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WORK PACKAGE 7

 

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» Non-cancer effects

 

WP7 Non-cancer effects

Objectives

The overarching strategic objective of WP7 is:

  • To implement a long-term, integrated approach in-volving several disciplines, namely, epidemiology, radiobiology, immunology, and toxicology, for the purpose of risk evaluation for radiation-induced non-cancer effects. The epidemiological evidence for the non-cancer effects of low doses is still suggestive rather than persuasive and the multi targeted biological effects observed in chronically exposed experimental models with internal emitters are quite puzzling. At present, no convincing mechanistic explanations are available that can account for the findings observed.
  • To elucidate these scientific issues, a cross scientific network of experts in epidemiology, radiopathol-ogy, cell/molecular biology, immunology, and toxicology is needed, to formulate open questions to be addressed, choose working hypotheses, design relevant cohort studies, decide on experimental models and protocols, and organize dedicated workshops.

Such an integrated view with shared common approaches should facilitate the interpretation and syn-thesis of results and should certainly help to better define future orientations.

The scientific objectives of WP7 are as follows:

  • To design well-controlled molecular epidemiology studies having in prospect (i) the identifica-tion of markers of the initial steps of low-dose radiation-induced non-cancer health effects, (ii) the record of biological non-radiation “risk factors” connected to diseases under study and (iii) the monitoring of pertinent blood biomarkers of biological radiation effects.
  • To promote, in the field of experimental radiobiology and radiotoxicology, high-throughput technologies (e.g. “omics”) and systems biology approaches that would be expected to better describe the complexity of low dose radiation-induced tissue level responses.
  • To challenge the classical molecular DNA strand break paradigm in search for the mechanisms behind non-cancer effects, and in this way to promote research activities in the field of cell physiology (i.e. cell senescence, long term cell phenotypic changes) and the radiobiology of in-tercellular communications and signalling.
  • To differentiate radiation-induced tissue and cell responses due to adaptation to the radiation stress, from true adverse alterations, involved in immunological and pathological processes.
  • To support research on mechanisms of radiation action, adopting a multi-scale/system biology approach and putting the emphasis on the relationship between initial stochastic track struc-tures of low and high LET radiations, early chemical/biological processes and long term patho-physiological effects such as inflammatory response.
  • To assess whether there are scientific arguments for replacing the classical “threshold” para-digm for non-cancer effects with the “non–threshold” paradigm.

The final objective of WP7 is operational and dedicated to the assessment of the international sys-tem of radiation protection robustness regarding so-called deterministic effects.

 

Description of work

Non-cancer effects of ionizing radiation may be manifest as, amongst others, cardiovascular disease, cognitive impairment, immunological change (connection with Task 5.2.1), and the development of lens opacities. Epidemiological evidence linking these end-points to low dose exposures is strongest for vascular effects, which will be the focus of the first research programme of WP7.

The acute damaging effects of high dose exposures of ionizing radiation on the endothelial cell system (loss of cell-cell integrity, failure of fluid barrier maintenance, cell death without replacement, new phenotype chronic activation) are well recognised. At low doses there is no evidence for the develop-ment of acute and/or chronic radiation pathology. However, epidemiological studies of cardiovascular morbidity seem to indicate that damage to the vasculature may indeed be a late effect of low dose irra-diation. In contrast, in situations of internal contamination, effects that could exhibit several physiolog-ical systems are not known so far. Now, a correlation between accumulation of low dose of radioactive material internally incorporated and vascular impairment remains an open question that could chal-lenge the radiation protection system. The full interpretation of this epidemiological data for the pur-poses of radiation protection at low doses is hindered by the almost complete lack of knowledge about the mechanism of the radiation effects. WP7 will undertake a two-pronged strategy to address this problem.

Firstly we will organise exploratory/consultation meeting to design a detailed roadmap and define new integrated issues for the network of excellence on non-cancer effects to be addressed in coming years –Task 7.1.

Secondly we will conduct feasibility/pilot studies:
– The first one in cooperation with a transversal working group on epidemiology to determine if the systems biology approach can enable future molecular epidemiological to more accurately define the dose response relationship for the development of vascular damage at low dose ex-posures (external irradiation and internal contamination) –Task 7.2.


– The second one will aim to develop a mathematical representation of the radiation response of the endothelium at different radiation doses, delivered through external irradiation and/or inter-nal contamination –Task 7.3.


– The third study will explore lens opacities among a small cohort of interventional radiologists and cardiologists –Task 7.4.

– The fourth study will consist of determining how neurogenesis could be disturbed as a result of an exposure to low dose of ionising radiation (external irradiation and internal contamination –Task 7.5.

– The fifth study will examine how low dose X-radiation contributes to anti-inflammatory im-mune mechanisms –Task 7.6.


– The sixth study will analyse the aortic defects in Fibulin-4 deficient mice after low dose IR –Task 7.7.

– The seventh study will investigate low and moderate dose radiation effects on primary Human Lens Epithelial cells using multiple stand systems approaches to determine the low dose response of the initial cellular events and the delayed radiation effects down to 1-mGy X-irradiation – Task 7.8

– The eighth study will address low dose induced molecular and functional alterations of the microvascular component of the brain by clarifying the role of pericytes in this system – Task 7.9