Schimmelpfeng, J.

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KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH) www.kit.edu“Physiological biokinetic model for plutonium”Jutta Schimmelpfeng, EURADOS meeting in Rome, WG 7.2 BiokineticsKarlsruhe Institute of Technology (KIT)KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 2Physiological biokinetic model for plutoniumVarious approaches are possible individually or in combinations to develop a physiological biokineticmodel for a radioactive substance, such as plutonium:1. Comparison and optimization of an existing biokinetic model under physiological aspects(WG 7.3 “Towards a new DTPA treatment model”, since 2007).2. Creation of a physiological biokinetic model based on a central compartment and including physiological facts and transfer rates. (Self-made or pharmacokinetic model, ISF (FzK/KIT) since 2007)3. Assessment of biokinetic developments after incorporation of plutonium in analogy with biokinetics or pharmacokinetics of a substance showing comparable chemical and physiological behavior in the body. (WG 7.2 “Development and QA of Biokinetic Models”, since today)The quality of the resulting models depends on how accurately their assumptions reflect reality. Ideally, a biokinetic model develops which reproduces reality.Ideally, the three approaches result in similar or even identical compartment structures in a biokineticmodel reflecting reality. Schimmelpfeng, J.: Physiology-based modelling in radiation research – The biokinetics of Plutonium. Radiation Protection Dosimetry 136, 74-81, 2009.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 3Physiological biokinetic model for plutoniumAssumption 1: Plutonium can be incorporated by injection, ingestion, a wound (invulneration) or inhalation. Assumption 2: Plutonium occurs in compounds of oxidation levels +III to +VII. Mammalian fluids, such as blood plasma, urine and tissue fluids are dominated by Pu(IV) because most endogenous ligandsstabilize this state of oxidation.Assumption 3: The similarities of the chemical and biological transport and distribution properties of Fe(III) and Pu(IV)are remarkable. Plutonium is transported in the body in a similar way as iron.* Ansoborlo E, Bion L, Doizi D, Moulin C, Lourenco V, Madic C, Cote G, Van der Lee J, Moulin V. Current and future radionuclide speciation studies in biological media. Radiat Prot Dosimetry. 2007;127(1-4):97-102. Epub 2007 Jun 19. log K(Pu(IV)-ligand) / log K(Fe(III)-ligand) ~ (1 : 1)*KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 4Physiological biokinetic model for plutoniumAssumption 4: Fe3+ and Al3+ ions also show chemical similarity with respect to equivalent binding behavior. Assumption 5: Major reaction partnersare transferrin and citrate in the blood and in the extracellular fluid. That applies to plutonium and to aluminium. “The radius of Al3+ most resembles that of Fe3+ (Martin 1986). Thus appearance of Al3+ in Fe3+ sites seems likely.”„Aluminium will follow many of themetabolic pathways that exist for iron.This linkage is well established (Priest, 2004).“„Martin also suggests that, based on consideration of stability constantsplasma aluminium will bind to bothtransferrin and citrate“.Conclusion: The similarities of the chemical and biological transport and distribution properties of Fe(III), Al(III) and Pu(IV) are remarkable. Why not use them to create a physiological biokinetik model for plutonium.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 5Physiological biokinetic model for plutonium* Nolte, E., Beck, E., Winklhofer, C., and Steinhausen, C.: Compartmental model for aluminium biokinetics. Human & Experimental Toxicology  20, 111-117 (2001).Figure 2. Pharmacokinetic model for aluminium *.The central compartment is made up of aluminiumbound to transferrin (T) and citrate (C) in plasma (P) and the interstitial fluid (I). From this central compartment (PT, PC, IT, and IC) the aluminium is distributed into the peripheral compartments, P1 (liver and spleen), P2 (muscles), and P3 (bones). The gastro-intestinal tract is subdivided into the stomach (M), the duodenum (D), and the rest of the digestive tract (R). Transport among the compartment sections is described by rate constants which are inverse time constants. The time constants are added to the arrows describing transport. The urine excretion time is TU. KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 6Physiological biokinetic model for plutoniumFigure 3. Basic physiological-based compartment model *for the biokinetics of plutonium. This model is based on conclusion by analogy, precisely because Pu(VI), Fe(III) and Al(III) show comparable chemical and physiological behavior in the body. Relevant chemical reactions are modeled in their anatomical structures.Transport rate and time constants between the compartments might be similar to those in figure 2.* Schimmelpfeng, J.: Physiology-based modelling in radiation research – The biokinetics of Plutonium. Radiation Protection Dosimetry 136 (2), 74-81, 2009.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 7Proposal of new action (Dietmar, Jutta):1. Refine the new physiological model, if necessary (e.g. skeleton/bones: Andrea?, all)2. Test the new physiological model (with data from the literature and from USTUR: all)3. Validation by comparing simulation and published experimental kinetic data (all)4. Further experiments needed? (all)5. Comparison with present models, e.g. Leggett et al. 2005 (all)6. Development of a final physiological model and discussion of its reliability and applicability (all)Physiological biokinetic model for plutoniumFigure 4. Biokinetic compartment model for aluminium, modified after Priest et al. (2004). The Middlesex University biokinetic model was developed to fit data collected for subject P, who was injected > 500 Bq 26Al-citrate and followed for + 10 years. Retention halftime (T1/2) of aluminium deposited in any organ or tissue is given in days.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 8Physiological biokinetic model for plutoniumFigure 4. Pu(IV) biokinetics in mice: Tracer exchange in two-compartment system between blood plasma (P) andinterstitial water (I) with urinary excretion (EU).Table A3: Kinetics of i.v. injected 238Pu(IV) citratein plasma and interstitial water of miceData from the literatureDurbin WP, Kullgren B and Schmidt CT: Circulatory kinetics of intravenously injected 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: Comparison with rat, dog and Reference Man. Health Physics  72 (2), 222-235, 1997.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 9Physiological biokinetic model for plutoniumDurbin WP, Kullgren B and Schmidt CT: Circulatory kinetics of intravenously injacted 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: Comparison with rat, dog and Reference Man. Health Physics  72 (2), 222-235, 1997Data from the literatureKIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 10Physiological biokinetic model for plutoniumProposal of new action (Dietmar, Jutta):• Refine the new physiological model, if necessary (e.g. skeleton/bones: Andrea?, all)• Test the new physiological model (with data from the literature and from USTUR: all)• Validation by comparing simulation and published experimental kinetic data (all)• Further experiments needed? (all)• Comparison with present models, e.g. Leggett et al. 2005 (all)• Development of a final physiological model and discussion of its reliability and applicability (all)KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 11Physiological biokinetic model for plutoniumFinished…Thank you for your attention.The discussion is opened…References in chronological order:Martin RB: The chemistry of aluminium as related to biology and medicine. Clin. Chem. 32/10, 1797-1806, 1986.Durbin WP, Kullgren B and Schmidt CT: Circulatory kinetics of intravenously injacted 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: Comparison with rat, dog and Reference Man. Health Physics  72 (2), 222-235, 1997.Nolte, E., Beck, E., Winklhofer, C., and Steinhausen, C.: Compartmental model for aluminium biokinetics. Human & Experimental Toxicology  20, 111-117, 2001.Priest, ND: The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J. Environ. Monit. 6, 375-403, 2004.Leggett RW, Eckerman KF, Khokhryakov VF, Suslova KG, Krahenbuhl MP, Miller SC.: Mayak worker study: an improved biokinetic model for reconstructing doses from internally deposited plutonium. Radiat Res. 164(2), 111-122, 2005.Ansoborlo E, Bion L, Doizi D, Moulin C, Lourenco V, Madic C, Cote G, Van der Lee J, Moulin V. Current and future radionuclide speciation studies in biological media. Radiat Prot Dosimetry. 2007;127(1-4):97-102. Epub 2007 Jun 19. 2007. Schimmelpfeng, J.: Physiology-based modelling in radiation research - The biokinetics of Plutonium. Radiation Protection Dosimetry 136, 74-81, 2009.KIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 12Physiological biokinetic model for plutoniumFigures standbyKIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 13= Interstice/interstitial fluid?What is the meaning of Blood2/STO?Plutonium distributes quickly to Blood 1 and Blood 2. These two blood compartments have no evident physiological basis in the biokinetic model. They represent two theoretically different forms of plutonium in the blood with different rates of urine excretion (R. W. Leggett, personal communication).The Blood 1, Blood 2 and ST0 compartments are part of the extracellular fluid or, in Leggett’s words, ‘plutonium in circulation’. The soft tissue, STO (rapid turnover tissues), could represent extravascular fluid (R. W. Leggett, personal communication). Extravascular fluid may be interstitial fluid, because vascular is an anatomical term, meaning vessel (e.g. blood vessels and lymphatic vessels). Physiological biokinetic model for plutoniumKIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 14Physiological biokinetic model for plutoniumCOMMON FEATURES1. Blood 1 and Blood 2 represent two theoretically different forms of plutonium in the blood with different rates of urine excretion. In the aluminium model the blood serum and the adjacent interstice contain two different forms of aluminium. Physiologically, aluminium is in a kind of chemical equilibrium as a complex with citrate, a low-molecular molecule, and with transferrin, which is a high-molecular molecule. 2. The biokinetic model for plutonium contains transfers from Blood 1 (thus physiologically corresponding to the blood serum) to the bones, to the liver (60% of activity), the digestive tract, the soft tissues (other soft tissues ST1 and 2), and the bladder. Both models also offer a possibility of transfer from the blood (blood serum and Blood 1, respectively) into the digestive tract and thus the possibility of metals being excreted from the body by way of the feces.3. The Blood 1, Blood 2, and ST0 compartments are part of the extracellular fluid or, in Leggett’s words, “plutonium in circulation”. Circulating aluminium is contained in the blood vessels in the blood serum from where it enters the interstice (interstitial fluid). Physiologically, the interstice is the space between cell complexes typical of organs, which contains connective tissues, vessels, and nerves.Leggett versus SchimmelpfengKIT – The cooperation of Forschungszentrum Karlsruhe GmbH and Universität Karlsruhe (TH)Dr. Jutta Schimmelpfeng, KIT/ISF, 01.02.2010, EURADOS meeting in Rome, WG 7.2 15Physiological biokinetic model for plutoniumDIFFERENCES1. Biokinetic model for plutonium: the bone and liver compartments are “supplied” from Blood 1. Pharmacokinetic model for aluminium: blood serum only indirectly supplies the muscles and the bones through the interstice compartment.2. Biokinetic model for plutonium: possibility of unilateral direct transfer of plutonium from the liver into the digestive tract. Pharmacokinetic model for aluminium: transfer possibility for the metal is bilateral, always passing through blood-serum.3. Plutonium: can be transferred from Blood 1 to ST1 or ST2 (soft tissues). From ST1 or ST2, plutonium enters the Blood 2 compartment. Pharmacokinetic model: aluminium to and from the blood passes through interstice compartment into the muscle compartment. 4. Biokinetic model: plutonium can be excreted through the bladder into the urine via Blood 1 and Blood 2. Pharmacokinetic model: for aluminium, there is only one transfer route from the blood serum to the urine.5. Plutonium in circulation requires three compartments: from Blood 2 straight to Blood 1 or to ST0. From Blood 1 back to Blood 2 only indirectly via ST0, ST1 or ST2 (soft tissues). In case of aluminium, two compartments make up the extracellular fluid: aluminium can be transferred straight from blood to interstice and back. Fig. 3: Leggett versus SchimmelpfengLeggett versus Schimmelpfeng

Physiological biokinetic model for plutonium

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Physiological biokinetic model for plutonium

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