Design and functionalities of the MADOR® software suite for dose-reduction management after DTPA therapy.

A software suite on biokinetics of radionuclides and internal dosimetry intended for the occupational health practitioners of nuclear industry and for expert opinions has been developed under Borland C++ Builder™. These computing tools allow physicians to improve the dosimetric follow-up of workers in agreement with the French regulations and to manage new internal contaminations by radionuclides such as Pu and/or Am after diethylene triamine penta-acetic acid treatments. In this paper, the concept and functionalities of the first two computing tools of this MADOR(®) suite are described. The release 0.0 is the forensic application, which allows calculating the derived recording levels for intake by inhalation or ingestion of the main radioisotopes encountered in occupational environment. Indeed, these reference values of activity are convenient to interpret rapidly the bioassay measurements and make decisions as part of medical monitoring. The release 1.0 addresses the effect of DTPA treatments on Pu/Am biokinetics and the dose benefit. The forensic results of the MADOR(®) suite were validated by comparison with reference data.

Normalization of haemostatic alterations in overweight children with weight loss due to lifestyle intervention.

BACKGROUND: Obesity has been shown to be associated with a hypercoagulable state. However, the effect of weight loss on these haemostatic alterations has not been studied yet with an overall function test such as the thrombin generating test (TG) in obese children. METHODS: We prospectively determined weight status as SDS-BMI, fibrinogen, and performed TG determining time to peak (TTPeak), peak, time preceding the thrombin burst (lag-time), and "endogenous" thrombin potential (ETP) in 27 overweight children (mean age 11.9 ± 2.4 years, 45% female, mean BMI 27.5 ± 5.6 kg/m(2), mean SDS-BMI 2.31 ± 0.48) both at baseline and after 1 year lifestyle intervention based on nutrition education, exercise therapy, and psychological care. Furthermore, thrombin generating test and fibrinogen were determined in 50 healthy children of same age. RESULTS: Overweight children demonstrated significantly higher fibrinogen levels (p = 0.013), shorter lag-time (p < 0.001), and TTPeak (p = 0.028) compared to normal-weight children. ETP (p < 0.001) and peak (p < 0.001) were significantly higher in overweight than in normal-weight children. The overweight children reduced their degree of overweight significantly (-0.4 5 ± 0.22 SDS-BMI; p < 0.001). At the end of the lifestyle intervention, all haemostatic alterations normalized (significant decrease of fibrinogen (p = 0.036), ETP (p = 0.034), and peak (p = 0.001); significant increase of lag-time (p = 0.040) and TTPeak (p < 0.001)). CONCLUSIONS: The alterations in the haemostatic system in obese children normalized after weight loss due to lifestyle intervention demonstrating their reversibility.

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.

Late-occurring pulmonary pathologies following inhalation of mixed oxide (uranium + plutonium oxide) aerosol in the rat.

Accidental exposure by inhalation to alpha-emitting particles from mixed oxide (MOX: uranium and plutonium oxide) fuels is a potential long-term health risk to workers in nuclear fuel fabrication plants. For MOX fuels, the risk of lung cancer development may be different from that assigned to individual components (plutonium, uranium) given different physico-chemical characteristics. The objective of this study was to investigate late effects in rat lungs following inhalation of MOX aerosols of similar particle size containing 2.5 or 7.1% plutonium. Conscious rats were exposed to MOX aerosols and kept for their entire lifespan. Different initial lung burdens (ILBs) were obtained using different amounts of MOX. Lung total alpha activity was determined by external counting and at autopsy for total lung dose calculation. Fixed lung tissue was used for anatomopathological, autoradiographical, and immunohistochemical analyses. Inhalation of MOX at ILBs ranging from 1-20 kBq resulted in lung pathologies (90% of rats) including fibrosis (70%) and malignant lung tumors (45%). High ILBs (4-20 kBq) resulted in reduced survival time (N = 102; p < 0.05) frequently associated with lung fibrosis. Malignant tumor incidence increased linearly with dose (up to 60 Gy) with a risk of 1-1.6% Gy for MOX, similar to results for industrial plutonium oxide alone (1.9% Gy). Staining with antibodies against Surfactant Protein-C, Thyroid Transcription Factor-1, or Oct-4 showed differential labeling of tumor types. In conclusion, late effects following MOX inhalation result in similar risk for development of lung tumors as compared with industrial plutonium oxide.

Haemostatic alterations in overweight children: associations between metabolic syndrome, thrombin generation, and fibrinogen levels.

BACKGROUND: The metabolic syndrome (MetS) is associated with central obesity and leads to increased morbidity and mortality due to cardiovascular disease (CVD). Since obesity is associated with a hypercoagulable state, it has been speculated that hypercoagulation is linking MetS to CVD. METHODS: We prospectively examined 81 overweight children and 32 normal-weight children aged 10-16 years. We analyzed blood pressure, fasting lipids, glucose, insulin, fibrinogen, and thrombin generating test determining time to peak (TTPeak), peak, time preceding the thrombin burst (lag-time), and 'endogenous' thrombin potential (ETP). RESULTS: Overweight children demonstrated significantly higher fibrinogen levels (p<0.001), shorter lag-time (p<0.001), and TTPeak (p=0.038) compared to normal-weight children. Furthermore, ETP (p<0.001) and peak (p<0.001) were significantly higher in overweight than in normal-weight children. Fibrinogen and all parameters of the clotting test correlated significantly (p always <0.05) to body mass index (BMI) but not significantly to insulin resistance index HOMA-IR or occurrence of MetS in multiple linear backward regression analyses adjusted for age and gender. CONCLUSIONS: The increased fibrinogen levels and the changes in the thrombin generation test points towards a haemostatic alteration in overweight children. The parameters of the clotting test were related to the degree of overweight but not to insulin resistance or occurrence of MetS questioning a direct association between MetS and the coagulation system. Longitudinal studies are needed to confirm these findings.

Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations.

Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss-of-function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X-linked ichthyosis and alopecia areata. We report a parent-child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC.

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.

Biokinetic modelling of DTPA decorporation therapy: the CONRAD approach.

Administration of diethylene triamine pentaacetic acid (DTPA) can enhance the urinary excretion rate of plutonium (Pu) for several days, but most of this Pu decorporation occurs on the first day after treatment. The development of a biokinetic model describing the mechanisms of decorporation of actinides by administration of DTPA was initiated as a task of the coordinated network for radiation dosimetry project. The modelling process was started by using the systemic biokinetic model for Pu from Leggett et al. and the biokinetic model for DTPA compounds of International Commission on Radiation Protection Publication 53. The chelation of Pu and DTPA to Pu-DTPA was treated explicitly and is assumed to follow a second-order process. It was assumed that the chelation takes place in the blood and in the rapid turnover soft tissues compartments of the Pu model, and that Pu-DTPA behaves in the same way as administered DTPA. First applications of this draft model showed that the height of the peak of urinary excretion after administration of DTPA was determined by the chelation rate. However, repetitions of DTPA administration shortly after the first one showed no effect in the application of the draft model in contrast to data from real cases. The present draft model is thus not yet realistic. Therefore several questions still have to be answered, notably about where the Pu-DTPA complexes are formed, which biological ligands of Pu are dissociated, if Pu-DTPA is stable and if the biokinetics of Pu-DTPA excretion is similar to that of DTPA. Further detailed studies of human contamination cases and experimental data about Pu-DTPA kinetics will be needed in order to address these issues. The work will now be continued within a working group of EURADOS.

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.

Limits of DPUI application associated with the number of particles within actinide aerosols.

Dose per unit intake (DPUI) of radionuclides is obtained using International Commission on Radiological Protection (ICRP) models. After inhalation exposure, the first model calculates the fraction of activity deposited within the different regions of the respiratory tract, assuming that the aerosol contains an infinite number of particles. Using default parameters for workers, an exposure to one annual limit of intake (ALI) corresponds to an aerosol of 239PuO2 containing approximately 1 x 10(6) particles. To reach such an exposure, very low particle number might be involved especially for compounds having a high specific activity. This study provides examples of exposures to actinide aerosols for which the number of particles is too low for a standard application of the ICRP model. These examples, which involve physical studies of aerosols collected at the workplace and interpretation of bioassay data, show that the number of particles of the aerosol can be the main limit for the application of DPUI after inhalation exposure.

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.

Modelling of bioassay data from a Pu wound treated by repeated DTPA perfusions: biokinetics and dosimetric approaches.

The aim of this study is to model plutonium (Pu) excretion from the analysis of a well-documented Pu wound case involving repeated diethylene-triamine-penta-acetic acid (DTPA) perfusions up to 390 d and monitoring up to 3109 d. Three modelling approaches were simultaneously applied involving: (1) release of soluble Pu from the wound, estimated with the ICRP66 dissolution model, (2) systemic behaviour of Pu by using ICRP67 model, but also two new models recently reported and (3) additional 'Pu-DTPA' compartments which transfer Pu directly to urinary compartment from blood, interstitial fluids and liver. The best fit of simulations to biological data was obtained by using the new Leggett's systemic model and assuming the presence of three DTPA compartments. Calculations have shown that DTPA treatments have contributed to a 3-fold reduction of the effective dose. Thus, reduction of doses associated with the DTPA treatments can be estimated by modelling which is useful to improve the efficacy of a DTPA treatment schedule based on a diminution of risk.

Decorporation of plutonium by pulmonary administration of Ca-DTPA dry powder: a study in rat after lung contamination with different plutonium forms.

This study evaluates the decorporation efficacy of a pulmonary administration of a new Ca-DTPA (diethylenetriaminepentaacetic acid) dry powder (18 micromol kg(-1) of body mass) after pulmonary contamination of rats with different Pu compounds. After inhalation of PuO2, a delayed intratracheal administration of DTPA cannot reduce significantly the retention of Pu in the lungs but limits its transfer in liver and skeleton. After pulmonary contamination by Pu nitrate, early insufflation of the DTPA powder appears twice as more efficient than an i.v injection of DTPA (30 micromol kg(-1)) to reduce Pu retention in the lungs and is as effective as i.v. injection to limit the extrapulmonary deposit. In contrast, a delayed administration of DTPA cannot reduce the lung or extrapulmonary retention. In conclusion, the improvement of aerodynamic properties of DTPA powder leads to an increase of DTPA amount deposited in the lungs and enhances the body decorporation.

Comparison of metallothionein-overexpression with sentinel lymph node biopsy as prognostic factors in melanoma.

BACKGROUND: Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. Immunohistochemical MT overexpression in paraffin-embedded tissues of patients with primary melanoma is associated with poor prognosis. While sentinel lymph node (SLN) biopsy is an established surgical technique for high-risk melanoma patients with predictive value for progression, the benefit of this procedure for the individual patient's overall survival remains unclear. AIM AND METHODS: We examined the role of MT overexpression in comparison with SLN biopsy in melanoma patients as a prognostic marker for progression and survival. One hundred and fifty-eight (158) patients underwent SLN biopsy due to high-risk melanoma. Primary melanoma specimens were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. The patients were followed up (median 37 months); the data of disease free survival and overall survival were calculated with a broad panel of statistical analyses. RESULTS: Twenty-eight (18%) out of 158 recruited melanoma patients developed metastases, 17 (11%) patients died due to widespread disease. Kaplan-Meier curves gave significant disadvantages for the MT-positive as well as the SLN-positive group for progression and survival. In the Fisher's exact test and Pearson's chi(2)-test MT overexpression was highly significant for progression, whereas SLN biopsy failed significance. In univariate as well as multivariate Cox regression analysis MT overexpression proved an excellent marker for progression (P=0.007 and P=0.009), although the P-values for survival were not significant. In contrast, while in the univariate analysis SLN biopsy did not show significant results for progression it did for survival, and in the multivariate analysis reached a P-value < 0.05 for both measured endpoints. CONCLUSION: Results corroborate the validity of MT overexpression in primary melanoma as a useful prognostic marker in melanoma patients. Accuracy is comparable and to some degree supplementary to the results of SLN biopsy.

Direct lung delivery of a dry powder formulation of DTPA with improved aerosolization properties: effect on lung and systemic decorporation of plutonium.

DTPA, an actinide chelating agent, has demonstrated its ability to complex plutonium (Pu) and to facilitate its urinary excretion after internal contamination. This process, known as decorporation is crucial to diminish the burden of Pu in the body. The ability to deliver a chelating agent directly to the alveolar region may increase its local concentration as compared to systemic delivery and therefore increase the extent of decorporation. Second, inhalation offers the potential for needle-free, systemic delivery of small molecules and would be convenient in case of nuclear accident as a first pass emergency treatment. To benefit from the improvement of inhalation technology, we have formulated DTPA into porous particles by spray-drying with dl-Leucine, DPPC and ammonium bicarbonate. The optimized particles possess a volume mean geometric diameter around 4.5 mum and crumpled paper morphology. The in vitro aerodynamic evaluation shows that about 56% of the powder should deposits in the lungs, with about 27% in the alveolar region, an improvement as compared with the micronized powder available with the Spinhaler. After pulmonary administration to rats contaminated with PuO(2), a 3-fold increase of the Pu urinary excretion was observed, but the dissolution of PuO(2) in the lungs was not enhanced.

Uncertainties in doses calculated according to ICRP recommendations after inhalation of 239PUO2 and early chest monitoring.

This study estimates uncertainties in Pu biokinetics and effective doses calculated after an acute inhalation exposure to 239PuO2 according to ICRP recommendations (default values for aerosols size and PuO2 dissolution parameters). This was performed using the most recently reported variations in model parameters and simulations after a Monte Carlo approach. Without chest monitoring, uncertainties in thoracic retention and plutonium excretion was 8-10 (95% confidence interval as the ratio between 97.5 and 2.5 percentiles of the lognormal distributions) up to 900 d after exposure. Early chest monitoring reduces significantly the uncertainties in plutonium biokinetics and doses which remain within a 95% confidence interval of 2.3 as compared with 6.6, without monitoring. Analysis of bioassay data previously reported shows that the dose delivered to some individuals can be out of the confidence interval, which was mostly due to an inhibition of the late mechanical clearance of the alveolar interstitium.