Cancer risk estimates from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

Most information on the dose–response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to γ-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between 0 and 1 Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses above 1 Gy are becoming more important for radiotherapy patients and for long-term manned missions in space research. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation-induced solid cancer. The analysis of the A-bomb survivor’s data was extended by including two extra high-dose categories (4–6 Sv and 6–13 Sv) and by an attempted combination with cancer data on patients receiving radiotherapy for Hodgkin’s disease. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear, a linear-exponential and a plateau-dose–response relationship. Best agreement was found for the plateau model with a dose-varying RBE. It can be concluded that for doses above 1 Gy there is a tendency for a nonlinear dose–response curve. In addition, there is evidence of a neutron RBE greater than 10 for the A-bomb survivor data. Many problems and uncertainties are involved in combing these two datasets. However, since very little is currently known about the shape of dose–response relationships for radiation-induced cancer in the radiotherapy dose range, this approach could be regarded as a first attempt to acquire more information on this area. The work presented here also provides the first direct evidence that the bending over of the solid cancer excess risk dose response curve for the A-bomb survivors, generally observed above 2 Gy, is due to cell killing effects.     

The effect of the β-emitting yttrium-90 citrate on the dose–response of dicentric chromosomes in human lymphocytes: a basis for biological dosimetry after radiosynoviorthesis

The production of dicentric chromosomes in human lymphocytes by β-particles of yttrium-90 (Y-90) was studied in vitro to provide a basis of biological dosimetry after radiosynoviorthesis (RSO) of persistent synovitis by intra-articular administration of yttrium-90 citrate colloid. Since the injected colloid may leak into the lymphatic drainage exposing other parts of the body to radiation, the measurement of biological damage induced by β-particles of Y-90 is important for the assessment of radiation risk to the patients. A linear dose–response relationship (α = 0.0229 ± 0.0028 dicentric chromosomes per cell per gray) was found over the dose range of 0.2176–2.176 Gy. The absorbed doses were calculated for exposure of blood samples to Y-90 activities from 40 to 400 kBq using both Monte Carlo simulation and an analytical model. The maximum low-dose RBE, the RBE_M which is equivalent to the ratio of the α coefficients of the dose–response curves, is well in line with published results obtained earlier for irradiation of blood of the same donor with heavily filtered 220 kV X-rays (3.35 mm copper), but half of the RBE_M relative to weakly filtered 220 kV X-rays. Therefore, it can be concluded that for estimating an absorbed dose during RSO by the technique of biological dosimetry, in vitro and in vivo data for the same radiation quality are necessary.     

Modeling hematopoietic system response caused by chronic exposure to ionizing radiation

A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950–1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose–effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose-rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia).     

Linear-no-threshold is a radiation-protection standard rather than a mechanistic effect model

The linear-no-threshold (LNT) controversy covers much more than the mere discussion whether or not “the LNT hypothesis is valid”. It is shown that one cannot expect to find only one or even the only one dose–effect relationship. Each element within the biological reaction chain that is affected by ionizing radiation contributes in a specific way to the final biological endpoint of interest. The resulting dose–response relationship represents the superposition of all these effects. Till now there is neither a closed and clear picture of the entirety of radiation action for doses below some 10 mSv, nor does clear epidemiological evidence exist for an increase of risk for stochastic effects, in this dose range. On the other hand, radiation protection demands for quantitative risk estimates as well as for practicable dose concepts. In this respect, the LNT concept is preferred against any alternative concept. However, the LNT concept does not necessarily mean that the mechanism of cancer induction is intrinsically linear. It could hold even if the underlying multi-step mechanisms act in a non-linear way. In this case it would express a certain “attenuation” of non-linearities. Favouring LNT against threshold-, hyper-, or sub-linear models for radiation-protection purposes on the one hand, but preferring one of these models (e.g. for a specific effect) because of biological considerations for scientific purposes on the other hand, does not mean a contradiction.     

An investigation of hormesis of trichloroethylene in L-02 liver cells by differential proteomic analysis

Hormesis is the dose–response pattern of the biological responses to toxic chemicals, characterized by low-dose stimulation and high-dose inhibition. Although it is known that some cell types exhibit an adaptive response to low levels of cytotoxic agents, its molecular mechanism is still unclear and it has yet to be established whether this is a universal phenomenon that occurs in all cell types in response to exposure to every chemical. Trichloroethylene (TCE) is an organic solvent widely used and is released into the atmosphere from industrial degreasing operations. Acute (short-term) and chronic (long-term) inhalation exposure to trichloroethylene can affect the human health. In order to elucidate a cell-survival adaptive response of L-02 liver cells exposed to low dose of TCE, CCK-8 assay was used to assess cytotoxicity, and examined the possible mechanisms of hormesis by proteomics technology. We found that exposure of L-02 liver cells to low level of TCE resulted in adaptation to further exposure to higher level, about 1,000 protein-spots were obtained by two-dimensional electrophoresis (2-DE) and five protein spots were identified by matrix-assisted laser desorption/ionization mass spectrometry and tandem mass spectrometry sequencing of tryptic peptides. Our results suggest that a relationship may exist between identified proteins and TCE-induced hormesis, which are very useful for further study of the mechanism and risk assessment of TCE.     

Reconstruction of daily solar UV irradiation from 1893 to 2002 in Potsdam,Germany

Long-term records of solar UV radiation reaching the Earth’s surface are scarce. Radiative transfer calculations and statistical models are two options used to reconstruct decadal changes in solar UV radiation from long-term records of measured atmospheric parameters that contain information on the effect of clouds, atmospheric aerosols and ground albedo on UV radiation. Based on earlier studies, where the long-term variation of daily solar UV irradiation was derived from measured global and diffuse irradiation as well as atmospheric ozone by a non-linear regression method [Feister et al. (2002) Photochem Photobiol 76:281–293], we present another approach for the reconstruction of time series of solar UV radiation. An artificial neural network (ANN) was trained with measurements of solar UV irradiation taken at the Meteorological Observatory in Potsdam, Germany, as well as measured parameters with long-term records such as global and diffuse radiation, sunshine duration, horizontal visibility and column ozone. This study is focussed on the reconstruction of daily broad-band UV-B (280–315 nm), UV-A (315–400 nm) and erythemal UV irradiation (ER). Due to the rapid changes in cloudiness at mid-latitude sites, solar UV irradiance exhibits appreciable short-term variability. One of the main advantages of the statistical method is that it uses doses of highly variable input parameters calculated from individual spot measurements taken at short time intervals, which thus do represent the short-term variability of solar irradiance.     

Auxin concentration control of the average DNA content in cells of in vitro cultures: a theoretical model and comparison to experimental data for <Emphasis Type="Italic">Allium cepa</Emphasis> and <Emphasis Type="Italic">Allium sativum</Emphasis>

A theoretical model explaining the average DNA content in cells of in vitro cultures as a function of concentration of auxin 2,4-D in medium is provided. The model assumes influence of auxin on the functioning of the main G1/S and G2/M control points of the cell cycle. Theoretical results are compared to experimental data obtained from the callus cultures of Allium sativum and Allium cepa conducted during 18 months. Adaptation of the model to explanation of the shape of the dose–response curves is suggested and successfully verified for the example of Nicotiana tabacum cultures.     

Radiation-induced carcinogenesis: mechanistically based differences between gamma-rays and neutrons, and interactions with DMBA

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis.     

Dose–response relationship of dicentric chromosomes in human lymphocytes obtained for the fission neutron therapy facility MEDAPP at the research reactor FRM II

The biological effectiveness of neutrons from the neutron therapy facility MEDAPP (mean neutron energy 1.9 MeV) at the new research reactor FRM II at Garching, Germany, has been analyzed, at different depths in a polyethylene phantom. Whole blood samples were exposed to the MEDAPP beam in special irradiation chambers to total doses of 0.14–3.52 Gy at 2-cm depth, and 0.18–3.04 Gy at 6-cm depth of the phantom. The neutron and γ-ray absorbed dose rates were measured to be 0.55 Gy min⁻¹ and 0.27 Gy min⁻¹ at 2-cm depth, while they were 0.28 and 0.25 Gy min⁻¹ at 6-cm depth. Although the irradiation conditions at the MEDAPP beam and the RENT beam of the former FRM I research reactor were not identical, neutrons from both facilities gave a similar linear-quadratic dose–response relationship for dicentric chromosomes at a depth of 2 cm. Different dose–response curves for dicentrics were obtained for the MEDAPP beam at 2 and 6 cm depth, suggesting a significantly lower biological effectiveness of the radiation with increasing depth. No obvious differences in the dose–response curves for dicentric chromosomes estimated under interactive or additive prediction between neutrons or γ-rays and the experimentally obtained dose–response curves could be determined. Relative to ⁶⁰Co γ-rays, the values for the relative biological effectiveness at the MEDAPP beam decrease from 5.9 at 0.14 Gy to 1.6 at 3.52 Gy at 2-cm depth, and from 4.1 at 0.18 Gy to 1.5 at 3.04 Gy at 6-cm depth. Using the best possible conditions of consistency, i.e., using blood samples from the same donor and the same measurement techniques for about two decades, avoiding the inter-individual variations in sensitivity or the differences in methodology usually associated with inter-laboratory comparisons, a linear-quadratic dose–response relationship for the mixed neutron and γ-ray MEDAPP field as well as for its fission neutron part was obtained. Therefore, the debate on whether the fission-neutron induced yield of dicentric chromosomes increases linearly with dose remains open.     

Effects of solar ultraviolet radiation on photochemical efficiency of <Emphasis Type="Italic">Chaetoceros curvisetus</Emphasis> (Bacillariophyceae)

To assess the short- and long-term impacts of Ultraviolet radiation (UVR, 280–400 nm) on the red tide alga Chaetoceros curvisetus, we exposed cells to three different solar radiation treatments–PAB:280–700 nm, PA:320–700 nm, and P:400–700 nm under 20°C incubated temperature. Short-term exposures were investigated: the photochemical efficiency (Φ_PSII) versus irradiance curves under six levels of solar radiation by covering the incubators with a variable number of neutral density screens (the irradiance thus varied from 100 to 3%) lasting 1 h, and long-term exposures were designed to assess how the cells acclimate to solar radiation (the growth, UV_abc and ratio of repair to damage rates of D1 protein were detected). A significant decrease in the photochemical efficiency (Φ_PSII) at high irradiance (100% of incident solar radiation, 261.6 Wm⁻²) was observed in short-term exposure (1 h). UVR-induced photoinhibition was reduced to 7% in 3% solar radiation (4.08 Wm⁻²), compared with 66% in 100% solar radiation (261.6 Wm⁻²). In long-term experiments (11 days) using batch cultures, cell densities during the first 6 days were relatively constant for treatment P, and decreased slightly under PA and PAB treaments, reflecting a change in the irradiance experienced in the laboratory to that of incident solar irradiance. Thereafter, cell density increased and UV-induced photoinhibition decreased with the following days, indicating acclimation to solar UV. At the end of experiment, cells were found to exhibit both higher ratios of repair to UV-related damage and increased concentrations of UV-absorbing compounds, whose maximum absorption was found to be at 329 nm. Our data indicate that C. curvisetus is sensitive to ultraviolet radiation, but was able to acclimate relatively rapidly (ca. 6 days) by synthesizing UV-absorbing compounds and by increasing the rates of repair processes of D1 protein in PSII.     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy

Cytokine-induced killer (CIK) cells are T cell derived ex vivo expanded cells with both NK and T cell properties. They exhibit potent anti-tumor efficacy against various malignancies in preclinical models and have proven safe and effective in clinical studies. We combined CIK cell adoptive immunotherapy with IL-12 cytokine immunotherapy in an immunocompetent preclinical breast cancer model. Combining CIK cells with IL-12 increased anti-tumor efficacy in vivo compared to either therapy alone. Combination led to full tumor remission and long-term protection in 75% of animals. IL-12 treatment sharply increased the anti-tumor efficacy of short-term cultured CIK cells that exhibited no therapeutic effect alone. Bioluminescence imaging based in vitro cytotoxicity and in vivo homing assays revealed that short-term cultured CIK cells exhibit full cytotoxicity in vitro, but display different tumor homing properties than fully expanded CIK cells in vivo. Our data suggest that short-term cultured CIK cells can be “educated” in vivo, producing fully expanded CIK cells upon IL-12 administration with anti-tumor efficacy in a mouse model. Our findings demonstrate the potential to improve current CIK cell-based immunotherapy by increasing efficacy and shortening ex vivo expansion time. This holds promise for a highly efficacious cancer therapy utilizing synergistic effects of cytokine and cellular immunotherapy.     

A recombinant peroxisome proliferator response element-driven luciferase assay for evaluation of potential environmental obesogens

A recombinant Huh7-PPRE-Luc cell line for analyzing the peroxisome proliferator response element (PPRE)-driven luciferase activity was established. The cells exhibited a good dose–response induction in PPRE-driven luciferase activity by three subtypes of peroxisome proliferator-activated receptor (PPAR) agonists as well as by a retinoid X receptor agonist, 9-cis-retinoic acid. Among five environmental chemicals tested, benzyl butyl phthalate and bisphenol induced PPRE-driven luciferase activation in Huh7-PPRE-Luc cells and caused adipogenic differentiation of 3T3-L1 cells. This recombinant Huh7-PPRE-Luc cell line would be useful for screening potential environmental obesogens with PPAR activity.     

Cellular Stress Responses,Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose–response, challenging long-standing beliefs about the nature of the dose–response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.     

Effect of temperature on the dose–response curves for auxin-induced elongation growth in maize coleoptile segments

The dose–response curves for IAA-induced growth in maize coleoptile segments were studied as a function of time and temperature. In addition, the kinetics of growth rate responses at some auxin concentrations and temperatures was also compared. It was found that the dose–response curves for IAA-induced elongation growth were, independently of time and temperature, bell-shaped with an optimal concentration at 10⁻⁵ M IAA. The kinetics of IAA-induced growth rate responses depended on IAA concentration and temperature, and could be separated into two phases (biphasic reaction). The first phase (very rapid) was followed by a long lasting one (second phase), which began about 30 min after auxin addition. For coleoptile segments incubated at 30°C, the amplitudes of the first and second phase were significantly higher, when compared with 25°C, at all IAA concentrations studied. However, when coleoptile segments were incubated at 20°C, the elongation growth of coleoptile segments treated with suboptimal IAA concentrations was diminished, mainly as a result of both phases reduction. In conclusion, we propose that the shape of the dose–response curves for IAA-induced growth in maize coleoptile segments is connected with biphasic kinetic of growth rate response.     

Chromosome aberrations in peripheral blood lymphocytes of individuals living in high background radiation areas of Ramsar,Iran

In order to investigate the biological effects of exposure to low-dose radiation and to assess the dose–effect relationship in residents of high background radiation areas (HBRAs) of Ramsar, cytogenetic investigation of unstable-type aberrations was performed in 15 healthy elderly women in a HBRA of Ramsar, Talesh mahalle, and in 10 elderly women living in a nearby control area with normal background radiation. In total, 77,714 cells were analyzed; 48,819 cells in HBRA residents and 28,895 cells in controls. On average, 3,108 cells per subject were analyzed (range 1,475–5,007 cells). Significant differences were found in the frequency of dicentric plus centric rings in 100 cells (0.207 ± 0.103 vs. 0.047 ± 0.027, p < 0.0005), total chromosome-type aberrations per 100 cells (0.86 ± 0.44 vs. 0.23 ± 0.17, p < 0.0005), and chromatid-type aberrations per 100 cells (3.31 ± 2.01 vs. 1.66 ± 0.63, p = 0.01) by the Mann–Whitney U test between HBRA and the control, respectively. Using chromosomal aberrations as the main endpoint to assess the dose–effect relationship in residents of HBRAs in Ramsar, no positive correlation was found between the frequency of dicentric plus centric ring aberrations and the cumulative dose of the inhabitants estimated by direct individual dosimetry; however, obvious trends of increase with age appeared in the control group. Based on these results, individuals residing in HBRAs of Ramsar have an increased frequency of detectable abnormalities in unstable aberrations.     

Three-dimensional finite element modeling of pericellular matrix and cell mechanics in the nucleus pulposus of the intervertebral disk based on in situ morphology

Nucleus pulposus (NP) cells of the intervertebral disk (IVD) have unique morphological characteristics and biologic responses to mechanical stimuli that may regulate maintenance and health of the IVD. NP cells reside as single cell, paired or multiple cells in a contiguous pericellular matrix (PCM), whose structure and properties may significantly influence cell and extracellular matrix mechanics. In this study, a computational model was developed to predict the stress–strain, fluid pressure and flow fields for cells and their surrounding PCM in the NP using three-dimensional (3D) finite element models based on the in situ morphology of cell–PCM regions of the mature rat NP, measured using confocal microscopy. Three-dimensional geometries of the extracellular matrix and representative cell–matrix units were used to construct 3D finite element models of the structures as isotropic and biphasic materials. In response to compressive strain of the extracellular matrix, NP cells and PCM regions were predicted to experience volumetric strains that were 1.9–3.7 and 1.4–2.1 times greater than the extracellular matrix, respectively. Volumetric and deviatoric strain concentrations were generally found at the cell/PCM interface, while von Mises stress concentrations were associated with the PCM/extracellular matrix interface. Cell–matrix units containing greater cell numbers were associated with higher peak cell strains and lower rates of fluid pressurization upon loading. These studies provide new model predictions for micromechanics of NP cells that can contribute to an understanding of mechanotransduction in the IVD and its changes with aging and degeneration.     

Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapy

The complex of vanadyl(IV) cation with oxodiacetate, VO(oda) caused an inhibitory effect on the proliferation of the human colon adenocarcinoma cell line Caco-2 in the range of 25–100 μM (P < 0.001). This inhibition was partially reversed by scavengers of free radicals. The difference in cell proliferation in the presence and the absence of scavengers was statistically significant in the range of 50–100 μM (P < 0.05). VO(oda) altered lysosomal and mitochondria metabolisms (neutral red and MTT bioassays) in a dose–response manner from 10 μM (P < 0.001). Morphological studies showed important transformations that correlated with the disassembly of actin filaments and a decrease in the number of cells in a dose response manner. Moreover, VO(oda) caused statistically significant genotoxic effects on Caco-2 cells in the low range of concentration (5–25 μM) (Comet assay). Increment in the oxidative stress and a decrease in the GSH level are the main cytotoxic mechanisms of VO(oda). These effects were partially reversed by scavengers of free radicals in the range of 50–100 μM (P < 0.05). Besides, VO(oda) interacted with plasmidic DNA causing single and double strand cleavage, probably through the action of free radical species. Altogether, these results suggest that VO(oda) is a good candidate to be evaluated for alternative therapeutics in cancer treatment.     

Hematopoietic cell renewal systems: mechanisms of coping and failing after chronic exposure to ionizing radiation

On the occasion of the first international workshop on systems radiation biology we review the role of cell renewal systems in maintaining the integrity of the mammalian organism after irradiation. First, 11 radiation emergencies characterized by chronic or protracted exposure of the human beings to ionizing irradiation were “revisited”. The data provide evidence to suggest that at a daily exposure of about 10–100 mSv, humans are capable of coping with the excess cell loss for weeks or even many months without hematopoietic organ failure. Below 10 mSv/day, the organisms show some cellular or subcellular indicators of response. At dose rates above 100 mSv/day, a progressive shortening of the life span of the irradiated organism is observed. To elucidate the mechanisms relevant to tolerance or failure, the Megakaryocyte–thrombocyte cell renewal system was investigated. A biomathematical model of this system was developed to simulate the development of thrombocyte concentration as a function of time after onset of chronic radiation exposure. The hematological data were taken from experimental chronic irradiation studies with dogs at the Argonne National Laboratory, USA. The results of thrombocyte response patterns are compatible with the notion of an “excess cell loss” (compared to the steady-state) in all proliferative cell compartments, including the stem cell pool. The “excess cell loss” is a function of the daily irradiation dose rate. Once the stem cell pool is approaching an exhaustion level, a “turbulence region” is reached. Then it takes a very little additional stress for the system to fail. We conclude that in mammalian radiation biology (including radiation medicine), it is important to understand the physiology and pathophysiology of cell renewal systems in order to allow predicting the development of radiation induced lesions.