International expert group collaboration for developing an adverse outcome pathway for radiation induced leukemia

Abstract

Purpose

The concept of the adverse outcome pathway (AOP) has recently gained significant attention as to its potential for incorporation of mechanistic biological information into the assessment of adverse health outcomes following ionizing radiation (IR) exposure. This work is an account of the activities of an international expert group formed specifically to develop an AOP for IR-induced leukemia. Group discussions were held during dedicated sessions at the international AOP workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations to consolidate knowledge into a number of biological key events causally linked by key event relationships and connecting a molecular initiating event with the adverse outcome. Further knowledge review to generate a weight of evidence support for the Key Event Relationships (KERs) was undertaken using a systematic review approach.

Conclusions

An AOP for IR-induced acute myeloid leukemia was proposed and submitted for review to the OECD-curated AOP-wiki (aopwiki.org). The systematic review identified over 500 studies that link IR, as a stressor, to leukemia, as an adverse outcome. Knowledge gap identification, although requiring a substantial effort via systematic review of literature, appears to be one of the major added values of the AOP concept. Further work, both within this leukemia AOP working group and other similar working groups, is warranted and is anticipated to produce highly demanded products for the radiation protection research community.

Keywords:

• Leukemia
• ionizing radiation
• acute myeloid leukemia
• AML
• radiation-induced leukemia
• adverse outcome pathway
• key event
• low-dose radiation
• molecular initiating event
• radiation protection
• risk assessment

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was partially supported by the Research Council of Norway (RCN) under the Center of Excellence (CoE) funding scheme [Project No. 223268]; RadoNorm project under the program EURATOM Horizon 2020; intramural research funding at the Institut de Radioprotection et de Sûreté Nucléaire (IRSN).

Notes on contributors

Dmitry Klokov

Dmitry Klokov, Ph.D., is a head of the Laboratory of Experimental Radiotoxicology and Radiobiology (LRTOX), Institute of Radioprotection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France. He also holds an Adjunct Professor position at the Department of Biochemistry, Microbiology and Immunology of University of Ottawa. Previously, Dmitry Klokov has led a low-dose radiobiology program at the Canadian Nuclear Laboratories. His research interests include various domains within the field of low-dose radiation effects, with an overarching goal to understand mechanisms of early genotoxic and molecular responses and how they may contribute to long-term health outcomes, such as cancer, cardiovascular and neurological pathologies, and transgenerational effects. Dmitry Klokov has also been involved in various international initiatives in low-dose radiobiological research and cooperation, including those coordinated by UNSCEAR, NEA, MELODI, DOE and others.

Kimberly Applegate

Kimberly Applegate, M.D., M.S., is a member of NCRP Council and ICRP Main Commission as chair of Committee 3, focusing on radiation protection research and policy in medicine. Dr. Applegate is a retired professor of radiology and pediatrics from the University of Kentucky in Lexington. Dr. Applegate’s policy, education, and research work has contributed to documentation and awareness of the variation in care and improvement in the imaging justification and optimization processes, and health outcomes.

Christophe Badie

Christophe Badie, Ph.D., is a biologist who carried out his PhD in Radiobiology-Radiopathology at Gustave Roussy Institute in Villejuif near Paris. In 2005 he became the leader of the Cancer Mechanisms and Biomarkers group in the Radiation Effects department, Radiation Chemical and Environmental Hazards of UK Health Security agency near Oxford. He is working on the development of biomarkers, mainly using human blood as source of information. He has also developed several mouse models to get insights into the molecular mechanisms of radiation leukaemogenesis. He has significant involvement in radiation research in Europe, MELODI (European Multidisciplinary European Low Dose Risk Research Initiative). He is in the scientific committee of the International Association of Biological and EPR Radiation Dosimetry (IABERD), RENEB (European network of biological dosimetry, Realizing the European Network of Bio dosimetry). He is also a member of a NATO RTG group and a member of the ICRP C1 committee.

Dag Anders Brede

Dag Anders Brede, Ph.D., is a professor of Radioecology at the Faculty of Environmental Sciences and Natural Resource Management/Norwegian University of Life Sciences (NMBU). He is a principal investigator at the Center for Environmental Radioactivity (CERAD CoE) and co-lead on CERAD research on biological effects of ionizing radiation and species radiosensitivity.

Fieke Dekkers

Fieke Dekkers, Ph.D. is a mathematician and senior scientist working in the field of radiation research at the National Institute for Public Health and the Environment in the Netherlands and at the Department of Mathematics at Utrecht University, both in the Netherlands. Her research interest includes mathematical modeling of longs term health effects of exposure to ionizing radiation. She is secretary of the European low-dose platform MELODI and a member of the Belgian UNSCEAR delegation.

Melis Karabulutoglu

Melis Karabulutoglu joined Cancer Mechanisms and Biomarkers group as a D.Phil. student (January 2018) under supervision of Dr. Christophe Badie and Dr. Mark A Hill on a joint degree programme with the University of Oxford. Her PhD project focuses on investigating the mechanisms of radiation leukaemogenesis, characterization of hematopoietic stem cells and modulation of risk.

Eric Andreas Rutten

Eric Andreas Rutten is a D.Phil. student in the Department of Oncology, University of Oxford, working in the Cancer Mechanisms and Biomarkers Group at the United Kingdom Health Security Agency (UKHSA) on the role of extracellular vesicles in the development of radiation-induced acute myeloid leukaemias. Eric previously did his BSc and MRes in Imperial College London in the field of Biochemistry and Molecular and Cellular Bioscience. His research interests include the development of pre-cancer biomarkers for early risk assessment and preventative therapy, the use of extracellular vesicles as biomarkers or as therapeutic agents for cancers, as well as personalized treatment regimens for patients based on genetic and epigenetic markers and evolving biomarker landscape.

Katalin Lumniczky

Katalin Lumniczky M.D., Ph.D. is the head of the Radiation Medicine Unit, Department of Radiobiology and Radiohygiene, National Public Health, Budapest, Hungary. She is a radiation biologist, her main research interest is focused on understanding radiation-induced non-targeted effects, radiation-induced immune alterations and the impact of radiation on intercellular signaling.

Maria Gomolka

Maria Gomolka, Ph.D., is a biologist and senior scientist in the Radiation Biology working group of the Federal Office for Radiation Protection, Oberschleissheim, Germany. She focuses on biological radiation reactions, radiation sensitivity, biobanking of radiation exposed individuals and biomarker development for radiation protection. She is and has been involved in various international and national collaborative platforms and projects, such as MELODI, RadoNorm, Concert and DoReMi with a special focus on low-dose radiation research.