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.

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.

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.

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.

Competitive binding of Pu and Am with bone mineral and novel chelating agents.

Effective direct removal of actinides such as Pu and Am from bone in vivo has not been accomplished to date, even with the strong chelating agents CaNa3DTPA or ZnNa3DTPA. This study, using an established in vitro system, compared removal of Pu and Am bound to bone mineral by ZnNa3DTPA and 10 chelating agents designed specifically to sequester actinides, including Pu and Am. Ligands tested were tetra, hexa, and octadentate, with linear or branched backbones containing sulfocatechol [CAM(S)], hydroxycatechol [CAM(C)], hydroxipyridinone (1,2-HOPO, Me-3,2-HOPO), or hydroxamate functional groups. The wide range of Pu and Am removal exhibited by the test ligands generally agreed with their metal coordination and chemical properties. The most effective agents for Pu (100 microM concentration, 24-48 h contact) are all octadentate as follows: 3,4,3-LICAM(S) (54% unbound); 3,4,3-LICAM(C) (6.2%); 3,4,3-LI(1,2-HOPO) (3.8%); H(2,2)-(Me-3,2-HOPO) (2.2%) and DFO-(1,2-HOPO) (1.8%). The other ligands removed less than 1% of the bound Pu; and ZnNa3DTPA removed only 0.086%. The most effective ligands for Am removal (100 microM, 24-48 h contact) are as follows: octadentate H(2,2)-(Me-3,2-HOPO) (21% unbound); 3,4,3-LI(1,2-HOPO) (14.5%) and 3,4,3-LICAM(C) (5.9%); hexadentate TREN-(Me-3,2-HOPO) and TREN-(1,2-HOPO) (9.6%); and tetradentate 5-LIO(Me-3,2-HOPO) (5.2%). Am removal by ZnNa3DTPA was about 1.4%. Among the ligands presently considered for possible human use, only 3,4,3-LI(1,2-HOPO) removed potentially useful amounts of both Pu and Am from bone mineral.

Assessing the uniformity of plutonium alpha radiation dose in human lung: the Mayak experience.

Radiation-induced lung cancer risk is currently estimated based on epidemiological data from populations exposed either to relatively uniform, low-LET radiation, or from uranium miners who inhaled radon and its progeny. Inhaled alpha-emitting radionuclides (e.g. Pu and Am) produce distinctive dose patterns that may not be adequately modelled at present. Thus the distribution of Pu is being measured in formalin-fixed autopsy lung tissue from former workers at the Mayak Production Association, and which is maintained in a tissue archive at SUBI. Lungs are sampled using contemporary stereological techniques and Pu particle activities and locations are determined using quantitative autoradiography and morphological identification of lung structures. To date, > 80% of Pu particles have been observed in parenchymal lung tissues with higher concentrations being found in scar tissue. Concentrations of Pu particles in conducting airways are uniformly low, thus indicating that long-term-retained Pu particles are non-uniformly distributed in human lung, mostly in the parenchyma.

Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway.

Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.

Effect of flow rate on particle deposition in a replica of a human nasal airway.

Charge-coupled device (CCD) imaging technology was used to observe how the spatial deposition patterns of inhaled aerosols changed as a function of rate of airflow through the airway. This technology allows the experimenter to measure local particle deposition patterns of different sized fluorescent particles at different flow rates in a full-scale multisection replica of a human nasal airway. Total particle deposition efficiencies and particle deposition patterns were measured in the nasal airway for 5.5-microm-diameter particles at constant flow rates of 10, 20, 30, and 40 L/min. Images of fluorescing particles on each plate of the exposed model were taken with a CCD camera and combined to form three-dimensional particle deposition patterns. Total particle deposition efficiency as measured with the model was found to be consistent with in vivo data. Impaction was found to be the dominant mechanism by which 5.5-microm-diameter particles deposit within the model, in agreement with published inhalation data.

Review and critical analysis of available in vitro dissolution tests.

The procedures recommended in Publications 30 and 66 by ICRP for calculating radiation doses from inhaled or ingested radionuclides include classification of material on the basis of different parameters, among which transportability plays a major role, The allocation of transportable Classes or absorption Types should, whenever possible, be based on animal or human data. However, when such in vivo data are unavailable, it becomes appropriate to consider the use of other approaches, among which in vitro dissolution techniques are reasonable alternatives. This paper reviews and critically analyzes in vitro dissolution techniques that have been described historically and recommends methods shown to be useful in estimating the in vivo solubility of radioactive particles.

Comparative stochastic effects of inhaled alpha- and beta-particle-emitting radionuclides in beagle dogs.

The stochastic effects of inhaled, insoluble particles of alpha- or beta-particle-emitting radionuclides were compared in dogs. Male and female beagle dogs were exposed briefly by nasal inhalation to relatively insoluble aerosols of (239)PuO(2) or (144)Ce in fused aluminosilicate particles (FAP) and observed for cancer for their lifetimes. The initial lung burden and retention of each radionuclide was determined by whole-body counting of the emissions from (144)Ce-(144)Pr- or (169)Yb-labeled (239)PuO(2). Lung doses were calculated for each dog from these data. The lung doses ranged from 0.21 to 1200 Gy for (144)Ce FAP and 1.6 to 58 Gy for (239)PuO(2). Dogs with doses to the lung of about 60 Gy or greater from (144)Ce or about 2 Gy or greater from (239)PuO(2) had an increased incidence of lung carcinomas. In dogs exposed to (144)Ce FAP, three organs were targets for neoplasia: lung, tracheobronchial lymph nodes, and heart. The insoluble FAP carried to the lymph nodes draining the lung delivered high radiation doses to the nodes and adjacent heart, resulting in hemangiosarcomas of these organs. In the lung, high radiation doses induced hemangiosarcomas and carcinosarcomas. At lower doses, carcinomas of various histological patterns were induced in the lung. In dogs exposed to (239)PuO(2), the lung was the sole target organ for neoplasia. Nearly all of these neoplasms were carcinomas of various histological patterns. These results indicated that relatively low doses of alpha-particle radiation can induce pulmonary cancers, but relatively large doses of beta-particle radiation are required. In addition, inhaled beta-particle emitters can also induce cancers in lung-associated lymph nodes and heart at these larger absorbed radiation doses.