Article

Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA

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Abstract

Purpose: To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). Materials and methods: Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. Results: The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf), respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. Conclusions: The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. RESULTS of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms.

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... Moreover, Kastl et al. (2014) points out that certain human incorporation cases available in the literature may present a large number of uncertainties that make it difficult to determine the unknown chelation rate constants and to describe the data. Historical cases, for instance, may have missing information on their records. ...
... Sometimes, the time and duration of the intakes are unknown (Breustedt et al. 2019), and the available historical human data usually relies on urinary excretion only and on treatment regimens that are not in line with current practice. Kastl et al. (2014) suggest that the use of experimental data from controlled animal studies would make it possible to have precise knowledge of all experimental conditions and to better understand the principles of the involved mechanisms. ...
... Recently, the development of a physiologically based approach for modeling plutonium and americium decorporation therapy has been initiated in the scientific community. Different studies have started accomplishing this task by first proposing new systemic models for plutonium (Kastl et al. 2014) and americium (Miller et al. 2019). Follow-up animal research based on these studies were stated to be in progress, with focus on the chelation model itself, which will be linked to the new proposed systemic models. ...
Article
Chelating agents are administered to treat significant intakes of radioactive elements such as plutonium, americium, and curium. These drugs may be used as a medical countermeasure after radiological accidents and terrorist acts. The administration of a chelating agent, such as Ca-DTPA or Zn-DTPA, affects the actinide's normal biokinetics. It enhances the actinide's rate of excretion, posing a dose assessment challenge. Thus, the standard biokinetic models cannot be directly applied to the chelation-affected bioassay data in order to assess the radiation dose. The present study reviews the scientific literature, from the early 1970s until the present, on the different studies that focused on developing new chelation models and/or modeling of bioassay data affected by chelation treatment. Although scientific progress has been achieved, there is currently no consensus chelation model available, even after almost 50 y of research. This review acknowledges the efforts made by different research groups, highlighting the different methodology used in some of these studies. Finally, this study puts into perspective where we were, where we are, and where we are heading in regards to chelation modeling.
... These excretion models could be used to evaluate the actual urinary enhancement factor obtained with DTPA. Furthermore, these could serve as entry data in the development of a biokinetic model of Am after DTPA treatment for wound contamination, as the urinary excretion curve obtained for treated rats represents the kinetics of capture and elimination of Am by DTPA (Kastl et al. 2014;Poudel et al. 2017;Dumit et al. 2018;Miller et al. 2018). ...
Article
In the nuclear industry, wound contamination with americium is expected to increase with decommissioning and waste management. Treatment of workers with diethylenetriaminepentaacetic acid (DTPA) requires optimization to reduce internal contamination and radiation exposure. This work aimed at evaluating and comparing different DTPA protocol efficacies after wound contamination of rats with americium. Wound contamination was simulated in rats by depositing americium nitrate in an incision in the hind limb. Different routes, times, and frequencies of DTPA administration were evaluated. Individual daily urinary americium excretion and tissue retention were analyzed using the statistical tool STATBIODIS. Urinary profiles, urinary enhancement factors, and inhibition percentages of tissue retention were calculated. A single DTPA administration the day of contamination induced a rapid increase in americium urinary excretion that decreased exponentially over 7 d, indicating that the first DTPA administration should be delivered as early as possible. DTPA treatment limited americium uptake in systemic tissues irrespective of the protocol. Liver and skeleton burdens were markedly reduced, which would drive reduction of radiation dose. Local or intravenous injections were equally effective. Inherent difficulties in wound site activity measurements did not allow identification of a significant decorporating effect at the wound site. Repeated intravenous injections of DTPA also increased americium urinary excretion, which supports the use of multiple DTPA administrations shortly after wound contamination. Results from these statistical analyses will contribute to a better understanding of americium behavior in the presence or absence of DTPA and may aid optimization of treatment for workers.
... Models b) and c) are based on a physiological interpretation of data given by (Stather et al., 1983). Kastl (Kastl et al. 2014) described a revision and physiological interpretation of model a) based on animal experiments. The model and variations of it were refined using artificial scenarios and successfully applied to study several real contamination cases . ...
Article
The European Radiation Dosimetry Group (EURADOS) is a network of organizations and scientists promoting research and development in the dosimetry of ionizing radiation, contributing to harmonization in dosimetry practice across Europe, and offering education and training in areas relevant for dosimetry. As a registered nonprofit association under German law, EURADOS is currently running eight active working groups (WGs): WG2 on “Harmonization of Individual Monitoring”, WG3 on “Environmental Dosimetry”, WG6 on “Computational Dosimetry”, WG7 on “Internal Dosimetry”, WG9 on “Dosimetry in Radiotherapy”, WG10 on “Retrospective Dosimetry”, WG11 on “Dosimetry in High-Energy Radiation Fields”, and WG12 on “Dosimetry in Medical Imaging”. This paper presents recent scientific results obtained within these working groups, and additionally highlights the role of EURADOS as an organization which contributes to the development of a systematic strategy of radiation protection research in Europe.
... In the recent years a European collaboration within the frame of EURADOS (European Radiation Dosimetry Network) has been initiated to develop a compartmental model approach to this issue. The basic idea of the adopted approach is to consider the biokinetics of Pu/Am and of the injected DTPA separately and to couple them by a suitable mathematical description of the chelation mechanism as a second-order process [1,2]. Except the proposal presented by Konzen and Brey [3], which is based on the EURADOS approach, all other attempts existing in the literature [4][5][6][7][8][9] are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. ...
... Better understanding is needed. With the purpose of developing a physiologically-based model for plutonium decorporation, Kastl et al. (60) proposed modifications to the Luciani and Polig plutonium systemic model (54), which accounts for plutonium speciation in the blood. The efforts and progress made by different research groups, who worked on developing new strategies to chelation modeling, are discussed in the literature (7, 8, 17, 22-36, 60, 61). ...
Article
Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa3-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, "Human Alimentary Tract Model for Radiological Protection" and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment." Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved.
... Such models will enable dose assessments to be performed without delay, and support the evaluation and planning of further therapies. The development of a method based on coupling a biokinetic model for the chelating agent to ICRP's reference model for the biokinetics of actinides began during the CONRAD project (2005)(2006)(2007)(2008) and is continuing in Working Group 7 (Breustedt et al., 2009;Kastl et al., 2014). A major issue in this task is the physiological interpretation of the compartments and transfers in the biokinetic models, and the interpretation of the available (animal and human) data. ...
Article
European Radiation Dosimetry Group (EURADOS) Working Group 7 is a network on internal dosimetry that brings together researchers from more than 60 institutions in 21 countries. The work of the group is organised into task groups that focus on different aspects, such as development and implementation of biokinetic models (e.g. for diethylenetriamine penta-acetic acid decorporation therapy), individual monitoring and the dose assessment process, Monte Carlo simulations for internal dosimetry, uncertainties in internal dosimetry, and internal microdosimetry. Several intercomparison exercises and training courses have been organised. The IDEAS guidelines, which describe – based on the International Commission on Radiological Protection’s (ICRP) biokinetic models and dose coefficients – a structured approach to the assessment of internal doses from monitoring data, are maintained and updated by the group. In addition, Technical Recommendations for Monitoring Individuals for Occupational Intakes of Radionuclides have been elaborated on behalf of the European Commission, DG-ENER (TECHREC Project, 2014–2016, coordinated by EURADOS). Quality assurance of the ICRP biokinetic models by calculation of retention and excretion functions for different scenarios has been performed and feedback was provided to ICRP. An uncertainty study of the recent caesium biokinetic model quantified the overall uncertainties, and identified the sensitive parameters of the model. A report with guidance on the application of ICRP biokinetic models and dose coefficients is being drafted at present. These and other examples of the group’s activities, which complement the work of ICRP, are presented.
... An understanding of the second-order kinetics of interactions between plutonium and DTPA will be a useful aid in the development of a physiologically-based model for actinide decorporation therapy, as is being done by the health physics community (6)(7)(8). ...
Article
In 2008, Serandour et al. reported on their in vitro experiment involving rat plasma samples obtained after an intravenous intake of plutonium citrate. Different amounts of DTPA were added to the plasma samples and the percentage of low-molecular-weight plutonium measured. Only when the DTPA dosage was three orders of magnitude greater than the recommended 30 μmol/kg was 100% of the plutonium apparently in the form of chelate. These data were modeled assuming three competing chemical reactions with other molecules that bind with plutonium. Here, time-dependent second-order kinetics of these reactions are calculated, intended eventually to become part of a complete biokinetic model of DTPA action on actinides in laboratory animals or humans. The probability distribution of the ratio of stability constants for the reactants was calculated using Markov Chain Monte Carlo. These calculations substantiate that the inclusion of more reactions is needed in order to be in agreement with known stability constants.
... While data are unavailable for studies attempting to remove Gd deposits by chelation, strategies can be inferred from work in decorporation of radioactive actinides such as americium (Am) and plutonium (Pu) [21,22]. Traditionally, exposure to these radioactive elements would require prompt treatment with intravenous Caand Zn-DTPA because the amount that could be removed diminishes as time from exposure increased [23]. ...
Article
Gadolinium (Gd) and Gd-based contrast agents (GBCAs) have been observed to deposit in tissues of patients following multiple contrast enhanced MR imaging procedures. A conservative approach for chelation therapy of this toxic metal dictates the assumption that minimal intact GBCAs is present. Currently the extent to which these deposits are primarily de-chelated Gd remains uncertain, prevailing knowledge suggest that for linear agents much of the Gd is de-chelated, while for the macrocyclic agents, the Gd may be still largely chelated. To extract Gd from tissues and facilitate its release, chelation therapy should be both safe and effective. Here we discuss chelation therapy as it relates to Gd deposition. The principles of chelation are reviewed, initially with reference to ligand stability in complex biological fluids. A model of decorporation and how it relates to elimination of Gd deposits is also reviewed. When more is learned about Gd deposition, optimal removal strategies must be developed using basic thermodynamic and kinetic principles.
... As the administration of DTPA affects the regular biokinetics of the actinides, the standard biokinetic models used to assess the intake and dose for an individual contaminated with actinides but administered with DTPA are inadequate. The European Radiation Dosimetry Group (EURADOS) is developing new biokinetic models to address this issue (50,51) . This WG may seek future collaborations with EURADOS on this topic. ...
Article
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Following a radiological or nuclear emergency, first responders and the public may become internally contaminated with radioactive materials, as demonstrated during the Goiânia, Chernobyl and Fukushima accidents. Timely monitoring of the affected populations for potential internal contamination, assessment of radiation dose and the provision of necessary medical treatment are required to minimize the health risks from the contamination. This paper summarizes the guidelines and tools that have been developed, and identifies the gaps and priorities for future projects.
... , Hocine et al. 2014, Kreuzer et al. 2014, Van der Meeren et al. 2014, Vostrotin et al. 2014, Zhivin et al. 2014, Zhou 2014);(2) Biodosimetry, molecular biology and biochemistry, Mostapha et al. 2014); (3) Biokinetics, Giussani 2014, Leggett et al. 2014); (4) Medical countermeasures and decorporation, Bardot 2014, Griffiths et al. 2014a, Griffiths et al. 2014b, Kastl et al. 2014, Leiterer et al. 2014). ...
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For many years, the biokinetics of radioactive substances was calculated on the basis of mathematical criteria only. Biokinetic compartments in most cases did not correspond to anatomically defined distribution areas in an organism but were operational values. However, the quality of the resulting models depends on how accurately their assumptions reflect reality. Ideally, a biokinetic model develops which reproduces reality. In the past few years, this need has resulted increasingly in physiological operational sequences being modelled in realistic anatomical structures of the body along with physicochemical parameters. In this study, an estimate of the biokinetic operational sequence after an incorporation of plutonium is made similar to the pharmacokinetics of a substance showing comparable chemical and physiological behaviours in the body. These behaviours are found for metals, iron and aluminium. Thus, comparison of the biokinetics of plutonium with the pharmacokinetics of aluminium results in some commonalities and some differences. A new model with physiological compartments for plutonium is presented on the basis of the biokinetics of aluminium.
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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.
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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.
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An empirical urinary excretion model was derived from two puncture wound cases and several inhalation cases treated with DTPA. Important excretion mechanisms for chelated plutonium and the chemistry of plutonium under physiological conditions are related to the derivation of mathematical models for single and multiple DTPA treatments. hese models are used as a basis for assessing plutonium body burdens after DTPA therapy, determining the optimal DTPA dosage regimen, and evaluating the effectiveness of DTPA therapy. DTPA therapy initiated immediately after a contamination ncident will reduce a body burden by a factor of about three. A larger fraction of plutonium loosely deposited in body tissues can be removed by prolonged therapy. An inhalation incident involving six workers in a 238Pu oxide production facility is discussed. Worker bioassay data are compared with urinary excretion rates predicted by the Pu-DTPA model. (C)1978Health Physics Society
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The binding of plutonium to human apo-transferrin and to rat serum was investigated following delivery of the metal to the protein either as the plutonium-tri-n-butyl phosphate (Pu-TBP) complex in n-dodecane or as plutonium nitrate. Chromatographic behaviour, the failure to bind to iron-saturated transferrin and the release of plutonium by the chelating agents CaNa3DTPA and 3,4,3-LICAM(C) suggest that the transferrin complexes formed from the two plutonium compounds are similar. The tetracatechoylamide ligand LICAM(C) was found to be about 500 times more effective than DTPA, on a molar basis, for the release of plutonium from transferrin in rat serum.
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Urinary excretion data are reviewed for selected human cases which were treated with DTPA following plutonium intake via inhalation and injection. Data obtained out to several years post intake are compared to the data for non-treated cases. These data point out the difficulties involved in determining the effectiveness of the DTPA and in evaluating the systemic deposition. Utilizing urine results obtained between treatment dates to determine the DTPA effect may be misleading, underestimate the effectiveness and result in a premature cessation of treatment. The extended data indicate that the urine excretion rates eventually stabilize to the rates predicted by the Langham or Healy models. However, the rates appear to remain elevated above that expected for periods up to a hundred days post treatment. Evaluations based on data in the period prior to stabilization of the excretion rate may lead to overestimates of the systemic deposition. (C)1972Health Physics Society
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This study in human volunteers was designed to compare the retention of diethylenetriaminepentaacetic acid (DTPA) in the body after intravenous (i.v.) injection with that following inhalation by using a 14C labelled tracer. After i.v. injection retention in the blood could be described by three exponential components with half-times of about 1.4 min (approximately 60%) 14.3 min (approximately 20%) and 95 min (approximately 20%). By 24 hr more than 99% of the 14C-DTPA had been excreted in the urine and less than 0.5% remained in the plasma. After inhalation of 14C-DTPA retention in the lungs could be represented by a single component with a half time of about 75 min. As a consequence the length of time that a therapeutically useful amount of DTPA is retained in the body is approximately twice that following intravenous injection.
Article
The metabolism of plutonium has been studied following intravenous injection of 237Pu as Pu (IV) citrate into two healthy male volunteers. Measurements of the tracer in samples of blood and excreta were made by gamma-ray spectrometry, and patterns of organ uptake were investigated through serial measurements with a scintillation counter viewing the liver and selected skeletal sites. Excretion in urine and feces measured during the first 3 wk accorded closely with the patterns deduced by Durbin from the report of Langham et al. on patients injected with 239Pu. However, concentrations in blood were roughly twice those suggested by Durbin during most of the 14 d covered by our measurements. In one subject, the liver deposit increased to a plateau after about 21 d, at roughly 55% of the injection; in the other, the increase was prolonged, reaching about 70% after several months.
Article
Kinetic analysis and integrated systems modeling have contributed substantially to our understanding of the physiology and pathophysiology of metabolic systems and the distribution and clearance of drugs in humans and animals. In recent years, many researchers have become aware of the usefulness of these techniques in the experimental design. With this has come the recognition that the discipline of kinetic analysis requires its own expertise. The expertise can impact experimental design in many ways, from the collaborative and service activities in which individuals interact in formal ways to the development of software tools to aid in kinetic analysis. The purpose of this report is to describe one such software tool, Simulation, Analysis, and Modeling Software II (SAAM II). In the first part, we describe in general how the user can take advantage of the capabilities of the software system, and in the second part, we give three specific examples using multicompartmental models found in lipoprotein (apolipoprotein B [apoB] kinetics) and diabetes (glucose minimal model) research.
Article
On the basis of the available data and empirical expressions for the plutonium excretion after injection, an age-related compartmental model has been developed. It provides a better agreement with measured urinary excretion data than the current ICRP 67 model. Moreover, the revised model avoids unphysiological assumptions such as the transfer of activity from soft tissue to urinary bladder, that were part of the ICRP model. The new predictions of the activity in feces and in blood after an injection are closer to the available data than the ICRP 67 estimations and there is also a good agreement with the partitioning of plutonium between skeleton and liver obtained from different autopsy studies. Furthermore, the urinary excretion estimated by the improved model has been checked using some data from occupationally exposed individuals. As the plutonium uptake in these workers occurred by inhalation, the improved model and the ICRP 67 model were compared by connecting them to the ICRP 66 respiratory tract model. The improved model consistently yields a better agreement with the measured excretion and higher estimations of intake than the ICRP 67 model.
Article
A worker noted a small wound to his thumb when leaving a work site that was undergoing decontamination because of past operations with plutonium (Pu) and americium (Am). Direct surveys of the wound site confirmed the presence of contamination. The chelating agent Ca-DTPA was administered via a nebulizer within an hour after discovery of the wound. External measurements were made of the wound site and wound dressings; 24-h urinary excretion data were collected periodically and the Pu and Am urine content was determined. Zn-DTPA was administered on three occasions. The ICRP Pu systemic model was modified to consider the enhanced urinary excretion following administration of the chelating agents. The analysis indicated that the wound resulted in an initial deposition of 400 Bq 238Pu, 2240 Bq 239/240Pu and 1060 Bq 241Am. About 70% of the initial wound activity was removed by surgical procedures and less than 1% of the wound activity was removed by chelation therapy. This paper compares the observed urinary excretion data with that indicated by a simulation of the kinetics of the transfer from the wound site and the kinetics of the chelating agent and Pu.
Article
The plutonium production facility known as the Mayak Production Association was put into operation in June 1948. A high incidence of cancer in the Mayak workers has been related to the level of exposure to plutonium, but uncertainties in tissue doses have hampered development of dose-risk relationships. As part of an effort to improve dose estimates for these workers, the systemic biokinetic model for plutonium currently recommended by the International Commission on Radiological Protection (ICRP) has been modified to reflect recently developed data and facilitate interpretation of case-specific information. This paper describes the proposed model and discusses its implications for dose reconstruction for the Mayak workers.
Article
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.
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