Low Dose and Non-Targeted Radiation Effects in Environmental Protection and Medicine-A New Model Focusing on Electromagnetic Signaling.

The role of signalling in initiating and perpetuating effects triggered by deposition of ionising radiation energy in parts of a system is very clear. Less clear are the very early steps involved in converting energy to chemical and biological effects in non-targeted parts of the system. The paper aims to present a new model, which could aid our understanding of the role of low dose effects in determining ultimate disease outcomes. We propose a key role for electromagnetic signals resulting from physico-chemical processes such as excitation decay, and acoustic waves. These lead to the initiation of damage response pathways such as elevation of reactive oxygen species and membrane associated changes in key ion channels. Critically, these signalling pathways allow coordination of responses across system levels. For example, depending on how these perturbations are transduced, adverse or beneficial outcomes may predominate. We suggest that by appreciating the importance of signalling and communication between multiple levels of organisation, a unified theory could emerge. This would allow the development of models incorporating time, space and system level to position data in appropriate areas of a multidimensional domain. We propose the use of the term "infosome" to capture the nature of radiation-induced communication systems which include physical as well as chemical signals. We have named our model "the variable response model" or "VRM" which allows for multiple outcomes following exposure to low doses or to signals from low dose irradiated cells, tissues or organisms. We suggest that the use of both dose and infosome in radiation protection might open up new conceptual avenues that could allow intrinsic uncertainty to be embraced within a holistic protection framework.

Influence of common dietary supplements (curcumin, andrographolide, and d-limonene) on the radiobiological responses of p53-competent colonic cancer epithelial cells.

PURPOSE: The main goal of the research was to determine whether commercially available common dietary phytochemical supplements (curcumin, andrographolide, and d-limonene) have radiomodulatory effects on p53-competent human colonic epithelial cells. METHODS: Clonogenic survival assays were used to characterize effects of the phytochemicals on cultured colonic epithelial cells (HCT116 p53+/+) in direct irradiation or upon receipt of irradiated-cell conditioned media (for bystander effects). In direct irradiation, feeding regimen experiments included compound administration pre- and post-irradiation, which was used as a basis to define effects as radioprotective and radiomitigative, respectively. In the bystander effect experiments, either donor or recipient cell cultures were fed with the phytochemicals and bystander-induced clonogenic cell death was quantitatively evaluated. Dose challenge was in the range of 0.5 - 5 Gy using the gamma source (Cs-137). RESULTS: Curcumin, andrographolide, and d-limonene appeared to not exhibit radioprotective and radiomitigative properties in HCT116 p53+/+ cells. D-limonene was found to induce radiosensitization in post-irradiation administration. All three compounds appeared not to modulate the radiation-induced bystander signal production and response in HCT116 p53+/+ cells. CONCLUSIONS: Curcumin, andrographolide, and d-limonene are known to have many chemoprotective benefits. This work shows that they, however, did not protect colonic epithelial HCT116 p53+/+ cells from radiation killing. As HCT116 p53+/+ cells are tumourigenic in nature, this finding implies that these three dietary compounds would not reduce the killing efficacy of radiation in gastrointestinal tumorigenesis. The post-irradiation radiosensitizing effect of d-limonene was an intriguing observation worth further investigation.

Targets, pools, shoulders, and communication - a reflection on the evolution of low-dose radiobiology.

This reflection aims to look at the evolution of thinking about radiation dose response relationships from the early years of the journal when target theory prevailed to the present day when dose response is seen as a more holistic process involving multiple levels of organization and communication. The review is structured to consider how the old ideas evolved leading to apparently abrupt paradigm shifts. The odd data leading to these conceptual shifts are reviewed. Topics, which are currently still not mainstream are considered with a view to how they may change the future of radiobiology. Finally some personal reflections on the insights gained during the writing of the review are presented. The major conclusion from this study is that ideas concerning survival curves and radiation dose responses evolved and (epi)mutated gradually, driven in a large part by the techniques available for studying radiobiological processes. The illusion of abrupt paradigm shifts is not really borne out by the history when primary references are studied rather than textbooks or reviews. The textbooks necessarily simplify and distil complex data to provide a 'take-home message' while reviews are usually very personal collations selected among the vast amount of scientific literature. Primary references reveal the context of the discussion and the caveats and uncertainties of the authors.

Use of synchrotron medical microbeam irradiation to investigate radiation-induced bystander and abscopal effects in vivo.

The question of whether bystander and abscopal effects are the same is unclear. Our experimental system enables us to address this question by allowing irradiated organisms to partner with unexposed individuals. Organs from both animals and appropriate sham and scatter dose controls are tested for expression of several endpoints such as calcium flux, role of 5HT, reporter assay cell death and proteomic profile. The results show that membrane related functions of calcium and 5HT are critical for true bystander effect expression. Our original inter-animal experiments used fish species whole body irradiated with low doses of X-rays, which prevented us from addressing the abscopal effect question. Data which are much more relevant in radiotherapy are now available for rats which received high dose local irradiation to the implanted right brain glioma. The data were generated using quasi-parallel microbeams at the biomedical beamline at the European Synchrotron Radiation Facility in Grenoble France. This means we can directly compare abscopal and "true" bystander effects in a rodent tumour model. Analysis of right brain hemisphere, left brain and urinary bladder in the directly irradiated animals and their unirradiated partners strongly suggests that bystander effects (in partner animals) are not the same as abscopal effects (in the irradiated animal). Furthermore, the presence of a tumour in the right brain alters the magnitude of both abscopal and bystander effects in the tissues from the directly irradiated animal and in the unirradiated partners which did not contain tumours, meaning the type of signal was different.

Alternative medicine techniques have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects.

Many so-called "alternative medicine" techniques such as Reiki and acupuncture produce very good outcomes for intractable pain and other chronic illnesses but the efficacy is often dismissed as being psychosomatic. However a plausible mechanism does exist i.e. that the treatments alter the electromagnetic fields in living organisms and thereby prevent or reduce activity of neurons which lead to the pain. Low doses of ionising radiation have similar effects on electromagnetic fields and are known to induce signaling cascades in tissues due to ion gradients. To test this hypothesis cell cultures were exposed to Reiki - like and to acupuncture - like treatments, both performed by qualified practitioners. The cells were exposed either before or after the treatment to x-rays and were monitored for production of direct damage or bystander signals. The data suggest that the alternative techniques altered the response of cells to direct irradiation and altered bystander signal mechanisms. We conclude that alternative medicine techniques involving electromagnetic perturbations may modify the response of cells to ionizing radiation. In addition to the obvious implications for mechanistic studies of low dose effects, this could provide a novel target to exploit in radiation protection and in optimizing therapeutic gain during radiotherapy.

Radiation-induced bystander effects and adaptive responses--the Yin and Yang of low dose radiobiology?

Our current knowledge of the mechanisms underlying the induction of bystander effects by low doses of high or low LET ionizing radiation is reviewed. The question of what actually constitutes a protective effect is discussed in the context of adaptive (often referred to as hormetic or protective) responses. Finally the review considers critically, how bystander effects may be related to observed adaptive responses or other seemingly protective effects of low doses exposures. Bystander effects induce responses at the tissue level, which are similar to generalized stress responses. Most of the work involving low LET radiation exposure discussed in the existing literature measures a death response. Since many cell populations carry damaged cells without being exposed to radiation (so-called "background damage"), it is possible that low doses exposures cause removal of cells carrying potentially problematic lesions, prior to exposure to radiation. This mechanism could lead to the production of "U-shaped" or hormetic dose-response curves. The level of adverse, adaptive or apparently beneficial response will be related to the background damage carried by the original cell population, the level of organization at which damage or harm are scored and the precise definition of "harm". This model may be important when attempting to predict the consequences of mixed exposures involving low doses of radiation and other environmental stressors.