Characterisation, implementation and quality assurance of biokinetic models. The experience of the CONRAD Task Group 5.2.

Characterisation, implementation and quality assurance of biokinetic models. The experience of the CONRAD Task Group 5.2. Augusto Giussani a*, Dietmar Noßke b, Alan Birchall c, Eric Blanchardon d, Bastian Breustedt e, Andrea Luciani f, James Marsh c, Uwe Oeh a, Gennadii Ratia g, Maria Antonia Lopez h a Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Radiation Protection, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. b Federal Office for Radiation Protection, Department of Radiation Protection and Health, 85762 Oberschleißheim, Germany. c Health Protection Agency, Radiation Protection Division, Chilton, Didcot, Oxon OX11 RQ, UK. d IRSN, Radiological Protection and Human Health Division, BP17-92262 Fontenayaux-Roses Cedex, France. e Forschungszentrum Karlsruhe GmbH, Hauptabteilung Sicherheit (HS-KES), Hermannvon Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany. f ENEA Radiation Protection Institute, via dei Colli 16, 4136 Bologna, Italy. g Ukrainian Radiation Protection Institute, Melnikova 53, 45 Kiev, Ukraine. h CIEMAT, Avda Complutense 22, 284 Madrid, Spain. Abstract. CONRAD (Coordinated Network on Radiation Dosimetry) was an action funded by the European Commission within the 6 th Framework Programme in order to link groups undertaking research relating to radiation dosimetry at workplaces. Workpackage 5 of CONRAD was dedicated to internal dosimetry. Task Group 5.2 "Research Studies on Biokinetic Models" dealt with the development, implementation, characterization and quality assurance of biokinetic models. The new ICRP model of the human alimentary tract (HATM), the new NCRP model for contaminated wounds, new systemic recycling models of the biokinetics of radioisotopes of polonium and plutonium presented in the scientific literature were implemented into the computer codes of five different institutions. Also new systemic biokinetic models for zirconium and molybdenum, developed on the basis of own results from stable tracer studies, were implemented. The excellent agreement among the results obtained by the different groups indicate that all the present models can be easily implemented into available software codes and that the outputs are independent of the computational approach used. It was also possible to better characterize the systemic models of plutonium by use of a partition factor expressing the relative distribution of material between skeleton and liver, and the NCRP wound model, by derivation of the exact analytical solutions for the wound retention resulting from the model formulation. KEYWORDS: biokinetics, systemic models, wound model, HATM, internal dosimetry. 1. Introduction CONRAD (COordinated Network for RAdiation Dosimetry) was a coordinated action supported by the European Commission in the frame of the 6 th Framework Programme for research and training in nuclear energy under contract No. FI6R-12684. The action started in January 5 and was concluded in March 8. The main partners of the project were EURADOS (EUropean RAdiation DOSimetry group), University of St.Gallen (Switzerland), and TU Delft (The Netherlands). * Presenting author, E-mail: augusto.giussani@helmholtz-muenchen.de 1

EURADOS was founded in 1981 with the aim of collecting, processing and disseminating information on research in dosimetry for all types of ionising radiation, co-ordinating ongoing research projects, and planning jointly future programmes. EURADOS (which is currently a registered society in Germany) includes 54 institutions from 25 European countries as "voting members". Nearly scientists are registered as "associate members" of EURADOS. The general aims of the CONRAD actions were the coordination and harmonization of radiation protection practices all over Europe, and the maintenance and consolidation of competences in the field of radiation dosimetry. Specific objectives pursued by the project Work Packages (WPs) were: the analysis of sustainable networks linking researchers and end users, performed by the University of St.Gallen (WP 2), the dissemination of knowledge (WP 3), and the coordination of research on dose assessment and evaluation (WPs 4-7). In detail, WP 4, headed by G.Gualdrini (ENEA, Italy), dealt with "Computational dosimetry", WP 5, headed by M.A.Lopez (CIEMAT, Spain), dealt with "Internal dosimetry", WP 6, headed by D.Bartlett (HPA, UK) dealt with "Complex mixed radiation fields at workplaces" and WP 7, headed by F.d'Errico (University of Pisa, Italy) dealt with "Radiation protection and dosimetry of medical staff". A general overview of the project structure is given in Figure 1. Figure 1: General overview of the CONRAD project and of its work-packages. results of co-ordinated research Research community, end users questions use of existing network and dissemination channels, joint meetings answers WP 2 Potential for a sustainable network (HSG/Enkel) EURADOS Member Institutes, Council study design analysis of results European Commission resources reports WP 3 Dissemination of knowledge (EURADOS/Schmitzer) organising workshops, updating databases reports resources WP 1 Project management (EURADOS/Schuhmacher) composition of working groups, definition of tasks Working groups co-ordinating research WP 4 Computational dosimetry (EURADOS/Gualdrini) WP 5 Internal dosimetry (EURADOS/Lopez) analysing and solving computational problems WP 6 Complex mixed radiation fields at workplaces (EURADOS/Bartlett) WP 7 Radiation protection dosimetry of medical staff (EURADOS/d'Errico) Forty-one scientists from 19 institutions of 14 European countries (Austria, Belgium, Czech Republic, Finland, France, Germany, Greece, Hungary, Italy, Russia, Spain, Switzerland, UK, Ukraine), together with one corresponding member from Canada and one IAEA representative, were active in WP5 2

"Coordination of Research on Internal Dosimetry" [1]. This Work Package was on its turn divided into 5 Task Groups: T5.1: Assessment of internal doses: uncertainty study and update of IDEAS guidelines (coordinated by Carlo Maria Castellani, ENEA, Italy, and James Marsh, HPA, UK); T5.2: Research studies on biokinetic models (coordinated by Dietmar Noßke, BfS, Germany); T5.3: New developments on Monte Carlo applications to in-vivo assessments of intakes (coordinated by Didier Franck, IRSN, France); T5.4: Interpretation of monitoring data after accidental or deliberate releases (coordinated by George Etherington, HPA, UK); T5.5: Update of IDEAS databases (coordinated by Christian Hurtgen, SCK CEN, Belgium). 2. The work of Task Group 5.2 of CONRAD WP5 The work of the Task Group had the objective of evaluating the impact that the recent and foreseen revisions of biokinetic models performed by the International Commission on Radiological Protection ICRP may have on dose assessment. Specifically, the focus was on the following topics: i. implementation of new biokinetic models, such as the ICRP Human Alimentary Tract Model HATM [2] and the Wound Model of the National Council on Radiation Protection and Measurements NCRP [3]; ii. quality assurance procedures consisting of both intercomparison calculations and verification of model formulation; iii. characterization and re-parametrization of specific models; iv. analysis of stable tracer studies in humans for assessing possible modifications to current ICRP systemic models; v. elaboration of a compartmental model to describe the basic mechanisms of the DTPA-chelation therapy employed for decorporation of plutonium. Progress was discussed during the annual EURADOS meetings in Oxford (UK, January 6), in Madrid (Spain, January 7) and in Paris (France, January 8). Extra meetings were organized in Vienna (Austria, April 5), Athens (Greece, October 7) and Munich (Germany, March 8) for Work Package 5 members, and in Montpellier (France, October 6) and in Karlsruhe (Germany, May 7) for T5.2. This last event was completely dedicated to decorporation modelling, and was open to experts from the European Consortium TIARA (Treatment Initiatives After Radiological Accidents). The results of the activities on the DTPA-model can be found in the contribution by B.Breustedt et al. to these proceedings [4]. 2.1 Implementation and quality assurance of new biokinetic models 2.1.1 ICRP Human Alimentary Tract Model (HATM) The ICRP HATM [2] differs significantly from the previous model of the gastro-intestinal tract [5]. It includes some compartments that were not present in the GI-tract model, such as mouth (oral cavity) and oesophagus, with very fast transit times. Absorption into blood is possible from different sites of the alimentary tract, and not only from the small intestine, with potential retention in the walls and subsequent recycling into the contents of the tract. Moreover, different sets of parameters depending on age, sex and on type of ingested materials (liquid, solid, diet) are provided. The model was implemented by six different groups into codes especially developed locally for dosimetric calculations [6, 7] (and, if necessary, suitably modified in order to account for the new biokinetic features) as well as into commercial codes generally employed for development of compartment models [8, 9]. The impact of the introduction of the HATM was assessed by comparing the results to those obtained with the GI-tract model. In our calculations, the HATM parameters recommended for "total diet" and adult male were used. Quality assurance procedures consisted of calculations of the number of transformations in the regions of the HATM and daily faecal excretion rates for a selected number of radionuclides (see Table 1) differing with regard to half-life (from few minutes to billions of years) and to fraction of ingested activity which is transferred to blood (from.5 to.99). 3

Table 1: Characteristic features of the radionuclides used in the quality assurance tests of the HATM. Radionuclide Half-life f A 18 F 19.8 min.99 6 Co 5.271 y.1 99m Tc 6.2 h.5 111 In 2.83 d.2 123 I 13.2 h.99 129 I 1.57 1 7 y.99 127 Te 9.35 h.3 133 Te 12.45 min.3 141 Ce 32.51 d.5 1 Tl 3.44 d.99 238 U 4.468 1 9 y.2 In spite of the large variations of the characteristics of the radionuclides considered, the results obtained with the different codes showed excellent agreement, with percentage deviations well below 1% also in the case of mouth and oesophagus, which have very rapid transit times of a few seconds. This fact is particularly significant since some codes were based on analytical methods and others relied on numerical algorithms or on interpolation functions. Beyond the verification of the calculation results, these tests proved the ease of implementation of the new model in existing codes. Concerning the comparison between the old GI-tract model and the new HATM, a slight increase of the number of transformations in the stomach and a decrease of the number of transformations in the small intestine and in the colon were observed (Table 2). These changes can be ascribed to the specific parameters introduced in the HATM: transit rates for the total diet are.57 d -1 for stomach (it was 24 d -1 in the GI-tract model) and 6 d -1 in the small intestine (as in the previous model).the colon is divided into three subregions each with transfer rate equal to 2 d -1 (in the previous model the colon was divided into two subregions with transfer rates equal to 1.8 d -1 and 1 d -1 respectively). For very short lived radionuclides (half-lives of a few minutes), most of the nuclear transformations occur before the material can be cleared from the stomach, so the differences in the transfer rate from stomach do not play a very big role, whereas for longer-lived radionuclides, the increase in number of transformations (+ 16.7%) reflects the increase in retention time (+ 16.7%). For the colon, the picture is a little more complicated since the extent of variation is influenced by the relative combination of half-life and retention times. Table 2: Percentage deviation of the outputs of the HATM from those of the old GI-tract model. Parent Small Half-life f Radionuclide A Stomach intestine Colon (a) 133 Te 12.45 min.3 +1.2 % -13.6 % -12.2 % 1 Tl 3.44 d.99 + 16.7 % - - 1. % 238 U 4.468 1 9 y.2 + 16.7 % - - 4.6 % (a) Colon is the sum of Upper Large Intestine and Lower Large Intestine for the GI-tract model and the sum of Right Colon, Left Colon and Rectosigmoid Colon for the HATM. Excellent agreements between the different codes were obtained also in the calculation of fecal excretion rates and nuclear transformations in the HATM for three more complicated cases: (i) short decay chains: here both the option of progeny sharing the absorption fraction of the parent nuclide and of using separate specific f A values were considered (see Table 3); (ii) absorption from sites different from the small intestine, taking 131 I as an example on the assumption that half of the iodine in the stomach and 98% of the iodine in the small intestine are absorbed to blood; (iii) recycling in the small intestine wall, as assumed in the model for 59 Fe presented in ICRP Publication 1 [2]. 4

Table 3: Characteristic features of the radionuclide chains used in the quality assurance tests of the HATM. Parent Radionuclide Half-life f A Progeny Half-life f A 9 Sr 28.8 y.3 9 Y 64 h.1 234 Pu 8.8 h.5 234 Np 4.4 d.5 23 U.8 d.2 226 Th 3.57 min.5 Of particular interest was the comparison between the predictions of the recycling model for 59 Fe and those of a simplified model without recycling presented in [2]. It was considered by ICRP that the implementation of the simpler model would lead to only very small differences in the calculated doses compared with that of the recycling one (p. 77, para. 174 [2]). The comparison (Fig. 2) shows that the "simplified" model underestimates the activity curve both in the small intestine and in its walls, implying discrepancies in the calculation of the number of transformations (-61 % in the small intestine, -56% in the walls). Also the prediction of the fecal excretion in the first days after incorporation is strongly affected by the model assumption (see Fig. 3): in the first day the "simplified" model overestimates the excretion (+36%), whereas in the following days the underestimation fluctuates between -1 and -36%. The discrepancies observed will affect the process of estimation of intake and consequently the assessment of dose. As the quality assurance process demonstrated, the currently available software codes are readily applied to implement recycling features in the compartmental model, and therefore the suggestion of a simpler model structure seems to be superfluous, as well as imprecise. Figure 2: Comparison of the activities of ingested 59 Fe in the small intestine (SI, left panel) and in the walls of the SI (right panel) as simulated by the recycling model (red lines) and by the "simplified" model (green lines). Please note the logarithmic scale of the x-axis. 7 5 6 SI Model with recycling "Simplified" model SI walls 4 5 Percentage of intake 4 3 1 3 1.1.1 1 1.1.1 1 1 5

Figure 3: Comparison of the fecal excretion after oral incorporation of 59 Fe as simulated by the recycling model (red lines) and by the "simplified" model (green lines). Left panel: daily excretion rate; right panel: cumulated excretion. 35 3 Model with recycling "Simplified" model 8 Excretion rate (%/d) 25 15 1 Cumulated excretion (% of intake) 6 4 5 5 1 15 1 2.1.2 NCRP Wound model The National Council on Radiation Protection and Measurement of the United States (NCRP) has developed a biokinetic model to describe retention and transfer of radionuclides incorporated into wounds [3]. The model consists of five compartments, representing five different chemical and physical forms in which the material may be present in the wound. The compartments may exchange material between each other and may clear material into the blood and/or into the lymph nodes. The NCRP Publication defines seven default wound retention categories (soluble material/weak retention; soluble material/moderate retention; soluble material/strong retention; soluble material/avid retention; colloid; particle; fragment), for which different separate sets of model parameters are given. A preliminary version of the model was implemented into the codes of five groups for simulating wound retention for 131 I and for 239 Pu (at the time of the analysis the final NCRP document was not yet available). Very good agreement between the results was obtained. Deviations were observed only as a consequence of different assumptions on the half-life of 131 I. Figure 4 shows the results for 239 Pu. It can be seen that the long-term retention of soluble/avid category is lower than that of soluble/strong category. It turned out that some model parameters for the avid material had been imprecisely estimated in the preliminary model formulation; the final version of the NCRP document contains the correct parameter values. 2.1.3 Polonium model The biokinetics of polonium gained particular attention during the time of the project due to the poisoning of Mr. Litwinenko and the public contamination cases in London and Hamburg. The recent systemic model for polonium presented by Leggett and Eckerman [1], which contains specific and separate inputs for ingestion (plasma 1) and for inhalation and wounds (plasma 2) was implemented 6

by the Task Group. Compared to the current ICRP model, less disintegrations occur in liver, kidneys and spleen, whereas bone surfaces, skin and gonads are now explicitly included as source regions, and therefore receive a significant radiation dose ( 21 Po decays mainly by alpha emission). Figure 4: Percentage retention of 239 Pu in contaminated wounds. Comparison of the model predictions for the different retention categories. 1 Percentage retention in the wound 8 6 4 Soluble/weak Soluble/moderate Soluble/strong Soluble/avid Colloid Particle Fragment 4 6 8 2.2 Characterization and re-parameterization of specific models 2.2.1 Partitioning factor for plutonium model Three models for the biokinetics of plutonium are available in the literature: the recycling model presented in ICRP Publication 67 [11], a revised model by Leggett et al. [12] and an additional structure with age-dependent transfer rates within the skeleton proposed by Luciani and Polig [13]. The models were implemented by the Task Group and very good agreement was observed in each case including the Luciani/Polig model, although different approaches were used by the different participants for taking the age-dependencies of the transfer rates into account. The plutonium models were also employed to evaluate the convenience of using specific indicators based on the relative accumulation of Pu in skeleton and liver to characterize and/or identify the initial scenario of contamination. In particular, the so-called "partitioning factor" was analysed, defined as p skel = f fskel + f skel liv where f skel and f liv are the fractions of systemic activity distributed initially to the skeleton and to the liver, respectively. In a sensitivity analysis conducted with the current ICRP model for plutonium, it was shown that the ratio between daily urinary and fecal excretion, measured at least ten days after incorporation of plutonium, may be a valuable estimator of p skel (see Figure 5). Therefore, the experimental determination of the urinary to fecal ratio in an exposed subject might give indications on the initial distribution of plutonium between liver and skeleton and thus help in providing a more realistic assessment of the internal dose, as might be required for epidemiological studies. Comparison with autopsy data are foreseen in order to verify the predictive power of the "partitioning factor". p skel [,1] 7

Figure 5: Ratio of daily urinary to fecal excretion after injection of 239 Pu for some values of the partitioning factor p skel. ratio of 24 h urinary to fecal excretion 15 1 5.3125.5.625.75.9375 1 1 1 1 1 2.2.2 Retention functions for the NCRP wound model The NCRP Publication presents, in addition to the models, multi-exponential functions to approximate the retention of material in the wounds. These exponential functions were estimated independently from the model, and it was observed that the predictions of the model sometime deviated from those of the approximation functions (see Figure 6). In addition, the analysis indicated that the approximation function given for colloid might have been erroneously evaluated assuming input into the "soluble" compartment and not into the "colloid and intermediate state". It was therefore decided to estimate the coefficients of the multi-exponential approximation functions by finding the "exact" solutions to the model equations. To this purpose different methodologies were employed, including analytical eigenvalue solution of the model differential equations, application of Cardano's formulas etc. The results are shown in Table 4 and Fig. 6. The same computational approaches will be used to calculate input functions into the lymph nodes and into blood compartment. Table 4: Coefficients of the multi-exponential approximation functions λ 1 t λ2t e λ3t R(t) = a e + a e + a as obtained in the CONRAD analysis. 1 2 3 retention category a 1 λ 1 (d -1 ) a 2 λ 2 (d -1 ) a 3 λ 3 (d -1 ) Weak.6734 65.89.2897 2.16.369.77 Moderate.5974 75.16.399.36.927.18 Strong.518 1.28.261.23.221 9.6E-4 Avid.1888 37.3.7 1.815 9.7E-4 Colloid.966.57.948 7.7E-4 -.14 3.2 Particle.75.47.925 2.9E-4 - - Fragment.9947 2.84E-6.54 8.E-3-6.52E-5 7.4E-1 8

Figure 6: Comparison between the predictions of the NCRP model (red dashed line), the approximation functions given in the NCRP publication (green line) and those obtained in the CONRAD analysis (blue line) for four of the seven retention categories. 1 SOLUBLE/WEAK 1 SOLUBLE/MODERATE 8 6 CONRAD Analysis NCRP Model NCRP Function 8 6 4 4 Percentage retention in the wound.1.1 1 1 1 1 8 6 Percentage retention in the wound 1. 99.5 99..1.1 1 1 1 4 COLLOID 98.5 FRAGMENT.1.1 1 1 1 1 98. 4 6 8 1 2.3 Analysis of stable tracer studies in humans Investigations on the biokinetics of molybdenum, strontium, ruthenium and zirconium were conducted at the Helmholtz Zentrum München in collaboration with the University of Milan. The results of these studies (intestinal absorption, plasma clearance and urinary excretion patterns) indicated some significant deviations from the current models recommended by ICRP. The revised recycling model structures developed for the elements molybdenum [14] and zirconium [15] were successfully implemented by the Task Group. 2.4 Dissemination and exploitation of the results The results of the Task Group have been presented to several international events [16, 17]. They have also provided useful inputs for the work of Task Groups INDOS (INternal DOSimetry) and DOCAL (DOse CALculation) of Committee 2 of the International Commission on Radiological Protection ICRP. After the end of the CONRAD project, the activities of Work Package 5 have been transferred to EURADOS Working Group 7, maintaining the same organizational structure in Task Groups. One of the first commitments of WG7 is the organization of the "EURADOS/IAEA Regional Training Course on Advanced Methods for Internal Dose Assessment: Application of IDEAS Guidelines and dissemination of CONRAD internal dosimetry results". The course will be held in February 9 in Prague (Czech Republic). As indicated in the subtitle, it will mainly rely on the outputs of the CONRAD action. Further information on the course can be found at following address: http://www.fjfi.cvut.cz/kdaiz/amida/index.html. 9

Acknowledgements CONRAD was a coordinated action supported by the European Commission in the frame of the 6 th Framework Programme for research and training in nuclear energy under contract No. FI6R-12684. The contributions of Wolfgang Klein from Forschungszentrum Karlsruhe, of Demetrio Gregoratto and of Katie Davis (both from HPA) to the modelling activities are gratefully acknowledged. REFERENCES [1] LOPEZ, M.A, et al., Coordination of Research on Internal Dosimetry in Europe: the CONRAD Project, Radiat. Prot. Dosim. 127 (7) 311-316. [2] INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION, Human Alimentary Tract Model for Radiological Protection, Publication 1, Elsevier, Oxford (7). [3] NATIONAL COUNCIL ON RADIATION PROTECTION AND MEASUREMENTS, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedure for Their Assessment, Dosimetry and Treatment, Report No. 156, NCRP, Bethesda (7). [4] BREUSTEDT, B., et al., Modeling the effects of decorporation-therapy with DTPA after incorporation of actinides, in these Proceedings (8). [5] INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION, Limits for Intakes of Radionuclides by Workers: Part I, Publication 3, Pergamon Press,Oxford, (1979). [6] BERKOVSKI, V., et al., Internal Dosimetry Support System: Multipurpose Research Computer Code, Radiat Prot Dosim. 79 (1998) 371-374. [7] BIRCHALL, A., et al., IMBA Professional Plus: a flexible approach to internal dosimetry, Radiat. Prot. Dosim. 125 (7) 194-197. [8] BARRETT, P.H.R., et al., SAAM II: Simulation, analysis, and modeling software for tracer and pharmacokinetic studies, Metab. Clin. Exp. 47 (1998) 484-492. [9] WOLFRAM RESEARCH INC., Mathematica. Version 4., Wolfram Research Inc., Champaign, Illinois (1999). [1] LEGGETT, R.W., ECKERMAN, K.F., A systemic biokinetic model for polonium, Sci. Total Environ. 275 (1) 19-125. [11] INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION, Age-dependent DOses to Members of the Public from Intake of Radionulides, Publication 67, Pergamon Press, Oxford (1993). [12] LEGGETT, R.W. et al., Mayak worker study: an improved biokinetic model for reconstructing doses from internally deposited plutonium, Rad. Res. 164 (5) 111-122. [13] LUCIANI, A., POLIG, E. Verification and modification of the ICRP-67 model for plutonium dose calculation, Health Phys. 78 () 33-31. [14] GIUSSANI, A., A recycling systemic model for the biokinetics of molybdenum radionuclides, Sci. Total Environ. in press, doi: 1.116/j.scitotenv.8.6.19 (8) [15] GREITER, M., Study of the biokinetics of zirconium isotopes in humans and its relevance to internal dosimetry, Diploma Thesis, Technische Universität München (8). [16] NOßKE, D., et al., The work of the CONRAD Task Group 5.2: Research studies on biokinetic models, Radiat. Prot. Dosim. 127 (7) 93-96. [17] NOßKE, D., et al., Development implementation and quality assurance of biokinetic models within CONRAD, Radiation Prot. Dosim. in press (8). 1