together form an integrated strategy for carcinogenicity testing.
VOICE OVER: Replacement of the lifetime rodent study by a dedicated set of in vitro and in silico experiments will lead to a better, mechanism-based prediction of the risk of non-genotoxic carcinogenicity due to chemical exposure.
DR. MIRJAM LUIJTEN: The current activities aimed at building AOP networks for pesticides, which is a class of compounds that is particularly data rich due to legal information and data requirements. As a next step, we will broaden the AOP networks and assess their relevance to humans, to ensure that ultimately the testing strategy for cancer risk assessment is applicable across different regulatory frameworks. By having a continued dialogue with all stakeholders including regulators as well as industry, we aim to build confidence in this mechanism-based approach for cancer risk assessment.
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The way in which a substance can cause cancer is often divided into two categories: genotoxic and non-genotoxic. Reliable testing strategies for the genotoxic properties of a substance already exist, making extensive use of both cell-based testing and computer modelling. This does not yet exist for non-genotoxic mechanisms, for which life-time rodent studies are still performed.
RIVM's research focuses on creating an overview of how chemical substances can be carcinogenic. This overview is based on biological knowledge about human tumours and non-genotoxic mechanisms that can cause cancer. There is a wealth of data available from OECD guideline studies performed for pesticides that can be used for this purpose.
The knowledge from these studies will be organised into so-called Adverse Outcome Pathways (AOPs), which can be connected to each other in AOP networks. These networks guide the selection of appropriate in vitro and in silico methods. Together, these form a testing strategy for testing the carcinogenic properties of substances, both genotoxic and non-genotoxic. As a result, fewer animals are needed and will lead to a better, mechanism-based prediction of the risk of non-genotoxic carcinogenicity due to chemical exposure.
Key publications
| Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals | Heusinkveld, H., Braakhuis, H., Gommans, R., Botham, P., Corvaro, M., van der Laan, J.W., Lewis, D. Madia, F., Manou, I., Schorsch, F., Wolterink, G., Woutersen, R., Corvi, R., Mehta, J., Luijten, M. | Crit Rev in Toxicol 2020; 50(9):725-39 |
| A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals | Luijten, M., Corvi, R., Mehta, J., Corvaro, M., Delrue, N., Felter, S., Haas, B., Hewitt, N.J., Hilton, G., Holmes, T., Jacobs, M.N., Jacobs, A., Lamplmair, F., Lewis, D., Madia, F., Manou, I., Melching-Kollmuss, S., Schorsch, F., Schutte, K., Sewell, F., Braakhuis, H. | Regul Toxicol and Pharmacol 2020; 104789 |