A BRIEF OVERVIEW OF COMPARTMENTAL MODELING FOR INTAKE OF PLUTONIUM VIA WOUNDS.

The aim of this study is to present several approaches that have been used to model the behavior of radioactive materials (specifically Pu) in contaminated wounds. We also review some attempts by the health physics community to validate and revise the National Council on Radiation Protection and Measurements (NCRP) 156 biokinetic model for wounds, and present some general recommendations based on the review. Modeling of intake via the wound pathway is complicated because of a large array of wound characteristics (e.g. solubility and chemistry of the material, type and depth of the tissue injury, anatomical location of injury). Moreover, because a majority of the documented wound cases in humans are medically treated (excised or treated with chelation), the data to develop biokinetic models for unperturbed wound exposures are limited. Since the NCRP wound model was largely developed from animal data, it is important to continue to validate and improve the model using human data whenever plausible.

Efficacy of Prussian blue on 137Cs decorporation therapy.

Prussian blue (PB) is an efficient drug for enhancing cesium elimination from the body. Literature data on the efficacy of PB treatment in dosages that vary from 1-10 g d was reviewed. Cesium biokinetics was simulated using a detailed systemic biokinetic model. The same model was used to simulate the maximum action of PB by interrupting the enterohepatic circulation. Model results reproduced reasonably well the literature data on the efficacy of PB administered to humans after incidental cesium intakes, as well as results from animal experiments. Maximum efficiency of the reduction of the long-term half-time is obtained with the administration of 3 g d PB to the adult. Maximum efficiency of reducing the Cs body burdens is obtained when PB is administered on the first day after the intake, due to the increase of the short-term elimination of cesium. The model predicts that reduction of the long-term half-life is not affected by the time after intake that PB is administered, as long as it is given within the interval from 1 h to 1 y after the intake.

Uncertainties in internal doses calculated for Mayak workers--a study of 63 cases.

This study makes use of 63 cases of Mayak workers exposed to Pu-239 with autopsy data and some late-time urine bioassay data. In addition, air-concentration data--used to construct monthly average values--are available for each case, which provide the time dependence and potential magnitudes of normal inhalation intakes for each case. The purpose of the study is to develop and test Bayesian methods of dose calculation for the Mayak workers. The first part of the study was to quantitatively characterise the uncertainties of the bioassay data. Then, starting with three different published biokinetic models, the data are fit by varying intake and model perturbation parameters, e.g., parameters influencing the lung, thoracic lymph nodes, liver and bone retention. Statistical self-consistency arguments are used to check the measurement uncertainty parameters within the Poisson-lognormal model. The second part of the study is to set up and test Bayesian dose calculations, which use the point determinations of biokinetic parameters from the study cases within a discrete, empirical Bayes approximation. The main conclusion of the study is that these methods are now ready to be applied to the entire Mayak worker population.

IMPDOS (improved dosimetry and risk assessment for plutonium-induced diseases): internal dosimetry software tools developed for the Mayak worker study.

A collection of software tools developed for the Mayak worker study is described. IMPDOS is software for modelling, data analysis, and activity and dose calculations using the bioassay and postmortem data from Mayak workers provided by Southern Urals Biophysics Institute. The capabilities include: parameter fitting of data for individual cases, Bayesian dose calculations using the fit results for collections of cases with extensive data as a biokinetic prior, and database storage of results for retrieval, analysis and interpretation.

A study of early Los Alamos internal exposures to plutonium.

Internal dose caused by exposure to (239)Pu/(240)Pu is calculated for a group of 210 former Los Alamos workers who participated in the urine bioassay programme during the years 1944-45. An iterative Bayesian procedure is employed, where the distribution of intake amounts resulting from an initial calculation is used to define a prior probability distribution of inhalation intakes for an iterated second calculation. The urine bioassay data from this time period were not of high quality, and the more accurate intake prior tempers the effect of spurious high samples, which were probably caused by sample contamination.

Comparison of dose estimation from occupational exposure to 239Pu using different modelling approaches.

Several approaches are available for bioassay interpretation when assigning Pu doses to Mayak workers. First, a conventional approach is to apply ICRP models per se. An alternative method involves individualised fitting of bioassay data using Bayesian statistical methods. A third approach is to develop an independent dosimetry system for Mayak workers by adapting ICRP models using a dataset of available bioassay measurements for this population. Thus, a dataset of 42 former Mayak workers, who died of non-radiation effects, with both urine bioassay and post-mortem tissue data was used to test these three approaches. All three approaches proved to be adequate for bioassay and tissue interpretation, and thus for Pu dose reconstruction purposes. However, large discrepancies are observed in the resulting quantitative dose estimates. These discrepancies can, in large part, be explained by differences in the interpretation of Pu behaviour in the lungs in the context of ICRP lung model. Thus, a careful validation of Pu lung dosimetry model is needed in Mayak worker dosimetry systems.

Internal dose assessment data management system for a large population of Pu workers.

This paper describes the design and implementation of the Los Alamos National Laboratory (LANL) dose assessment (DA) data system. Dose calculations for the most important radionuclides at LANL, namely plutonium, americium, uranium and tritium, are performed through the Microsoft Access DA database. DA includes specially developed forms and macros that perform a variety of tasks, such as retrieving bioassay data, launching the FORTRAN internal dosimetry applications and displaying dose results in the form of text summaries and plots. The DA software involves the following major processes: (1) downloading of bioassay data from a remote data source, (2) editing local and remote databases, (3) setting up and carrying out internal dose calculations using the UF code or the ID code, (3) importing results of the dose calculations into local results databases, (4) producing a secondary database of 'official results' and (5) automatically creating and e-mailing reports. The software also provides summary status and reports of the pending DAs, which are useful for managing the cases in process.

In vitro dissolution study of plutonium in aerosol particles from the Mayak PA: a tool for individualised dose estimates.

Chronic inhalation of Pu particles during Mayak processing is a potential concern for workers. Of the many particle properties that affect individualised dose estimates, particle solubility in lung fluids can be most important. This study compares in vitro dissolution rates of several plutonium industrial compounds present at different stages of the Mayak processing cycle using three different solvents. The results are then used to develop values of absorption parameters for individual dose assessments. In this study, the dissolution rates of nitrate, oxide and mixed plutonium aerosols were determined using a serum ultrafiltrate stimulant (SUF), phagolysosomal simulant fluid and Ringer's solution, all using a static system. According to the results obtained with SUF, Pu nitrate is absorbed into the blood to a larger extent than predicted using model parameters currently applied for Mayak workers. Absorption into the blood of 21.5 vs. 3% of deposited nuclide as current model predicts results in underestimation of systemic burden and overestimation of the lung dose. These data are being used to provide improved retrospective dose assessments for inhaled plutonium aerosols.

Worldwide bioassay data resources for plutonium/americium internal dosimetry studies.

Biokinetic models are the scientific underpinning of internal dosimetry and depend, ultimately, for their scientific validation on comparisons with human bioassay data. Three significant plutonium/americium bioassay databases, known to the authors, are described: (1) Sellafield, (2) Los Alamos and (3) the United States Transuranium Registry. A case is made for a uniform standard for database format, and the XML standard is discussed.

Updating the ICRP human respiratory tract model.

The ICRP Task Group on Internal Dosimetry is developing new Occupational Intakes of Radionuclides (OIR) documents. Application of the Human Respiratory Tract Model (HRTM) requires a review of the lung-to-blood absorption characteristics of inhaled compounds of importance in radiological protection. Where appropriate, material-specific absorption parameter values will be given, and for other compounds, assignments to default Types will be made on current information. Publication of the OIR provides an opportunity for updating the HRTM in the light of experience and new information. The main possibilities under consideration relate to the two main clearance pathways. Recent studies provide important new data on rates of particle transport from the nasal passages, bronchial tree (slow phase) and alveolar region. The review of absorption rates provides a database of parameter values from which consideration can be given to deriving typical values for default Types F, M and S materials, and element-specific rapid dissolution rates.

Internal dosimetry verification and validation database.

Simulated-data internal dosimetry cases for use in intercomparison exercises or as a software verification and validation tool have been published on the internet (www.lanl.gov/bayesian/software Bayesian software package II). A user may validate their internal dosimetry code or method using this simulated bioassay data. Or, the user may choose to try out the Los Alamos National Laboratory codes ID and UF, which are also supplied. A Poisson-lognormal model of data uncertainty is assumed. A collection of different possible models for each nuclide (e.g. solubility types and particle sizes) are used. For example, for 238Pu, 14 different biokinetic models or types (8 inhalation, 4 wound and 2 ingestion) are assumed. Simulated data are generated for all the assumed biokinetic models, both for incidents, where the time of intake is known, and for non-incidents, where it is not. For the dose calculations, the route of intake, but not the biokinetic model, is considered to be known. The object is to correctly calculate the known true dose from simulated data covering a period of time. A 'correct' result has been defined in two ways: (1) that the credible limits of the calculated dose include the correct dose and (2) that the calculated dose is within a factor of 2 of the correct dose.

Characterization of phagolysosomal simulant fluid for study of beryllium aerosol particle dissolution.

A simulant of phagolysosomal fluid is needed for beryllium particle dissolution research because intraphagolysosomal dissolution is believed to be a necessary step in the cellular immune response associated with development of chronic beryllium disease. Thus, we refined and characterized a potassium hydrogen phthalate (KHP) buffered solution with pH 4.55, termed phagolysosomal simulant fluid (PSF), for use in a static dissolution technique. To characterize the simulant, beryllium dissolution in PSF was compared to dissolution in the J774A.1 murine cell line. The effects of ionic composition, buffer strength, and the presence of the antifungal agent alkylbenzyldimethylammonium chloride (ABDC) on beryllium dissolution in PSF were evaluated. Beryllium dissolution in PSF was not different from dissolution in the J774A.1 murine cell line (p = 0.78) or from dissolution in another simulant having the same pH but different ionic composition (p = 0.73). A buffer concentration of 0.01-M KHP did not appear adequate to maintain pH under all conditions. There was no difference between dissolution in PSF with 0.01-M KHP and 0.02-M KHP (p = 0.12). At 0.04-M KHP, beryllium dissolution was increased relative to 0.02-M KHP (p = 0.02). Use of a 0.02-M KHP buffer concentration in the standard formulation for PSF provided stability in pH without alteration of the dissolution rate. The presence of ABDC did not influence beryllium dissolution in PSF (p = 0.35). PSF appears to be a useful and appropriate model of in vitro beryllium dissolution when using a static dissolution technique. In addition, the critical approach used to evaluate and adjust the composition of PSF may serve as a framework for characterizing PSF to study dissolution of other metal and oxide particles.

Plutonium microdistribution in the lungs of Mayak workers.

The degree of nonuniform distribution of plutonium in the human lung has not been determined; thus current dosimetric models do not account for nonuniform irradiation. A better scientific basis is needed for assessing the risk of developing radiation-induced disease from inhaled alpha-particle-emitting radionuclides. We measured the distribution of plutonium activity in the lung by autoradiography and related the activity to specific compartments of the lung. The study materials were lung specimens from deceased workers employed by the Mayak Production Association. The approach to analyzing these lung samples used contemporary stereological sampling and analysis techniques together with quantitative alpha-particle autoradiography. For the first time, plutonium distribution has been quantified in the human lung. The distribution of long-term retained plutonium is nonuniform, and a significant portion of plutonium was retained in pulmonary scars. In addition, a large fraction of plutonium was present in the parenchyma, where it was retained much longer than was estimated previously. The sequestration of plutonium particles in scars would greatly reduce the radiation exposure of the critical target cells and tissues for lung cancer. Thus the prolonged retention of plutonium in lung scars may not increase the dose or risk for lung cancer.

Efficacy of 3,4,3-LI(1,2-HOPO) for decorporation of Pu, Am and U from rats injected intramuscularly with high-fired particles of MOX.

This study aimed to assess the efficacy of 3,4,3-LI(1,2-HOPO) for reducing uranium, plutonium and americium in rats after intramuscular injection of (U-Pu)O2 particles (MOX). Sixteen rats were contaminated by intramuscular injection of a 1 mg MOX suspension and then treated daily for 7 d with LIHOPO (30 or 200 micromol kg(-1)) or DTPA (30 micromol kg(-1)). LIHOPO was inefficient for removing Pu, Am and U from the wound site. However, it reduced Pu retention in carcass and liver by factors of 2 and 6 respectively, and Am retention in carcass and liver by factors of 10 and 30. In contrast, the effect of LIHOPO on U was to decrease the retention in kidneys by a factor of 75. These results confirm that LIHOPO is a good candidate for use after contamination with MOX, in combination with localised wound lavage or surgical treatment aimed at removing most of the contaminant at the wound site.

Practical application of the ICRP Human Respiratory Tract Model.

The ICRP Publication 66 Human Respiratory Tract Model (HRTM) has been applied to calculate dose coefficients and bioassay functions using default values of parameters relating to the material and the subjects. The ICRP Task Group on Internal Dosimetry (INDOS) has developed a guidance document on application of the HRTM in situations where using specific information can improve dose assessments. INDOS is now revising the worker exposure documents (ICRP Publications 68 and 78). Application of the HRTM requires a review of the lung-to-blood absorption characteristics of inhaled radionuclides. Where appropriate, compound-specific absorption parameter values will be derived, and other compounds will be assigned to default Types using current information. Although no major changes to the HRTM are envisaged, this revision provides an opportunity for some refining and updating in the light of experience and new information.

Distribution of plutonium particles in the lungs of Mayak workers.

Lung tissues from workers at the Mayak Production Association were examined to determine the distribution of plutonium (Pu) activity in various lung compartments. Stereological sampling methods and autoradiography were used. Pu particles were identified by microscopic examination of autoradiographs and localised in one of six normal anatomic sites and two sites of fibrosis (parenchymal, non-parenchymal). Particle activity was determined by counting the number of tracks emanating from the particles. Over 50% of the Pu activity was localised in sites of fibrosis, which had significantly higher than average activity for the lung. Over 40% of the activity was in lung parenchyma. Activity in the bronchovascular interstitium was significantly lower than average. These results support the hypothesis that Pu activity is not uniformly distributed in the lung, with long-term retained particles concentrated in scars of the lung. The results may significantly affect estimates of dose from inhaled Pu.

Modifying the ICRP 66 dosimetry model based on results obtained from Mayak plutonium workers.

Results obtained in a study of the microscopic distribution of plutonium in the lungs of deceased Pu workers from the Mayak Production Association showed that the long-term retention of Pu was greater than predicted by the current ICRP 66 respiratory tract dosimetry model (HRTM). These data were therefore applied to the HRTM by modifying selected parameters, namely the transfer rate of Pu from the transformed state compartment and the fraction of Pu that transfers to the bound state compartment. Invoking the latter compartment into the modelling allowed a better representation of the long-term Pu retention as well as providing a convenient means of describing the workplace-specific characteristics of the different Pu aerosols found in the Mayak plant. In particular, the present model describes a significantly greater long-term retention of Pu nitrate aerosols in the lung compared with the Type M default.

Comparison of absorption after inhalation and instillation of uranium octoxide.

Values for the absorption parameters were compared after inhalation or intratracheal instillation of 1.5 microm mass median aerodynamic diameter (MMAD) 233U3O8 particles into the lungs of HMT strain rats. The two sets of parameter values were similar, as were the calculated dose coefficients and predicted biokinetics for workers. Hence the inhalation and instillation techniques can probably both be used to generate values of the absorption parameters for U3O8.

Scientific basis for the development of biokinetic models for radionuclide-contaminated wounds.

Radionuclide-contaminated wounds are of radiological concern because the wound provides a portal of entry of the radionuclide to the systemic circulation, and can also be a tissue at risk if sufficient dose is deposited at the wound site. Accordingly, a scientific committee established jointly by the US National Council on Radiation Protection and the International Commission on Radiological Protection has been developing an approach to describing the biokinetics of radionuclides deposited in wounds and calculating dose to the wound site. This paper focuses on the analyses, performed principally using experimental animal data, that have led to the development of a biokinetic model for deposited soluble radionuclides as well as more insoluble forms, such as colloids, particles and fragments. The available data for injected soluble materials have provided a basis for categorising 48 different elements (from Be to Cm and representing all of the chemical groups, except halogens and noble gases) into four distinct retention groups. In general, the data are adequate for developing a mechanistically based biokinetic model, whose application is exemplified for soluble radionuclides.

The application of Bayesian techniques in the interpretation of bioassay data.

The inverse problem of internal dosimetry is naturally posed as a problem of Bayesian inference. The Bayesian approach is of practical importance in three areas: (1) avoiding false positives in the detection of rare events, (2) the calculation of uncertainties, and (3) the calculation of multiple intakes, all of which are important for internal dosimetry. In this paper, the Bayesian approach to the interpretation of measurements is first reviewed using a simple conceptual example. Then, a simple 239Pu case using IMBA expert is discussed, and finally a current cutting-edge example is discussed involving real 238Pu data calculated with a Markov Chain Monte Carlo algorithm and with exact calculation of poisson likelihood functions.