University of Oulu

Pelkonen, O., Terron, A., Hernandez, A.F. et al. Arch Toxicol (2017) 91: 2763.

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

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Author: Pelkonen, Olavi1; Terron, Andrea2; Hernandez, Antonio F.3;
Organizations: 1Department of Pharmacology and Toxicology and Clinical Research Unit, University of Oulu, Finland
2European Food Safety Authority (EFSA), Parma, Italy
3University of Granada School of Medicine, Granada, Spain
4Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona
5Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona
6Centro de Investigación Biomédica en Red en Cancer del ISCIII (CIBERONC), Spain
7The Danish EPA, Copenhagen, Denmark
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.4 MB)
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Language: English
Published: Springer Nature, 2017
Publish Date: 2019-10-25


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.

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on behalf of the EFSA WG EPI1 and its other members:

Karine Angeli, ANSES, France, Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Dusseldorf, Germany, Marcel Leist, University of Konstanz, Germany, Alberto Mantovani, Istituto Superiore di Sanità, Rome, Italy, Anna Price, EU JRC, Ispra, Italy, Barbara Viviani, University of Milan, Italy

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Series: Archives of toxicology
ISSN: 0340-5761
ISSN-E: 1432-0738
ISSN-L: 0340-5761
Volume: 91
Issue: 8
Pages: 2763 - 2780
DOI: 10.1007/s00204-017-1986-x
Type of Publication: A2 Review article in a scientific journal
Field of Science: 317 Pharmacy
3122 Cancers
Funding: P.M is supported by the European Research Council (CoG-2014-646903), the Spanish Ministry of Economy-Competitiveness (SAF-SAF2013-43065), the Asociación Española Contra el Cáncer, the ISCIII/FEDER (PI14/01191-PI13/00168), the Obra Social La Caixa-Fundaciò Josep Carreras, the Inocente–Inocente Foundation and Generalitat de Catalunya. P.M is investigator of the Spanish Cell Therapy cooperative network (TERCEL). The EFSA Working Group EPI1 included also the following members: Karine Angeli, ANSES, France. Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Dusseldorf, Germany. Marcel Leist, University of Konstanz, Germany. Alberto Mantovani, Istituto Superiore di Sanità, Rome, Italy. Anna Price, EU JRC, Ispra, Italy. Barbara Viviani, University of Milan, Italy.
Copyright information: © Springer-Verlag Berlin Heidelberg 2017. This is a post-peer-review, pre-copyedit version of an article published in Archives of Toxicology. The final authenticated version is available online at: