[ RadSafe ] Lisbon

[Ludwig E. Feinendegen]

Dear friends:

The forthcoming conference on low-dose effects in Lisbon, from November 27 to 29, appears very attractive to me. I have a presentation there and I take the liberty of giving below the abstract of my paper - with Neumann and Pollycove.  The abstract may add some thoughts to the current discussion. 

Best regards,
Ludwig

Ludwig E. Feinendegen, M.D.
Wannental 45
D - 88131 Lindau
Germany

Tel: +49 8382 75673

Systems Biology applied to Radiobiology in Low-Dose Risk Assessment

 

Ludwig E. Feinendegen 1,  Myron Pollycove 2, Ronald D. Neumann 3 

 

1 Heinrich-Heine-University Düsseldorf. Germany; and Brookhaven National Laboratory, Upton, NY, USA.  2 School of Medicine, University of California San Francisco, San Francisco, CA, USA.   3 Department of Nuclear Medicine, Clinical Center, The National Institutes of Health, 

 Bethesda, MD, USA.

 

Abstract

 

Intricate signal loops connect all functionally relevant components in a biological organism, also in humans.  This signalling is essential for sustaining homeostasis at and between ascending hierarchical levels such as molecules, cells, tissue-organs and the whole organism.  It helps to preserve coordinated function within environments causing potentially toxic impacts at each hierarchical level.  Each level presents a composure of elements, each of which again conforms to a system at a lower level with its elements.  Ionizing radiation primarily interferes at the basic molecular level proportional to dose, with potential damage amplification to higher levels.  -  One may discern principally two types of barriers against propagation of perturbations from lower to higher levels, a physical-static one and a metabolic-dynamic one.  -  Regarding the first, structural damage with functional consequences at a lower level may perturb the next higher level only if sufficiently many of its elements are sufficiently damaged.  If damage at the higher system level again surpasses a certain threshold, it may become severe enough to affect the next higher level, such as from molecules to cells, to tissue-organs, and subsequently even cause the entire system eventually to become dysfunctional and collapse.  This cascade of physical-static barriers operates deterministically.  -  Secondly, there are again at each level various metabolically regulated protective responses, that usually involve enzymes and include: - scavenging of toxins at the molecular level; - repair of vital molecules, especially of DNA, at the cellular level; - removal of damage carrying cells either by apoptosis or senescence, or by immune responses, at the tissue-organ level; - finally, there is replacement of elemental components from molecules to tissues by new synthesis and cell proliferation.  These metabolic barriers are part of the body's homeostatic control, regulated by genes, and expected to vary between individuals, tissue-organs and cells.  A particular feature of this dynamic, multi-tier protection scheme is its capability, after a sufficiently severe perturbation at any level, to strengthen corresponding barriers, with a delay and temporarily, against renewed damage impact.  This delayed and temporary protection amplification, summarily called adaptive protection, improves the chance of organism survival in the face of repeat threats, also if it comes from sources other than the initial trigger.  Thus, on average, DNA double strand breaks from endogenous-metabolic sources are about 1000 times more frequent than those from background ionizing radiation, even if a large fraction of the radiation damage may be more severe.  Indeed, acute low-dose irradiation (?150 mGy) can adaptively protect against non-radiogenic DNA damage and its consequences in the body.  In this way, low-dose irradiation can exert a dual response, one of instant molecular damage proportional to dose, and its consequences, and the other of adaptive protection under genetic control mainly against endogenous damage and its consequences, such as cancer.  Applied to assessing cancer risk of low-dose irradiation, the balance between the two types of low-dose responses principally determines the clinical outcome, the probability of which obviously does not simply follow a linear function of dose but rather agrees with a dose threshold, or even shows hormesis with clinical benefit. 

 

To be presented at the 7th Lowrad Conference 2008, in Lisbon, Portugal, November 27-29.