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Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

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PELKONEN, Olavi, Andrea TERRON, Antonio F. HERNANDEZ, Pablo MENENDEZ, Susanne HOUGAARD BENNEKOU, 2017. Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research. In: Archives of Toxicology. 91(8), pp. 2763-2780. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-1986-x

@article{Pelkonen2017-08Chemi-41183, title={Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research}, year={2017}, doi={10.1007/s00204-017-1986-x}, number={8}, volume={91}, issn={0340-5761}, journal={Archives of Toxicology}, pages={2763--2780}, author={Pelkonen, Olavi and Terron, Andrea and Hernandez, Antonio F. and Menendez, Pablo and Hougaard Bennekou, Susanne} }

Menendez, Pablo Terron, Andrea Hernandez, Antonio F. 2018-01-31T14:12:46Z 2018-01-31T14:12:46Z eng Hougaard Bennekou, Susanne Hougaard Bennekou, Susanne Pelkonen, Olavi Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research Menendez, Pablo Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future. 2017-08 Pelkonen, Olavi Terron, Andrea Hernandez, Antonio F.

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