The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research.

The assessment and management of risks associated with exposures to ionising radiation are defined by the general radiological protection system, proposed by the International Commission on Radiological Protection (ICRP). This system is regarded by a large majority of users as a robust system although there are a number of dissenting voices, claiming that it is not suitable for estimating the risks resulting from internal exposures. One of the specific issues of internal exposure involves short-range radiations such as Auger and beta particles. Auger- and beta-emitting radionuclides can be distributed preferentially in certain tissue structures and even in certain cellular organelles, according to their chemical nature and the vector with which they are associated. Given the limited range of the low-energy electrons in biological matter, this heterogeneous distribution can generate highly localised energy depositions and exacerbate radiotoxic responses at cellular level. These particularities in energy distribution and cellular responses are not taken into account by the conventional methods for the assessment of risk.Alternative systems have been proposed, based on dosimetry conducted at the cellular or even molecular level, whose purpose is to determine the energy deposition occurring within the DNA molecule. However, calculation of absorbed doses at the molecular level is not sufficient to ensure a better assessment of the risks incurred. Favouring such a microdosimetric approach for the risk assessments would require a comprehensive knowledge of the biological targets of radiation, the dose-response relationships at the various levels of organisation, and the mechanisms leading from cellular energy deposition to the appearance of a health detriment. The required knowledge is not fully available today and it is not yet possible to link an intracellular energy deposition to a probability of occurrence of health effects or to use methods based on cellular dosimetry directly.The imperfections of the alternative approaches proposed so far should not discourage efforts. Protection against exposure to Auger and low-energy beta emitters would benefit from mechanistic studies, dedicated to the study of energy depositions of the radionuclides in various cellular structures, but also from radiotoxicological studies to define the relative biological effectiveness of the various Auger emitters used in medicine and of certain low-energy beta emitters, whose behaviour may depend greatly on their chemical form during intake. The scientific expertise, as well as the human and physical resources needed to conduct these studies, is available. They could be now mobilised into international low-dose research programmes, in order to ultimately improve the protection of people exposed to these specific radionuclides.

MEDOR, a didactic tool to support interpretation of bioassay data after internal contamination by actinides.

A didactic software, MEthodes DOsimètriques de REférence (MEDOR), is being developed to provide help in the interpretation of biological data. Its main purpose is to evaluate the pertinence of the application of different models. This paper describes its first version that is focused on inhalation exposure to actinide aerosols. With this tool, sensitivity analysis on different parameters of the ICRP models can be easily done for aerosol deposition, in terms of activity and particle number, actinide biokinetics and doses. The user can analyse different inhalation cases showing either that dose per unit intake cannot be applied if the aerosol contains a low number of particles or that an inhibition of the late pulmonary clearance by particle transport can occur which contributes to a 3-4 fold increase in effective dose as compared with application of default parameters. This underlines the need to estimate systematically the number of deposited particles, as well as to do chest monitoring as long as possible.

Hair dosimetry following neutron irradiation.

Use of hair as a biological dosimeter of neutron exposure was proposed a few years ago. To date, the (32)S(n,p)(32)P reaction in hair with a threshold of 2.5 MeV is the best choice to determine the fast neutron dose using body activation. This information is essential with regards to the heterogeneity of the neutron transfer to the organism. This is a very important parameter for individual dose reconstruction from the surface to the deeper tissues. This evaluation is essential to the adapted management of irradiated victims by specialized medical staff. Comparison exercises between clinical biochemistry laboratories from French sites (the CEA and COGEMA) and from the IRSN were carried out to validate the measurement of (32)P activity in hair and to improve the techniques used to perform this examination. Hair was placed on a phantom and was irradiated at different doses in the SILENE reactor (Valduc, France). Different parameters were tested: variation of hair type, minimum weight of hair sample, hair wash before measurement, delivery period of results, and different irradiation configurations. The results obtained in these comparison exercises by the different laboratories showed an excellent correlation. This allowed the assessment of a dose-activity relationship and confirmed the feasibility and the interest of (32)P measurement in hair following fast neutron irradiation.

Differential qualitative and temporal changes in the response of the hypothalamus-pituitary-adrenal axis in rats after localized or total-body irradiation.

Stress such as exposure to ionizing radiation is able to activate the hypothalamus-pituitary-adrenal axis. The present study sought to examine the effects of different configurations of a 10-Gy gamma irradiation in rats on the hypothalamus-pituitary-adrenal axis to understand the mechanism of negative feedback by glucocorticoids induced by ionizing radiation. Specifically, we determined adrenocorticotropin and corticosterone levels in plasma as well as corticotrophin-releasing factor expression in the paraventricular nucleus of the hypothalamus by in situ hybridization from 6 h to 4 days after total-body, abdominal or head irradiation. In this study, we found an activation of the hypothalamus-pituitary-adrenal axis after radiation exposure. Plasma adrenocorticotropin and corticosterone levels were significantly increased after total-body and abdominal irradiation 3 days after exposure, in parallel with decreased labeling of corticotrophin-releasing factor mRNA in the parvocellular region of the paraventricular nucleus of the hypothalamus. Our results suggest that ionizing radiation activates the neuroendocrine system to protect the organism from the occurrence of radiation-induced inflammation.

Effect of heavy ions on neuro-endocrine regulations.

During American and Russian short and long-term space flights neuroimmune dysregulations have been observed in man and rats for up to three months after the return. During Extra-Vehicular Activity, radiation exposure risk is greater to elicit short and/or long-term deleterious effects on the functional capacity of the neuroimmune system. In order to assess the effects of high LET events on neuroimmune networks, our preliminary ground-based study was to investigate brain inflammatory responses in mouse after low dose radiation exposure with high LET particles (12C, 95MeV/u, 42 mGy). Plasma corticosterone levels were rapidly (6 hours) increased by two-fold, then decreased 24 hours post-irradiation. At 3 days plasma corticosterone and ACTH concentrations were also two- to three-fold increased. Plasma ACTH levels were still elevated up to seven days to two months. Furthermore immune functions are under current assessment. The results of this study should allow a greater understanding of the effects of high LET particles on neuroimmune system.

Assessing exposure to cosmic radiation on board aircraft.

The assessment of exposure to cosmic radiation on board aircraft is one of the preoccupations of organizations responsible for radiation protection. The cosmic radiation particle flux increases with altitude and latitude and depends on the solar activity. The radiation exposure has been estimated on several airlines using transatlantic, Siberian and transequatorial routes on board subsonic and supersonic aircraft, to illustrate the effect of these parameters. Measurements have been obtained with a tissue equivalent proportional counter using the microdosimetric technique. Data have been collected at maximum solar activity in 1991-92 and at minimum in 1996-98. The lowest mean dose rate measured was 3 microSv/h during a Paris-Buenos Aires flight in 1991; the highest was 6.6 microSv/h during a Paris-Tokyo flight using a Siberian route and 9.7 microSv/h on Concorde in 1996-97. The mean quality factor is around 1.8. The corresponding annual effective dose, based on 700 hours of flight for subsonic aircraft and 300 hours for Concorde, can be estimated between 2 mSv for least-exposed routes and 5 mSv for more exposed routes.

Characterization of the acute inflammatory response after irradiation in mice and its regulation by interleukin 4 (Il4).

The aim of this study was to determine the effects of total-body irradiation of mice on the acute release of a panel of several mediators of inflammation and to evaluate the efficacy of Il4 in regulating these radiation-induced modifications. We studied the effects of exposure of C57BL6/J mice to 8 Gy gamma rays on the early release of cytokines, chemokines, acute-phase proteins, prostaglandins and corticosterone in either plasma or tissues compared to those observed after intraperitoneal injection of lipopolysaccharide from 1 h to 3 days after stimulation. During the characterization of the acute inflammatory response induced by radiation or lipopolysaccharide, we observed differences both in the type of mediators produced and in the time course of release. We next determined the anti-inflammatory potential of Il4 in this model of total-body irradiation. We found that Il4 was able to down-regulate the radiation-induced production of mediators of inflammation such as Gro1 (also known as KC, N51) in plasma and lung, corticosterone in blood, Il1b in lung, and prostaglandin E(2) in colon, suggesting the anti-inflammatory potential of Il4 in regulating the radiation-induced response.

Behavioural consequences of an 8 Gy total body irradiation in mice: regulation by interleukin-4.

The effects of an 8 Gy gamma total body irradiation (TBI) on exploration and locomotion activities as well as temperature were studied in C57BL6/J mice. Survival, body weight, and blood cell counts were also assessed in irradiated mice treated with placebo or interleukin (IL)-4. The efficacy of IL-4 treatment on improvement in exploration activity was evaluated. The study was carried out from 3 h to 30 days following exposure. Our results showed a biphasic response to irradiation concerning the exploration activity of mice. Irradiated mice had reduced activity as early as 3 h after exposure, with recovery of activity within 24 h. The exploration activity again decreased 4 days after irradiation and the recovery occurred slowly after day 17. IL-4 ameliorated the exploration status in mice in both phases. The locomotion activity was studied using a telemetry apparatus. A similar pattern to that of the exploration data was observed, with a minimal activity observed between days 13 and 17. A radiation-induced hypothermia was also noticed over the same time period.

Assessing exposure to cosmic radiation during long-haul flights.

The assessment of exposure to cosmic radiation on board aircraft is one of the concerns of organizations responsible for radiation protection. Cosmic-particle flux increases with altitude and latitude and depends on solar activity. To illustrate the effect of these parameters, exposure has been estimated on several airlines operating subsonic and supersonic aircraft on transatlantic, Siberian and transequatorial routes. Measurements have been made with a tissue-equivalent proportional counter using the microdosimetric technique. This type of system provides the absorbed dose, the ambient dose equivalent, the mean quality factor, and the dose distribution as a function of lineal energy. Data were collected at maximum solar activity in 1991-1992 and at minimum activity in 1996-1998. The lowest mean dose rate measured was 3 microSv h(-1) during a Paris-Buenos Aires flight in 1991. The highest rates were 6.6 microSv h(-1) during a Paris-Tokyo flight on a Siberian route and 9.7 microSv h(-1) on Concorde in 1996-1997. The mean quality factor is around 1.8. The corresponding annual effective dose, based on 700 h of flight for subsonic aircraft and 300 h for Concorde, can be estimated at between 2 mSv for the least-exposed routes and 5 mSv for the more-exposed routes.

Ionizing radiation stimulates muscarinic regulation of rat intestinal mucosal function.

The aim of this study was to determine whether ionizing radiation modifies muscarinic regulation of intestinal mucosal function. Rats exposed to total body 8-Gy gamma-irradiation or sham irradiated were studied up to 21 days after irradiation. Basal and carbachol-stimulated short-circuit current (Isc) and transepithelial conductance (Gt) of stripped ileum were determined in Ussing chambers. Muscarinic receptor characteristics using the muscarinic antagonist [3H]quinuclidinyl benzilate and three unlabeled antagonists were measured in small intestinal plasma membranes together with two marker enzyme activities (sucrase, Na+-K+-ATPase). Enzyme activities were decreased 4 days after irradiation (day 4). Basal electrical parameters were unchanged. Maximal carbachol-induced changes in Isc and Gt were increased at day 4 (maximal DeltaIsc = 195.8 +/- 14.7 microA/cm2, n = 19, vs. 115.4 +/- 8.2 microA/cm2, n = 63, for control rats) and unchanged at day 7. Dissociation constant was decreased at day 4 (0.73 +/- 0.29 nM, n = 10, vs. 2.14 +/- 0.39 nM, n = 13, for control rats) but unchanged at day 7, without change in binding site number. Thus total body irradiation induces a temporary stimulation of cholinergic regulation of mucosal intestinal function that may result in radiation-induced diarrhea.

New results for the space radiation environment of MIR space station obtained by Liulin dosimeter-radiometer. Comparison with LET spectrometer NAUSICAA.

Since 1988 high sensitivity semiconductor dosimeter-radiometer "Liulin" worked on board of MIR space station. Device measured the absorbed dose rate and the flux of penetrating particles. The analysis of the data shows the following new results: In October 1989 and after March 24, 1991, two additional stable maximums in flux channel were observed in the southern-eastern part of South Atlantic Anomaly (SAA). These two maximums existed at least several months and seem to be due to trapped high energy electron and proton fluxes. In April 1991 additional maximums were localized in the following geographical coordinates regions: latitude = (-35 degrees)-(-50 degrees) longitude = 332 degrees-l6 degrees and lat.(-46 degrees)-(-52 degrees) long. 360 degrees-60 degrees. Additional maximums diffusion occurs inside radiation belt. Appearance of these maximums seems to be closely connected with preceding powerful solar proton events and associated geomagnetic dynamics of new belt disturbances. Alter the series of solar proton events in June 1991 we observed significant enhancement of this new radiation belt formation. To achieve sufficient accuracy of dose rate predictions in low Earth orbits the structure and dynamics of new belt should be carefully analyzed to be included in a new environment model. From the inter comparison of the data from "Liulin" and French developed tissue equivalent LET spectrometer NAUSICAA in the time period August-November 1992 we come to the following conclusions: Mainly there is good agreement between both data sets for absorbed dose in the region of SAA; Different situation of the instruments on the station can explain the cases when differences up to 2 times are observed; At high latitudes usually the tissue equivalent absorbed dose observations are 2 times larger than "Liulin" doses.

Proposal for a new radiation dose control system for future manned space flights.

Radiation risk on a future long-duration manned space mission appears to be one of the basic factors in planning and designing the mission. Since 1988 different active dosimetric investigations has been performed on board the MIR space station by the Bulgarian-Russian dosimeter-radiometer LIULIN and French tissue-equivalent proportional counters CIRCE and NAUSICAA. A joint French-Bulgarian-Russian dosimetry experiment and the dosimetry-radiometry system RADIUS-MD have been developed for the future MARS-96 mission. On the base of the results and experience of these investigations a conception for a new radiation dose control system for the future orbital stations, lunar bases and interplanetary space ships is proposed. The proposed system which consists of different instruments will allow personal radiation control for crew members, radiation monitoring inside and outside each habitat, analysis and forecasting of the situation and will suggest procedures to minimize the radiation risk.

Real time dose rate and LET spectrum aboard MIR station during 1992.

Since the end of July 1992, the NAUSICAA system, a low gas pressured tissue equivalent proportional counter, recorded in real time the dose equivalent rate, the absorbed dose rate, the quality factor and the Linear Energy Transfer spectra, aboard the Russian orbital station MIR. The results since the ANTARES mission are presented. Some parameters like the proton flux, the previous solar cycles, the location of the NAUSICAA system inside the station and the South Atlantic Anomaly crossing seem to have an influence on these results. The total dose equivalent (H) during the ANTARES mission (between 1992 July the 30th and August the 10th) was 12 mSv and the total absorbed dose (D) 6.4 mGy with a quality factor (Q) equal to 1.9. The NAUSICAA system gives a good knowledge of LET spectra for the first time in space dosimetry.