MADOR: a new tool to calculate decrease of effective doses in human after DTPA therapy.

Abstract models have been developed to describe dissolution of Pu/Am/Cm after internal contamination by inhalation or wound, chelation of actinides by diethylene triamine penta acetic acid (DTPA) in different retention compartments and excretion of actinide-DTPA complexes. After coupling these models with those currently used for dose calculation, the modelling approach was assessed by fitting human data available in IDEAS database. Good fits were obtained for most studied cases, but further experimental studies are needed to validate some modelling hypotheses as well as the range of parameter values. From these first results, radioprotection tools are being developed: MAnagement of DOse Reduction after DTPA therapy.

Structure of a single model to describe plutonium and americium decorporation by DTPA treatments.

The aim of this study is to propose a single modeling structure to describe both plutonium and americium decorporation by DTPA, which is based on hypotheses mostly validated by experimental data. Decorporation efficacy of extracellular retention depends on the concentration ratio of DTPA vs. actinides and varies in each compartment according to the amount of biological ligands and their affinity for actinides. By contrast, because the relatively long residence time of DTPA after its cell internalization and the stability of actinide-DTPA complexes, intracellular decorporation efficacy is mainly controlled by a DTPA/actinide ratio, which is specific to each retention compartment. Although the affinity of DTPA is much lower for americium than for plutonium, a larger decorporation of americium can be obtained, which is explained by different biological ligands and/or their affinity for the actinide. Altogether, these results show that the relative contribution of intra vs. extracellular decorporation varies depending on the actinide, the chemical form of radionuclides, the galenic formulation of DTPA, and the treatment schedule.

Isotopic and elemental composition of plutonium/americium oxides influence pulmonary and extra-pulmonary distribution after inhalation in rats.

The biodistribution of plutonium and americium has been studied in a rat model after inhalation of two PuO(2) powders in lungs and extra-pulmonary organs from 3 d to 3 mo. The main difference between the two powders was the content of americium (approximately 46% and 4.5% of total alpha activity). The PuO(2) with a higher proportion of americium shows an accelerated transfer of activity from lungs to blood as compared to PuO(2) with the lower americium content, illustrated by increased urinary excretion and higher bone and liver actinide retention. The total alpha activity measured reflects mostly the americium biological behavior. The activity contained in epithelial lining fluid, recovered in the acellular phase of broncho-alveolar lavages, mainly contains americium, whereas plutonium remains trapped in macrophages. Epithelial lining fluid could represent a transitional pulmonary compartment prior to translocation of actinides to the blood and subsequent deposition in extra-pulmonary retention organs. In addition, differential behaviors of plutonium and americium are also observed between the PuO(2) powders with a higher dissolution rate for both plutonium and americium being obtained for the PuO(2) with the highest americium content. Our results indicate that the biological behavior of plutonium and americium after translocation into blood differ two-fold: (1) for the two actinides for the same PuO(2) aerosol, and (2) for the same actinide from the two different aerosols. These results highlight the importance of considering the specific behavior of each contaminant after accidental pulmonary intake when assessing extra-pulmonary deposits from the level of activity excreted in urine or for therapeutic strategy decisions.

Simplified structure of a new model to describe urinary excretion of plutonium after systemic, liver or pulmonary contamination of rats associated with Ca-DTPA treatments.

This study validates, by targeted experiments, several modeling hypotheses for interpretation of urinary excretion of plutonium after Ca-DTPA treatments. Different formulations and doses of Ca-DTPA were administered to rats before or after systemic, liver or lung contamination with various chemical forms of plutonium. The biokinetics of plutonium was also characterized after i.v. injection of Pu-DTPA. Once formed, Pu-DTPA complexes are stable in most biological environments. Pu-DTPA present in circulating fluids is rapidly excreted in the urine, but 2-3% is retained, mainly in soft tissues, and is then excreted slowly in the urine after transfer to blood. Potentially, all intracellular monoatomic forms of plutonium could be decorporated after DTPA internalization involving slow urinary excretion of Pu-DTPA with half-lives varying from 2.5 to 6 days as a function of tissue retention. The ratio of fast to slow urinary excretion of Pu-DTPA depends on both plutonium contamination and Ca-DTPA treatment. Fast urinary excretion of Pu-DTPA corresponds to extracellular decorporation that occurs beyond a threshold of the free DTPA concentration in circulating fluids. Slow excretion corresponds mostly to intracellular decorporation and depends on the amount of intracellular DTPA. From these results, the structure of a simplified model is proposed for interpretation of data obtained with Ca-DTPA treatments after systemic, wound or pulmonary contamination by plutonium.

In vitro and in vivo assessment of plutonium speciation and decorporation in blood and target retention tissues after a systemic contamination followed by an early treatment with DTPA.

This study identifies the main sources of systemic plutonium decorporated in the rat after DTPA i.v. at the dose recommended for humans (30 mumol kg(-1)). For this purpose, standard biokinetic approaches are combined to plasma ultrafiltration for separation of plutonium complexes according to their molecular weight. In vitro studies show that at the recommended DTPA dose, less than 5% of the plasma plutonium of contaminated rats can be displaced from high-molecular-weight ligands. After i.v. administration of Pu-DTPA, early ultrafiltrability of plutonium in plasma decreases with total DTPA dose, which is associated with an increase in plutonium bone retention. This demonstrates the instability of Pu-DTPA complexes, injected in vivo, below the minimal Ca-DTPA dose of 30 mumol kg(-1). Plutonium biokinetics is compared in rats contaminated by plutonium-citrate i.v. and treated or not with DTPA after 1 h. No significant decrease in plasma plutonium is observed for the first hour after treatment, and the fraction of low-molecular-weight plutonium in plasma is nearly constant [5.4% compared with 90% in Pu-DTPA i.v. (30 mumol kg(-1)) and 0.7% in controls]. Thus plutonium decorporation by DTPA is a slow process that mainly involves retention compartments other than the blood. Plutonium-ligand complexes formed during plutonium deposition in the retention organs appear to be the main source of decorporated plutonium.