Ludwig E. Feinendegen

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection. This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation. These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of nonradiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging. The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms.

Reactive oxygen species in cell responses to toxic agents

This review first summarizes experimental data on biological effects of different concentrations of ROS in mammalian cells and on their potential role in modifying cell responses to toxic agents. It then attempts to link the role of steadily produced metabolic ROS at various concentrations in mammalian cells to that of environmentally derived ROS bursts from exposure to ionizing radiation. The ROS from both sources are known to both cause biological damage and change cellular signaling, depending on their concentration at a given time. At low concentrations signaling effects of ROS appear to protect cellular survival and dominate over damage, and the reverse occurs at high ROS concentrations. Background radiation generates suprabasal ROS bursts along charged particle tracks several times a year in each nanogram of tissue, i.e., average mass of a mammalian cell. For instance, a burst of about 200 ROS occurs within less than a microsecond from low-LET irradiation such as X-rays along the track of a Compton electron (about 6 keV, ranging about 1 μm). One such track per nanogram tissue gives about 1 mGy to this mass. The number of instantaneous ROS per burst along the track of a 4-meV ¬-particle in 1 ng tissue reaches some 70000. The sizes, types and sites of these bursts, and the time intervals between them directly in and around cells appear essential for understanding low-dose and low dose-rate effects on top of effects from endogenous ROS. At background and low-dose radiation exposure, a major role of ROS bursts along particle tracks focuses on ROS-induced apoptosis of damage-carrying cells, and also on prevention and removal of DNA damage from endogenous sources by way of temporarily protective, i.e., adaptive, cellular responses. A conclusion is to consider low-dose radiation exposure as a provider of physiological mechanisms for tissue homoeostasis.

Hormesis by Low Dose Radiation Effects: Low-Dose Cancer Risk Modeling Must Recognize Up-Regulation of Protection

Ionizing radiation primarily perturbs the basic molecular level proportional to dose, with potential damage propagation to higher levels: cells, tissues, organs, and whole body. There are three types of defenses against damage propagation. These operate deterministically and below a certain impact threshold there is no propagation. Physical static defenses precede metabolic-dynamic defenses acting immediately: scavenging of toxins;—molecular repair, especially of DNA;—removal of damaged cells either by apoptosis, necrosis, phagocytosis, cell differentiation-senescence, or by immune responses,—followed by replacement of lost elements. Another metabolic-dynamic defense arises delayed by up-regulating immediately operating defense mechanisms. Some of these adaptive protections may last beyond a year and all create temporary protection against renewed potentially toxic impacts also from nonradiogenic endogenous sources. Adaptive protections have a maximum after single tissue absorbed doses around 100–200 mSv and disappear with higher doses. Low dose-rates initiate maximum protection likely at lower cell doses delivered repetitively at certain time intervals. Adaptive protection preventing only about 2–3 % of endogenous lifetime cancer risk would fully balance a calculated-induced cancer risk at about 100 mSv, in agreement with epidemiological data and concordant with an hormetic effect. Low-dose-risk modeling must recognize up-regulation of protection.

Hemopoietic Response to Low Dose-Rates of Ionizing Radiation Shows Stem Cell Tolerance and Adaptation

Chronic exposure of mammals to low dose-rates of ionizing radiation affects proliferating cell systems as a function of both dose-rate and the total dose accumulated. The lower the dose-rate the higher needs to be the total dose for a deterministic effect, i.e., tissue reaction to appear. Stem cells provide for proliferating, maturing and functional cells. Stem cells usually are particularly radiosensitive and damage to them may propagate to cause failure of functional cells. The paper revisits 1) medical histories with emphasis on the hemopoietic system of the victims of ten accidental chronic radiation exposures, 2) published hematological findings of long-term chronically gamma-irradiated rodents, and 3) such findings in dogs chronically exposed in large life-span studies. The data are consistent with the hypothesis that hemopoietic stem and early progenitor cells have the capacity to tolerate and adapt to being repetitively hit by energy deposition events. The data are compatible with the “injured stem cell hypothesis”, stating that radiation–injured stem cells, depending on dose-rate, may continue to deliver clones of functional cells that maintain homeostasis of hemopoiesis throughout life. Further studies perhaps on separated hemopoietic stem cells may unravel the molecular-biology mechanisms causing radiation tolerance and adaptation.

Damage propagation in complex biological systems following exposure to low doses of ionising radiation

Biological organisms present hierarchical levels of organisation capable of maintaining homeostasis at low-level perturbations through intricate signalling between cells. Ionising radiation may damage DNA and other molecular components. This primary risk rises linearly with dose over a certain dose range. A second risk describes the probability of the initial DNA and other damage to propagate in the body to cause disease, such as cancer. The homeostatic control of the second risk does not function in a linear fashion. Moreover, low-dose irradiation may adaptively up-regulate protective responses at different organisational levels genetically controlled. Such adaptive protections (APs) usually defend also against the inevitable abundant non-radiogenic perturbations. Below ≅0.1Gy, APs are potentially beneficial in outweighing the consequences of the relatively rare radiogenic damage at low doses. The balance between health risk and benefit of low-level irradiation of an individual may become predictable by gene-expression profiles also for eventually treating disease.

Cancer Mortality Among People Living in Areas With Various Levels of Natural Background Radiation

There are many places on the earth, where natural background radiation exposures are elevated significantly above about 2.5 mSv/year. The studies of health effects on populations living in such places are crucially important for understanding the impact of low doses of ionizing radiation. This article critically reviews some recent representative literature that addresses the likelihood of radiation-induced cancer and early childhood death in regions with high natural background radiation. The comparative and Bayesian analysis of the published data shows that the linear no-threshold hypothesis does not likely explain the results of these recent studies, whereas they favor the model of threshold or hormesis. Neither cancers nor early childhood deaths positively correlate with dose rates in regions with elevated natural background radiation.

Low-dose radioimmuno-therapy of cancer.

Four decades of genomic, cellular, animal and human data have shown that low-dose ionizing radiation stimulates positive genomic and cellular responses associated with effective cancer prevention and therapy and increased life span of mammals and humans. 1—8 Nevertheless, this data is questioned because it seems to contradict the well demonstrated linear relation between ionizing radiation dose and damage to DNA without providing a clear mechanistic explanation of how low-dose radiation could produce such beneficial effects. This apparent contradiction is dispelled by current radiobiology that now includes DNA damage both from ionizing radiation and from endogenous metabolic free radicals, and coupled with the biological response to low-dose radiation. Acceptance of current radiobiology would invalidate long established recommendations and regulations of worldwide radiation safety organizations and so destroy the basis of the very expensive existing system of regulation and remediation. More importantly, current radiobiology would facilitate urgently needed clinical trials of low dose radiation (LDR) cancer therapy.

Cerebral Glucose Transport Implies Individualized Glial Cell Function

Previous positron emission tomography (PET) measurements of cerebral glucose transport using [11C]-3-O-methylglucose (CMG) suggested an interindividual variation in the values of the rate constant of tracer outflow (k2) larger than that for the clearance rate of inflow (K1). These two parameters were examined in healthy cerebral cortex by dynamic PET in 4 men and 2 women (aged 24 to 73 years) without neurologic disease, and in 1 man (42 years) with a recent left hemispheric cerebral infarction under normoglycemia (average blood plasma d-glucose concentration, 5.44 ± 1.94 μmol/mL) and again under hyperglycemia (average, 10.24 ± 1.44 μmol/mL). Time-radioactivity curves were obtained from healthy cortex (grey matter) and plasma and analyzed for the values of K1 and k2 by two graphical approaches and two fitting procedures. Both K1 and k2 significantly declined with increasing plasma glucose levels. A highly significant interindividual but not intraindividual variability for k2 was found at normoglycemia and hyperglycemia. The interindividual variability of K1, although borderline significant, was less than that of k2. Accordingly variable were the distribution volumes K1 /k2. These data suggest individualized glial cell function and may be relevant to pathogenesis of neuropsychiatric disease.

The high price of public fear of low-dose radiation

1 American Nuclear Society, Peshastin, WA, USA 2 DOE Low Dose Radiation Research Program, Washington, DC, USA 3 Canadian Nuclear Society, Toronto, Canada 4 Nuclear Medicine, Heinrich-Heine-University, Dusseldorf, Germany 5 United Nations Scientific Committee on the Effects of Atomic Radiation, Buenos Aires, Argentina 6 Pacific Northwest National Laboratory, Richland, WA, USA 7 BECS Department, Brookhaven National Laboratory, Upton, NY, USA

Commentary and response to reviewer critiques regarding ‘radiation-induced versus endogenous DNA damage: possible effects of inducible protective responses in mitigating endogenous damage’

We are pleased to have the opportunity to respond to the comments from Drs Barcellos-Hoff, Roti Roti, Tanooka, and Thomassen and Metting. Regarding the comments of Dr M.H. BarcellosHoff, we fully concur with the need to emphasize the important role of intercellular and matrix signaling. We attempted to acknowledge the importance of signaling as we knew it at the time of writing our paper. For instance, we referred in our paper to intercellular and tissue signaling repeatedly, for instance, in the Introduction and sections Quantitative aspect of DNA damage: ionizing radiation, DNA damage control system, The effect of low-dose of low-linear energy transfer (LET) radiation on the damage control system, Discussion and Summary. We unfortunately did not know the excellent paper by Barcellos-Hoff and Brooks at the time of our writing the paper for the BELLE Newsletter, but we are please to include it in the current version. We consider the summarizing review by Barcellos-Hoff and Brooks a concise account on tissue being a complex system with cellular non-cellular elements with different radiation sensitivities and responses, but reacting as a whole. We used in our paper terms such as ‘indirect effects’ and ‘intercellularly operating factors’; they include all tissue-related signaling effects. We share the argument by these authors that the stochastic effects of ionizing radiation in tissues produce cell effects that derive from all tissue factors induced by ionizing radiation, in contrast to cellular effects seen in studies with dedicated microbeam radiation that are directed to single cells and single cell responses including bystander effects. The comments of Dr Roti Roti furnish new avenues for analyzing various types of DNA damage by low-dose irradiation. We are pleased with the concordance between our data estimates on endogenously induced double-strand breaks (DSB), with the data on micronucleus formation that reflects the presence of DSB. We acknowledge the disagreement between our estimates and the data based on the ingenious application of the alkaline comet assay data. We appreciate his efforts to explain this discrepancy. We believe this is very useful for further experimental work. In taking the liberty of expanding the first of his three possible explanations of the inconsistency, we express our belief that it is conceivable that existing DNA oxyadducts at the steady state level may be sensitive to abrupt changes in intracellular homeostatic equilibrium brought about by handling cells in preparing them for the alkaline comet assay. For instance, minute alterations of temperature, pH, substrate and/or ionic composition of the culture medium into which cells are harvested after in vivo treatment, can result in an immediate drastic biochemical response. This was expressed, for instance, by the immediate elimination of the low-dose induced delayed and temporary depression of thymidine kinase activity in mouse bone marrow cells, when they were isolated into suboptimal culture media at various times after low-dose and low-LET irradiation in vivo . In addition to our possible underestimate of the number of radiation-induced base changes, for which we used earlier data from Ward, Dr Roti Roti pointed to the possible neglect of the contribution of dead cell DNA in the assay of endogenously gener*Correspondence: Myron Pollycove, School of Medicine, University of California San Francisco, San Francisco, CA, USA E-mail: pollycove@comcast.net Human & Experimental Toxicology (2003) 22: 321 ]/323