Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors.

The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates.

Breast cancer risk in atomic bomb survivors from multi-model inference with incidence data 1958-1998.

Breast cancer risk from radiation exposure has been analyzed in the cohort of Japanese a-bomb survivors using empirical models and mechanistic two-step clonal expansion (TSCE) models with incidence data from 1958 to 1998. TSCE models rely on a phenomenological representation of cell transition processes on the path to cancer. They describe the data as good as empirical models and this fact has been exploited for risk assessment. Adequate models of both types have been selected with a statistical protocol based on parsimonious parameter deployment and their risk estimates have been combined using multi-model inference techniques. TSCE models relate the radiation risk to cell processes which are controlled by age-increasing rates of initiating mutations and by changes in hormone levels due to menopause. For exposure at young age, they predict an enhanced excess relative risk (ERR) whereas the preferred empirical model shows no dependence on age at exposure. At attained age 70, the multi-model median of the ERR at 1 Gy decreases moderately from 1.2 Gy(-1) (90% CI 0.72; 2.1) for exposure at age 25 to a 30% lower value for exposure at age 55. For cohort strata with few cases, where model predictions diverge, uncertainty intervals from multi-model inference are enhanced by up to a factor of 1.6 compared to the preferred empirical model. Multi-model inference provides a joint risk estimate from several plausible models rather than relying on a single model of choice. It produces more reliable point estimates and improves the characterization of uncertainties. The method is recommended for risk assessment in practical radiation protection.

Lifetime radiation risk of stochastic effects - prospective evaluation for space flight or medicine.

The concept of lifetime radiation risk of stochastic detrimental health outcomes is important in contemporary radiation protection, being used either to calculate detriment-weighted effective dose or to express risks following radiation accidents or medical uses of radiation. The conventionally applied time-integrated risks of radiation exposure are computed using average values of current population and health statistical data that need to be projected far into the future. By definition, the lifetime attributable risk (AR) is an approximation to more general lifetime risk quantities and is only valid for exposures under 1 Gy. The more general quantities, such as excess lifetime risk (ELR) and risk of exposure-induced cancer, are free of dose range constraints, but rely on assumptions concerning the unknown total radiation effect on demographic and health statistical data, and are more computationally complex than AR. Consideration of highly uncertain competing risks for other radiation-attributed outcomes are required in appropriate assessments of time-integrated risks of specific outcomes following high-dose (>1 Gy) exposures, causing non-linear dose responses in the resulting ELR estimate.Being based on the current population and health statistical data, the conventionally applied time-integrated risks of radiation exposure are: (i) not well suited for projections many years into the future because of the large uncertainties in future secular trends in the population-specific disease rates; and (ii) not optimal for application to atypical groups of exposed persons not well represented by the general population. Specifically, medical patients are atypical in this respect because their prospective risks depend strongly on the original diagnosis, the treatment modality, general cure rates, individual radiation sensitivity, and genetic predisposition. Another situation challenging the application of conventional risk quantities is a projection of occupational radiation risks associated with space flight, both due to higher radiation doses and astronauts' generally excellent health condition due to pre-selection, training, and intensive medical screening.An alternative quantity, named 'radiation-attributed decrease of survival' (RADS), known in past general statistical literature as 'cumulative risk', is recommended here for applications in space and medicine to represent the cumulative radiation risk conditional on survival until a certain age. RADS is only based on the radiation-attributed hazard rendering an insensitivity to competing risks or projections of current population statistics far into the future. Therefore, RADS is highly suitable for assessing semi-personalised radiation risks after radiation exposures from space missions or medical applications of radiation.

Radiation risk modeling of thyroid cancer with special emphasis on the Chernobyl epidemiological data.

Two recent studies analyzed thyroid cancer incidence in Belarus and Ukraine during the period from 1990 to 2001, for the birth cohort 1968 to 1985, and the related (131)I exposure associated with the Chernobyl accident in 1986. Contradictory age-at-exposure and time-since-exposure effect modifications of the excess relative risk (ERR) were reported. The present study identifies the choice of baseline modeling method as the reason for the conflicting results. Various quality-of-fit criteria favor a parametric baseline model to various categorical baseline models. The model with a parametric baseline results in a decrease of the ERR by a factor of about 0.2 from an age at exposure of 5 years to an age at exposure of 15 years (for a time since exposure of 12 years) and a decrease of the ERR from a time since exposure of 4 years to a time since exposure of 14 years of about 0.25 (for an age at exposure of 10 years). Central ERR estimates (of about 20 at 1 Gy for an age at exposure of 10 years and an attained age of 20 years) and their ratios for females compared to males (about 0.3) turn out to be relatively independent of the modeling. Excess absolute risk estimates are also predicted to be very similar from the different models. Risk models with parametric and categorical baselines were also applied to thyroid cancer incidence among the atomic bomb survivors. For young ages at exposure, the ERR values in the model with a parametric baseline are larger. Both data sets cover the period of 12 to 15 years since exposure. For this period, higher ERR values and a stronger age-at-exposure modification are found for the Chernobyl data set. Based on the results of the study, it is recommended to test parametric and categorical baseline models in risk analyses.

New developments to support decision-making in contaminated inhabited areas following incidents involving a release of radioactivity to the environment.

The Chernobyl accident demonstrated that releases from nuclear installations can lead to significant contamination of large inhabited areas. A new generic European decision support handbook has been produced on the basis of lessons learned on the management of contaminated inhabited areas. The handbook comprises detailed descriptions of 59 countermeasures in a standardised datasheet format, which facilitates a comparison of features. It also contains guidance in the form of decision flowcharts, tables, check lists and text to support identification of optimised solutions for managing the recovery of inhabited areas within a framework consistent with ICRP recommendations. A new comprehensive inhabited-area dose model is also being developed for implementation in the ARGOS and RODOS decision support systems. Shortcomings of previous models are demonstrated. Decision support modelling in relation to malicious dispersion of radioactive matter in inhabited areas is also discussed. Here, the implications of, e.g., particle sizes and dispersion altitude are highlighted.

Improvement of modelling capabilities for assessing urban contamination: the EMRAS Urban Remediation Working Group.

The Urban Remediation Working Group of the International Atomic Energy Agency's Environmental Modelling for Radiation Safety (EMRAS) programme was established to improve modelling and assessment capabilities for radioactively contaminated urban situations, including the effects of countermeasures. An example of the Working Group's activities is an exercise based on Chernobyl fallout data in Ukraine, which has provided an opportunity to compare predictions among several models and with available measurements, to discuss reasons for discrepancies, and to identify areas where additional information would be helpful.

Soybean agglutinin-positive natural suppressor cells in mouse bone marrow inhibit interleukin 2 production and utilization in mixed lymphocyte reactions.

Although natural suppressor (NS) cells resident in bone marrow (BM) have been the subject of intensive study, the exact nature and mode of action of these potentially important immunoregulatory cells are still uncertain. Here we show that NS cells with potent inhibitory effects on mixed lymphocyte reactions (MLRs) can be isolated from BM of normal adult mice by agglutination with the plant lectin soybean agglutinin (SBA). Complement-dependent lysis of SBA receptor-bearing BM cells with antibodies to asialoGM1, Mac-1, Thy-1.2, J11d.2, and 2C1 phenotypic markers reveals the presence of at least two distinct populations of BM NS cells. Most of the SBA-binding BM cells with NS capacity have the null phenotype and resemble hematopoietic stem cells, and some inhibitory SBA+ BM cells express the 2C1 marker found on pregnancy-associated splenic NS cells and the J11d.2 antigen characteristic of B cells and immature T cells. Results of positive selective experiments confirmed these findings. The mechanism of natural suppression was also studied. Evidence is presented that SBA+ BM cells exert NS activity in MLRs by interfering with the production and utilization of interleukin 2. Indomethacin does not relieve natural suppression associated with SBA+ BM cells, indicating that prostaglandin synthesis is not a requirement for inhibitory function. However, neutralizing antibodies to transforming growth factor beta (TGF-beta) partially reverse the suppression mediated by SBA+ BM cells, suggesting that some BM NS cells may act through the release of an immunosuppressive molecule related to TGF beta.

Cardiovascular disease mortality of A-bomb survivors and the healthy survivor selection effect.

The latest A-bomb survivor data for cardiovascular diseases are analysed to investigate whether in the first years after the bombings the baseline rates of proximal survivors were markedly different compared with those of the distal survivors. This phenomenon relates to a healthy survivor selection effect. This question is important for the decision whether to include or exclude the early years of follow-up when analysing the biological effects from acute low and high dose exposures following the nuclear weapons explosions in Hiroshima and Nagasaki. The present study shows that for cerebrovascular diseases and heart diseases the baseline rates are not significantly different in the first two decades of follow-up. Thus, for these two detrimental health outcomes, there is no need to exclude distal survivors and the first decades of follow-up time when investigating the shapes of the related dose-responses.

CLIP2 as radiation biomarker in papillary thyroid carcinoma.

A substantial increase in papillary thyroid carcinoma (PTC) among children exposed to the radioiodine fallout has been one of the main consequences of the Chernobyl reactor accident. Recently, the investigation of PTCs from a cohort of young patients exposed to the post-Chernobyl radioiodine fallout at very young age and a matched nonexposed control group revealed a radiation-specific DNA copy number gain on chromosomal band 7q11.23 and the radiation-associated mRNA overexpression of CLIP2. In this study, we investigated the potential role of CLIP2 as a radiation marker to be used for the individual classification of PTCs into CLIP2-positive and -negative cases-a prerequisite for the integration of CLIP2 into epidemiological modelling of the risk of radiation-induced PTC. We were able to validate the radiation-associated CLIP2 overexpression at the protein level by immunohistochemistry (IHC) followed by relative quantification using digital image analysis software (P=0.0149). Furthermore, we developed a standardized workflow for the determination of CLIP2-positive and -negative cases that combines visual CLIP2 IHC scoring and CLIP2 genomic copy number status. In addition to the discovery cohort (n=33), two independent validation cohorts of PTCs (n=115) were investigated. High sensitivity and specificity rates for all three investigated cohorts were obtained, demonstrating robustness of the developed workflow. To analyse the function of CLIP2 in radiation-associated PTC, the CLIP2 gene regulatory network was reconstructed using global mRNA expression data from PTC patient samples. The genes comprising the first neighbourhood of CLIP2 (BAG2, CHST3, KIF3C, NEURL1, PPIL3 and RGS4) suggest the involvement of CLIP2 in the fundamental carcinogenic processes including apoptosis, mitogen-activated protein kinase signalling and genomic instability. In our study, we successfully developed and independently validated a workflow for the typing of PTC clinical samples into CLIP2-positive and CLIP2-negative and provided first insights into the CLIP2 interactome in the context of radiation-associated PTC.

Inhibition of DNA synthesis and IL-2 bioactivity in MLR by splenic pregnancy-associated natural suppressor cells involves the production of a TGF-beta 1-like molecule and a second distinct inhibitory factor.

Natural suppressor cells exhibiting a double-negative, immature T cell phenotype have been identified in maternal spleen during syngeneic murine pregnancy. In the present study, splenic pregnancy-associated natural suppressor (SPANS) cells are shown to express alpha/beta T cell receptors. SPANS cell-mediated inhibition of DNA synthesis by spleen cells responding in mixed lymphocyte reactions (MLR) is associated with a reduction in interleukin (IL)-2 bioactivity beginning after 96 h of culture. Although culture supernatants from suppressed MLR exhibit diminished ability to support the growth of IL-2-dependent CTLL-2 cells, SPANS cells themselves are unable to inhibit IL-2-driven CTLL-2 proliferation, suggesting that SPANS cells down-regulate IL-2 synthesis in MLR. IL-2 utilization in MLR is also inhibited by SPANS cells, since the addition of exogenous IL-2 fails to relieve the inhibitory effect of SPANS cells on lymphoproliferative responses in MLR. Flow cytofluorometric analysis reveals that MLR performed in the presence of SPANS cells contain normal percentages of CD4 and IL-2 receptor-bearing spleen cells. Thus, SPANS cells do not inhibit cellular proliferation in MLR by selectively interfering with clonal expansion of IL-2-producing helper T cells or by down-regulating IL-2 receptor expression. We have determined that SPANS cells inhibit DNA synthesis in MLR via the production of a transforming growth factor (TGF)-beta 1-like suppressor factor, since cellular proliferation in MLR is restored to normal levels in the presence of anti-TGF-beta 1 neutralizing antibody. However, IL-2 bioactivity in these cultures remains low in comparison to control MLR, suggesting the presence of a second distinct suppressor factor. Although the identity of this second inhibitory molecule has yet to be determined, neutralizing antibody studies have ruled out IL-10.

Pregnancy-associated suppressor cells in mice: functional characteristics of CD3+4-8-45R+ T cells with natural suppressor activity.

Natural suppressor (NS) cells are MHC-unrestricted regulatory cells with non-specific inhibitory activity for immune responses. In adult mice, NS cells are characteristically found in bone marrow and in splenic tissue following total lymphoid irradiation and cyclophosphamide treatments. Recently, we have shown that the spleens of pregnant mice harbour a population of lymphocytes which resemble NS cells in terms of phenotype and inhibitory activity. In this study, we use positive and negative selection techniques to further characterize splenic pregnancy-associated NS (SPANS) cells as predominantly 'double negative' T cells (CD3+4-8-) bearing receptors for the lectins wheat germ agglutinin and soybean agglutinin, as well as expressing CD45R and the heat-stable J11d.2 antigen. Taken together, these findings lead us to conclude that SPANS cells belong to an immature T cell lineage. In keeping with their T cell phenotype, SPANS cells do not express the natural killer (NK) cell-specific markers NK2.1 and asialoGM1 and do not mediate lytic activity against NK-sensitive YAC-1 cells, although natural cytotoxic activity against WEHI-164 cells was found to co-purify with SPANS cells. Suppressive activity of SPANS cells in mixed lymphocyte reactions (MLR) is abolished by treatment with mitomycin C, suggesting that natural suppression in this system is a proliferation-dependent phenomenon. Preincubation of SPANS cells with conditioned medium from Con A-stimulated T cell cultures results in augmented NS activity, indicating that SPANS cells respond to T cell signals. Our data suggest that SPANS cells mediate suppression via the elaboration of a soluble suppressor factor since SPANS cells do not require cell-cell contact to mediate suppression and supernatants from short-term cultures of SPANS cell-enriched SBA+ pregnancy spleen cells inhibit MLR. We believe that SPANS cell may be important in regulating hematopoiesis and maternal anti-fetal immunity during murine pregnancy.

Reactivity of monoclonal antibody 1E5.B5 with a novel phenotypic marker expressed on a murine natural suppressor cell subset.

Natural suppressor (NS) cells are antigen-nonspecific, MHC-independent immunoregulatory cells that are typically found in murine bone marrow (BM), newborn (NB) mouse spleen, and in splenic tissue of adult mice during pregnancy and following cyclophosphamide (CY) treatment. There has been a pressing need for the development of NS cell-specific monoclonal antibodies (mAb) since NS cells are generally described as null cells which lack the usual phenotypic markers of mature T cells, B cells, and macrophages. Here we present evidence that mAb 1E5.B5, which was raised in rats against murine splenic pregnancy-associated NS (SPANS) cells, recognizes a unique antigenic marker expressed by some, but not all, murine NS cells. In the presence of complement, mAb 1E5.B5 effectively eliminates SPANS activity, and diminishes NS activity of CY-treated spleen cells in mixed lymphocyte reactions (MLR). However, cytotoxic pretreatment with mAb 1E5.B5 had minimal effects on NS activity of BM and NB spleen cells. We also show that pregnancy spleen cells and CY-spleen cells with moderate NS activity in MLR can be positively selected for by "panning" with mAb 1E5.B5. In contrast, only weakly inhibitory cells are isolated from BM and NB spleen by this procedure. Cellular ELISA and flow cytometry confirm that mAb 1E5.B5 has specificity for pregnancy spleen cells and CY-spleen cells, as well as for NB spleen and BM cell preparations. Western blot analysis reveals that mAb 1E5.B5 reacts with a novel 50 kDa NS cell-associated antigen which we have termed NS-1. The NS-1 antigen is not present on other null cells such as natural killer (NK) cells and natural cytotoxic (NC) cells since cytotoxic pretreatment of pregnancy spleen cells with mAb 1E5.B5 does not affect antibody-dependent cell-mediated cytotoxicity, NK or NC activity.

A fast and simple approach for the estimation of a radiological source from localised measurements after the explosion of a radiological dispersal device.

After an explosion of a radiological dispersal device, decision-makers need to implement countermeasures as soon as possible to minimise the radiation-induced risks to the population. In this work, the authors present a tool, which can help providing information about the approximate size of source term and radioactive contamination based on a Gaussian Plume model with the use of available measurements for liquid or aerosolised radioactivity. For two-field tests, the source term and spatial distribution of deposited radioactivity are estimated. A sensitivity analysis of the dependence on deposition velocity is carried out. In case of weak winds, a diffusive process along the wind direction is retained in the model.

Modeling the impact of climate change in Germany with biosphere models for long-term safety assessment of nuclear waste repositories.

Biosphere models are used to evaluate the exposure of populations to radionuclides from a deep geological repository. Since the time frame for assessments of long-time disposal safety is 1 million years, potential future climate changes need to be accounted for. Potential future climate conditions were defined for northern Germany according to model results from the BIOCLIM project. Nine present day reference climate regions were defined to cover those future climate conditions. A biosphere model was developed according to the BIOMASS methodology of the IAEA and model parameters were adjusted to the conditions at the reference climate regions. The model includes exposure pathways common to those reference climate regions in a stylized biosphere and relevant to the exposure of a hypothetical self-sustaining population at the site of potential radionuclide contamination from a deep geological repository. The end points of the model are Biosphere Dose Conversion factors (BDCF) for a range of radionuclides and scenarios normalized for a constant radionuclide concentration in near-surface groundwater. Model results suggest an increased exposure of in dry climate regions with a high impact of drinking water consumption rates and the amount of irrigation water used for agriculture.

Modeling of the fate of radionuclides in urban sewer systems after contamination due to nuclear or radiological incidents.

After an accidental radioactive contamination by aerosols in inhabited areas, the radiation exposure to man is determined by complex interactions between different factors such as dry or wet deposition, different types of ground surfaces, chemical properties of the radionuclides involved and building development as well as dependence on bomb construction e.g. design and geometry. At short-term, the first rainfall is an important way of natural decontamination: deposited radionuclides are washed off from surfaces and in urban areas the resulting contaminated runoff enters the sewer system and is collected in a sewage plant. Up to now the potential exposure caused by this process has received little attention and is estimated here with simulation models. The commercial rainfall-runoff model for urban sewer systems KANAL++ has been extended to include transport of radionuclides from surfaces through the drainage to various discharge facilities. The flow from surfaces is modeled by unit hydrographs, which produce boundary conditions for a system of 1d coupled flow and transport equations in a tube system. Initial conditions are provided by a map of surface contamination which is produced by geo-statistical interpolation of γ-dose rate measurements taking into account the detector environment. The corresponding methodology is implemented in the Inhabited Area Monitoring Module (IAMM) software module as part of the European decision system JRODOS. A hypothetical scenario is considered where a Radiation Dispersal Device (RDD) with Cs-137 is detonated in a small inhabited area whose drainage system is realistically modeled. The transition of deposited radionuclides due to rainfall into the surface runoff is accounted for by different nuclide-specific entrainment coefficients for paved and unpaved surfaces. The concentration of Cs-137 in water is calculated at the nodes of the drainage system and at the sewage treatment plant. The external exposure to staff of the treatment plant is estimated. For Cs-137 radiation levels in the plant are low since wash-off of cesium from surfaces is an ineffective process.

Modelling the long-term consequences of a hypothetical dispersal of radioactivity in an urban area including remediation alternatives.

The Urban Remediation Working Group of the International Atomic Energy Agency's EMRAS (Environmental Modelling for Radiation Safety) program was organized to address issues of remediation assessment modelling for urban areas contaminated with dispersed radionuclides. The present paper describes the second of two modelling exercises. This exercise was based on a hypothetical dispersal of radioactivity in an urban area from a radiological dispersal device, with reference surface contamination at selected sites used as the primary input information. Modelling endpoints for the exercise included radionuclide concentrations and external dose rates at specified locations, contributions to the dose rates from individual surfaces, and annual and cumulative external doses to specified reference individuals. Model predictions were performed for a "no action" situation (with no remedial measures) and for selected countermeasures. The exercise provided an opportunity for comparison of three modelling approaches, as well as a comparison of the predicted effectiveness of various countermeasures in terms of their short-term and long-term effects on predicted doses to humans.

Identifying dose dependences of the two-stage clonal expansion model with simulated cohorts.

The two-stage clonal expansion model of cancer induction is tested on recorded and simulated cohort data of radon-exposed rats. Unfortunately, different versions of the model, for which radiation acts on different biological processes, can provide a good description of the data. This is the case for an initiation-transformation and an initiation-promotion model when they are applied to lung tumour data of radon-exposed rats and all malignant tumours are assumed to be incidental. However, if one were able to use information on fatal tumours as well, the two models could be separated by their deviances.

Post-chymopapain (chemonucleolysis)--clinical and computed tomography correlation: preliminary results.

Chymopapain was first used for treatment of lumbar disc herniation in 1964 and has been used extensively in Canada and Europe for the last decade, but was recently released for general use in the United States. The enzyme is thought to cause decrease in intradiscal pressure and in disc volume; however, little in vivo evidence exists to support this concept. High resolution computed tomography (CT) scans were performed for diagnosis and at a variable period following chemonucleolysis on 17 randomly selected patients. The results of the study were: disc space narrowing occurred almost invariably; retraction of the prolapsed or extruded disc occurred in many patients; clinical improvement was closely related to retraction of the prolapsed or extruded disc; the best clinical results were obtained in patients who were injected at a single level with a clearly demonstrable disc prolapse or herniation.