EGO to ECO: Tracing the History of Radioecology from the 1950's to the Present Day.

This paper starts with a brief history of the birth of the field of radioecology during the Cold War with a focus on US activity. We review the establishment of the international system for radiation protection and the science underlying the guidelines. We then discuss the famous ICRP 60 statement that if "Man" is protected, so is everything else and show how this led to a focus in radioecology on pathways to "Man" rather than concern about impacts on environments or ecosystems. We then review the contributions of Radiation Research Society members and papers published in Radiation Research which contributed to the knowledge base about effects on non-human species. These fed into international databases and computer-based tools such as ERICA and ResRad Biota to guide regulators. We then examine the origins of the concern that ICRP 60 is not sufficient to protect ecosystems and discuss the establishment of ICRP Committee 5 and its recommendations to establish reference animals and plants. The review finishes with current concerns that reference animals and plants (RAPs) are not sufficient to protect ecosystems, given the complexity of interacting factors such as the climate emergency and discusses the efforts of ICRP, the International Union of Radioecologists and other bodies to capture the concepts of ecosystem services and ecosystem complexity modelling in radioecology.

"Lethal Mutations" a Misnomer or the Start of a Scientific Revolution?

The aim of this paper is to review the history surrounding the discovery of lethal mutations, later described as delayed reproductive death. Lethal mutations were suggested very early on, to be due to a generalised instability in a cell population and are considered now to be one of the first demonstrations of "radiation-induced genomic instability" which led later to the establishment of the field of "non-targeted effects." The phenomenon was first described by Seymour et al. in 1986 and was confirmed by Trott's group in Europe and by Little and colleagues in the United States before being extended by Mendonca et al. in 1989, who showed conclusively that the distinguishing feature of lethal mutation occurrence was that it happened suddenly after about 9-10 population doublings in progeny which had survived the original dose of ionizing radiation. However, many authors then suggested that in fact, lethal mutations were implicit in the original experiments by Puck and Marcus in 1956 and were described in the extensive work by Sinclair in 1964, who followed clonal progeny for up to a year after irradiation and described "small colony formation" as a persistent consequence of ionizing radiation exposure. In this paper, we examine the history from 1956 to the present using the period from 1986-1989 as an anchor point to reach into the past and to go forward through the evolution of the field of low dose radiobiology where non-targeted effects predominate.

Factors Influencing Effects of Low-dose Radiation Exposure.

ABSTRACT: It is now well accepted that the mechanisms induced by low-dose exposures to ionizing radiation (LDR) are different from those occurring after high-dose exposures. However, the downstream effects of these mechanisms are unclear as are the quantitative relationships between exposure, effect, harm, and risk. In this paper, we will discuss the mechanisms known to be important with an overall emphasis on how so-called "non-targeted effects" (NTE) communicate and coordinate responses to LDR. Targeted deposition of ionizing radiation energy in cells causing DNA damage is still regarded as the dominant trigger leading to all downstream events whether targeted or non-targeted. We regard this as an over-simplification dating back to formal target theory. It ignores that last 100 y of biological research into stress responses and signaling mechanisms in organisms exposed to toxic substances, including ionizing radiation. We will provide evidence for situations where energy deposition in cellular targets alone cannot be plausible as a mechanism for LDR effects. An example is where the energy deposition takes place in an organism not receiving the radiation dose. We will also discuss how effects after LDR depend more on dose rate and radiation quality rather than actual dose, which appears rather irrelevant. Finally, we will use recent evidence from studies of cataract and melanoma induction to suggest that after LDR, post-translational effects, such as protein misfolding or defects in energy metabolism or mitochondrial function, may dominate the etiology and progression of the disease. A focus on such novel pathways may open the way to successful prophylaxis and development of new biomarkers for better risk assessment after low dose exposures.

Quantum Biology and the Potential Role of Entanglement and Tunneling in Non-Targeted Effects of Ionizing Radiation: A Review and Proposed Model.

It is well established that cells, tissues, and organisms exposed to low doses of ionizing radiation can induce effects in non-irradiated neighbors (non-targeted effects or NTE), but the mechanisms remain unclear. This is especially true of the initial steps leading to the release of signaling molecules contained in exosomes. Voltage-gated ion channels, photon emissions, and calcium fluxes are all involved but the precise sequence of events is not yet known. We identified what may be a quantum entanglement type of effect and this prompted us to consider whether aspects of quantum biology such as tunneling and entanglement may underlie the initial events leading to NTE. We review the field where it may be relevant to ionizing radiation processes. These include NTE, low-dose hyper-radiosensitivity, hormesis, and the adaptive response. Finally, we present a possible quantum biological-based model for NTE.

A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome.

Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE). Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments.

Investigation of presence and impact of radiation-induced bystander effect in Acheta domesticus.

PURPOSE: Radiation-induced bystander effect (RIBE), a non-targeted effect of ionizing radiation in which non-irradiated individuals behave as if they have been irradiated after interactions with irradiated individuals, has been well documented in vertebrates. However, little research has been done investigating RIBE in terrestrial insects, this paucity of invertebrate RIBE leads to lack of knowledge on invertebrates living in fallout and exclusion zones. This paper aims to better understand the impacts of RIBE on terrestrial insects.Methods and materials: House crickets who have interacted with irradiated crickets were examined to investigate population effects of ionizing radiation exposure to better understand RIBE in insects. RESULTS: The results demonstrated RIBE in crickets and found that cohabitated males had higher growth rate (mg/day) when compared to non-cohabitated males. Further, cohabitated males and females matured significantly faster with no significant difference in maturation weight than non-cohabitated populations. Experiment with adult irradiated crickets found saturability of bystander signals and similar shifts in maturation parameters. These results highlight that bystander signals can impacted development and maturation in crickets. CONCLUSION: Given long-term impacts of RIBE in insects, these results may have significant implications for interactions between insects inhabiting fringe nuclear exclusion zones and those outside of it.

X-ray-induced bio-acoustic emissions from cultured cells.

PURPOSE: We characterize for the first time the emission of acoustic waves from cultured cells irradiated with X-ray photon radiation. METHODS AND MATERIALS: Human cancer cell lines (MCF-7, HL-60) and control cell-free media were exposed to 1 Gy X-ray photons while recording the sound generated before, during and after irradiation using custom large-bandwidth ultrasound transducer. The effects of dose rate and cell viability were investigated. RESULTS: We report the first recorded acoustic signals captured from a collective pressure wave response to ionizing irradiation in cell culture. The acoustic signal was co-terminous with the radiation pulse, its magnitude was dependent on radiation dose rate, and live and dead cells showed qualitatively and quantitatively different acoustic signal characteristics. The signature of the collective acoustic peaks was temporally wider and with higher acoustic power for irradiated HL-60 than for irradiated MCF-7. CONCLUSIONS: We show that X-ray irradiation induces two cultured cancer cell types to emit a characteristic acoustic signal for the duration of the radiation pulse. The rapid decay of the signal excludes acoustic emissions themselves from contributing to the inter-organism bystander signal previously reported in intact animals, but they remain a potential component of the bystander process in tissues and cell cultures. This preliminary study suggests that further work on the potential role of radiation-induced acoustic emission (RIAE) in the inter-cellular bystander effect is merited.

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.

Isolated Clones of a Human Colorectal Carcinoma Cell Line Display Variation in Radiosensitivity Following Gamma Irradiation.

Objective: To determine whether the width of the shoulder and the size of the bystander effect are correlated using clonal lineages derived from a cultured cell line. Methods: HCT 116 (p53 wildtype) cells were grown at cloning density and individual viable colonies were picked off and grown to establish a series of cell lines from both unirradiated and irradiated progenitors. These cell lines were then irradiated to generate full survival curves. Highly variant clones were then tested to determine the level of the bystander effect using a medium transfer protocol. Results: The multi-target model gave the best fit in these experiments and size of the shoulder n is assessed in terms of radiosensitivity. The parent cell line has an n value of 1.1 while the most variant clones have n values of 0.88 (Clone G) and 5.5 (Clone A). Clonal lines subject to irradiation prior to isolation differed in bystander signal strength in comparison to clonal lines which were not initially irradiated (P = .055). Conclusions: Based on these experiments we suggest there may be a link between shoulder size of a mammalian cell line and the strength of a bystander effect produced in vitro. This may have implications for radiotherapy related to out-of-field effects.

Low dose radiation mechanisms: The certainty of uncertainty.

This paper reviews the current understanding of low dose radiobiology, and how it has evolved from classical target theory. It highlights the uncertainty around low dose effects, which is due in part to the complexity of "context" surrounding the ultimate expression of biological effects following low dose exposure. The paper makes special reference to low dose non-targeted effects which, are currently ignored in radiation protection and population level risk assessment, because it is unclear what they mean for risk. The view of the authors is that this "lack of clarity" about what the effects mean is precisely the point. It indicates the uncertainty of outcomes after a given exposure. The uncertainty stems from multiple outcome options resulting from the intrinsic uncertainty of the stochastic interaction of low dose radiation with matter. This uncertainty should be embraced rather than eschewed. The impacts of the uncertainties identified in this paper is explored and an approach to quantifying mutation probability in relation to dose is presented.

Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability?

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Cancer-Related Fatigue (CRF) are syndromes with considerable overlap with respect to symptoms. There have been many studies that have compared the two conditions, and some of this research suggests that the etiologies of the conditions are linked in some cases. In this narrative review, CFS/ME and cancer are introduced, along with their known and putative mechanistic connections to multiple stressors including ionizing radiation. Next, we summarize findings from the literature that suggest the involvement of HPA-axis dysfunction, the serotonergic system, cytokines and inflammation, metabolic insufficiency and mitochondrial dysfunction, and genetic changes in CRF and CFS/ME. We further suspect that the manifestation of fatigue in both diseases and its causes could indicate that CRF and CFS/ME lie on a continuum of potential biological effects which occur in response to stress. The response to this stress likely varies depending on predisposing factors such as genetic background. Finally, future research ideas are suggested with a focus on determining if common biomarkers exist in CFS/ME patients and those afflicted with CRF. Both CFS/ME and CRF are relatively heterogenous syndromes, however, it is our hope that this review assists in future research attempting to elucidate the commonalities between CRF and CFS/ME.

Radiobiological and social considerations following a radiological terrorist attack; mechanisms, detection and mitigation: review of new research developments.

PURPOSE: This review focuses on recent research in understanding the different aspects of what society should expect from a radiological attack. Although some scenarios of a radiologic event can be impossible to be prepared for, the effort put toward educating and better preparing for these types of events can help minimize some of the issues. The different areas discussed in this review include radioisotopes of concern, detection of radiation dose, biological effects of ionizing radiation exposures, low dose effects, targeted and non-targeted effects (NTE), psychological effects, mitigations, with a brief mention of other considerations such as medical preparedness, communication, policy implications and ethical issues. This review also discusses solutions to rectify the issues faced at hand that may come up in the event of a radiologic terrorist attack. CONCLUSIONS: A review of recent work in the area shows that a multi-layered and interdisciplinary approach is needed to prepare for a radiological terrorist attack. As well as medical preparedness, the approach needs to include sociological and psychological planning as well as an understanding of ethical issues. Since the likely 'dirty bomb' scenarios may involve low dose exposures to high numbers of people, a much better theoretical and practical understanding of low dose radiobiology and the development of robust low dose exposure biomarkers is needed as part of an integrated plan.

Copper uptake in adult rainbow trout irradiated during early life stages and in non-irradiated bystander trout which swam with the irradiated fish.

PURPOSE: This investigation forms part of a wider study into the legacy effects of exposure of rainbow trout eggs 38 h after fertilization, eyed eggs, yolk sac larvae (YSL) or first feeders to a single 0.5 Gy X-ray dose, including the induction of a bystander effect, by the irradiated fish, to non-irradiated fish. Fish may be exposed to multiple environmental stressors, including waterborne metals, during their lifespan and, while there are data on how the legacy of early life stage irradiation and bystander effect induction is affected by waterborne aluminum and cadmium, there are no studies into the effects radiation or the radiation induced bystander effect on metal uptake. Therefore the aim of this investigation was to determine if the legacy of early life stage irradiation included an effect on copper uptake by adult fish and by non-irradiated bystander adult trout which swam with the irradiated fish. METHODS: The four early life stages mentioned above were exposed to a single 0.5 Gy X-ray dose and then maintained, for two years with no further irradiation. At two years old the irradiated fish were allowed to swim, for 2 h with non-irradiated bystander trout (also two years old). After this time copper uptake was determined using 64Cu. RESULTS: Copper uptake was increased in adult trout irradiated as eggs at 48 h after fertilization and as first feeders but eyed egg or YSL irradiation had no effect. Copper uptake was also increased in the bystander trout which swam with trout irradiated as eggs at 48 h after fertilization and as eyed eggs but there was no effect on non-irradiated adult trout which swam with trout irradiated as YSL or first feeders. CONCLUSIONS: When put in context with the proteomic changes observed in these fish we propose the increased copper uptake in adult trout irradiated as eggs at 48 h after fertilization could be part of an anti-tumorigenic response and the increase in copper uptake in adult trout irradiated as first feeders could be part of a potentially protective pro-apoptotic response. Similarly we propose the increase in copper uptake in non-irradiated adult trout, induced by trout irradiated as eggs at 48 h after fertilization or as eyed eggs, was part of the universally anti-tumorigenic nature of the X-ray induced bystander effect in fish. However this was exclusive to embryonic irradiation.

Environmental and industrial developments in radiation cataractogenesis.

PURPOSE: This review discusses recent developments in our understanding of biological and physiological mechanisms underlying radiation cataractogenesis. The areas discussed include effects of low-dose exposures to the lens including potential relevance of non-targeted effects, the development of new personal-protective equipment (PPE) and standards in clinical and nuclear settings motivated by the updated ICRP recommendations to mitigate exposures to the lens of the eye. The review also looks at evidence from the field linking cataracts in birds and mammals to low dose exposures. CONCLUSIONS: The review suggests that there is evidence that cataractogenesis is not a tissue reaction (deterministic effect) but rather is a low dose effect which shows a saturable dose response relationship similar to that seen for non-targeted effects in general. The review concludes that new research is needed to determine the dose response relationship in environmental studies where field data are contradictory and lab studies confined to rodent models for human exposure studies.

A pilot study of radiation-induced bystander effect in radio-adapting frogs at a radiologically contaminated site located on the chalk river laboratories property.

PURPOSE: To measure medium borne bystander effects, to study the influence of radioadaptive response (RAR) on bystander response, and to discover reliable radioresponsive biomarkers in radio-adapting frogs from Duke Swamp contaminated with an above-background radiation level and in naïve frogs from Twin Lake as the background control site. MATERIALS AND METHODS: Frogs were captured at Duke Swamp and Twin Lake and brought to the lab at the Canadian Nuclear Laboratories facility. Half of the frogs from each site were irradiated with 4 Gy while the other half of the frogs were left with no further radiation treatment. Frog bladders were removed and placed in sterile culture media. Upon arrival at McMaster University, the bladders were processed for tissue cultures. After 48 h, the culture media conditioned by the bladder explants were harvested for clonogenic reporter survival assay and calcium flux measurements for assessing bystander effects. HPV-G cells were used as bystander reporter cells in all radiation-induced bystander effect (RIBE) assays. The frog bladder cultures were incubated for another 10-12 days followed by immunochemical staining for bcl-2 and c-myc expressions to analyze cellular anti-apoptotic (pro-survival) and pro-apoptotic (pro-death) responses, respectively. RESULTS: Only culture media conditioned by bladders from 4-Gy-irradiated naïve frogs from Twin Lake induced bystander effects (reduction of HPV-G reporter cells' clonogenic survival and presence of strong calcium flux activities). The 4 Gy irradiation dose increased pro-apoptotic c-myc expression in naïve frogs' bladder explants. Culture media conditioned by bladders from radio-adapting frogs from Duke Swamp enhanced HPV-G's clonogenic survival and a 4 Gy irradiation challenge did not change the enhanced clonogenic survival nature nor induce calcium flux. In bladder explants from both control and 4-Gy-irradiated radio-adapting frogs, anti-apoptotic bcl-2 expression for pro-survival responses was ubiquitous while c-myc expression for pro-death responses was limited to a small fraction of cells. CONCLUSION: The clonogenic RIBE reporter assay using HPV-G and calcium flux measurements are useful diagnostic tools for RIBE assessment of field biological samples, specifically those from frogs. RAR induced by environmentally relevant low-dose radiation induces protective bystander response. Bcl-2 and c-myc are reliable biomarkers for evaluating low dose radiation responses in wild populations of amphibians. Overall, this pilot study emphasizes the importance of looking at non-targeted effects (NTEs) in natural populations of non-human biota that could be vulnerable to chronic low-dose radiation exposures.

Women's contributions to radiobiology in Ireland; from small beginnings .

OBJECTIVES: To describe the contribution of women radiobiologists in Ireland to the development of the discipline internationally and at home and to discuss the history of radiobiology in Ireland to date. This parallels the history of the evolution of a small radiobiology group in Kevin Street, Dublin Institute of Technology (DIT) which was formerly part of the City of Dublin Vocational Education Committee. There followed years of development first as a radiobiological research center which evolved in the FOCAS Research Institute now embedded within Technological University Dublin (TU Dublin). CONCLUSIONS: Over the last 45 years, the women of the Radiation and Environmental Science Centre (RESC) contributed to the major paradigm shift in low dose radiobiology contributing exciting new research concerning non-targeted effects, including discovery of lethal mutations, medium transfer bystander mechanisms, and signaling pathways. They also developed translational research using human explant culture systems with unique immunocytochemical methods and more recently evolved to molecular and spectroscopic analysis of clinical samples. The RESC also developed unique in vitro research methods into effects of radiation on non-human species of concern in ecosystems.