Biokinetic Method on Simultaneous Intake of Radionuclides from Multiple Intake Scenarios for Application in Internal Exposures.

Biokinetics underlies the basis for assessment of internal exposures. This paper develops a biokinetic method on simultaneous intake of radionuclides from multiple intake scenarios in internal exposures. With numerical techniques that transform the whole biokinetics between the coupled and decoupled representations of the same problem, this method applies to coupled biokinetics with complex structures and has no restrictions of practical importance on the number of intake scenarios, the number of intake parent radionuclides and decay products, and the complexity of decay relationships between parent and progeny nuclides. For illustration, this method is applied to an assumed case of mixed inhalation and ingestion of weapon-grade plutonium material for reference workers that is focused on Pu and Am. Due to coupled biokinetics between the direct intake and ingrowth parts in different intake pathways, the multiple intake results (the contents of lungs, daily excretions, and cumulative contents) display richer behaviors as compared to single intake cases. This method benefits both the prospective and retrospective assessment of internal exposures for complex intake cases in actual applications.

Radiotoxicity of inhaled (239)PuO(2) in dogs.

Beagle dogs inhaled graded exposure levels of insoluble plutonium dioxide ((239)PuO(2)) aerosols in one of three monodisperse particle sizes at the Lovelace Respiratory Research Institute (LRRI) to study the life-span health effects of different degrees of alpha-particle dose non-uniformity in the lung. The primary noncarcinogenic effects seen were lymphopenia, atrophy and fibrosis of the thoracic lymph nodes, and radiation pneumonitis and pulmonary fibrosis. Radiation pneumonitis/ pulmonary fibrosis occurred from 105 days to more than 11 years after exposure, with the lowest associated alpha-particle dose being 5.9 Gy. The primary carcinogenic effects also occurred almost exclusively in the lung because of the short range of the alpha-particle emissions. The earliest lung cancer was observed at 1086 days after the inhalation exposure. The most common type seen was papillary adenocarcinoma followed by bronchioloalveolar carcinoma. These lung cancer results indicate that a more uniform distribution of alpha-particle dose within the lung has an equal or possibly greater risk of neoplasia than less uniform distributions of alpha-particle dose. The results are consistent with a linear relationship between dose and response, but these data do not directly address the response expected at low dose levels. No primary tumors were found in the tracheobronchial and mediastinal lymph nodes despite the high alpha-particle radiation doses to these lymph nodes, and no cases of leukemia were observed.

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.

A Monte Carlo method for calculating Bayesian uncertainties in internal dosimetry.

This paper presents a novel Monte Carlo method (WeLMoS, Weighted Likelihood Monte-Carlo sampling method) that has been developed to perform Bayesian analyses of monitoring data. The WeLMoS method randomly samples parameters from continuous prior probability distributions and then weights each vector by its likelihood (i.e. its goodness of fit to the measurement data). Furthermore, in order to quality assure the method, and assess its strengths and weaknesses, a second method (MCMC, Markov chain Monte Carlo) has also been developed. The MCMC method uses the Metropolis algorithm to sample directly from the posterior distribution of parameters. The methods are evaluated and compared using an artificially generated case involving an exposure to a plutonium nitrate aerosol. In addition to calculating the uncertainty on internal dose, the methods can also calculate the probability distribution of model parameter values given the observed data. In other words, the techniques provide a powerful tool to obtain the estimates of parameter values that best fit the data and the associated uncertainty on these estimates. Current applications of the methodology, including the determination of lung solubility parameters, from volunteer and cohort data, are also discussed.

COMPARING LUNGS, LIVER AND KNEE MEASUREMENT GEOMETRIES AT VARIOUS TIMES POST INHALATION OF 239Pu AND 241Am.

In-vivo measurement of Pu/241Am in workers is carried out by placing suitable detector above lungs, liver and skeleton, as major fraction of Pu/Am is transferred to liver and skeleton, after its retention in entry organ. In this work, committed effective dose (CED) corresponding to minimum detectable activity for Type M and Type S 239Pu/241Am deposited in these organs are presented and a monitoring protocol of organ measurement giving lowest CED at different time intervals post inhalation is described. We have observed, for Type M compounds, lung measurement is most sensitive method during initial days after exposure. Liver measurement yields lowest CED between 100 and 5000 d and beyond that bone measurement gives lowest CED. For Type S compounds lung measurement remains most sensitive method even up to 10 000 d post inhalation. This study will be useful for the assessment of CED due to internally deposited 239Pu/241Am in the workers.

Twenty-year follow-up of a Pu/Am inhalation case.

In 1983 a technician inhaled a mixture of Pu/Am aerosols in an accidental situation in the hotlab of Paul Scherrer Institute (PSI). This case is of interest for long-term follow-up since the technician was relatively young (26 y) at the time of intake, no chelating agent was used to alter retention and excretion and the inhaled activity was rather high (approximately 20 kBq of alpha emitters). The results obtained from periodic lung counts, urinary and faecal excretions as well as from some bone and liver measurements up to the year 2003 are presented. The measurements were mainly made at PSI but also at FZK Karlsruhe, Germany, and PNNL Hanford, USA. The evaluation and dose estimation of this case was done by several institutions, such as FZK, PNNL and NRPB in addition to PSI. Elements of the case were used in international biokinetic model validation programs by EURADOS/EULEP and IAEA and the 241Am data are given as example in Annex E of the ICRP 'Guide for the Practical Application of the ICRP Human Respiratory Tract Model'. An overview is given on the various results obtained by the different institutions using their models and methods for interpretation of the measured data. While estimation of intake varies by more than an order of magnitude, final estimation of effective committed dose varies only in the range of 0.5-1.5 Sv.

Comparisons of 239Pu inhalation doses calculated with ICRP 67 and proposed systemic models.

The International Commission on Radiological Protection (ICRP) has issued an age-specific systemic biokinetic model for plutonium (Pu), which was later modified to give better agreement with measured urinary excretion data. Recently, the current ICRP systemic Pu model was improved by Leggett et al. based on recently developed data. Incorporation of 239Pu in the human body may result in significant internal radiation exposure. In the present work, the retentions in organs and tissues, the equivalent dose and effective dose from 239Pu for workers and members of the public were estimated and compared under the current ICRP and the proposed models. 239Pu contents in liver and in other soft tissue calculated with the proposed model are higher than predicted by the ICRP model, whereas bone content is lower than predicted by the ICRP model. Based on the proposed model, the inhalation equivalent dose coefficient in some organs, e.g. liver and kidneys, is increased, but there is no significant change in the effective inhalation dose coefficients of 239Pu for workers and members of the public.

Practical action levels for chelation therapy in plutonium inhalation using nose swab.

The aim of this study is to propose action levels for chelation therapy in the case of inhalation of plutonium compounds using nose swabs. The relationship between the activity found in the nose swabs and early faecal excretion was investigated using actual cases at JAEA-NFCEL. The ratio was found to be in log-normal distribution. The action levels based on the activity of nose swab corresponding to 10 ALI (=200 mSv) are determined for the facilities at JAEA-NFCEL by using the relationship and specific information such as isotopic ratio and physicochemical characteristics of plutonium compounds.

Uncertainties in doses calculated according to ICRP recommendations after inhalation of 239PUO2 and early chest monitoring.

This study estimates uncertainties in Pu biokinetics and effective doses calculated after an acute inhalation exposure to 239PuO2 according to ICRP recommendations (default values for aerosols size and PuO2 dissolution parameters). This was performed using the most recently reported variations in model parameters and simulations after a Monte Carlo approach. Without chest monitoring, uncertainties in thoracic retention and plutonium excretion was 8-10 (95% confidence interval as the ratio between 97.5 and 2.5 percentiles of the lognormal distributions) up to 900 d after exposure. Early chest monitoring reduces significantly the uncertainties in plutonium biokinetics and doses which remain within a 95% confidence interval of 2.3 as compared with 6.6, without monitoring. Analysis of bioassay data previously reported shows that the dose delivered to some individuals can be out of the confidence interval, which was mostly due to an inhibition of the late mechanical clearance of the alveolar interstitium.

Decorporation of plutonium by pulmonary administration of Ca-DTPA dry powder: a study in rat after lung contamination with different plutonium forms.

This study evaluates the decorporation efficacy of a pulmonary administration of a new Ca-DTPA (diethylenetriaminepentaacetic acid) dry powder (18 micromol kg(-1) of body mass) after pulmonary contamination of rats with different Pu compounds. After inhalation of PuO2, a delayed intratracheal administration of DTPA cannot reduce significantly the retention of Pu in the lungs but limits its transfer in liver and skeleton. After pulmonary contamination by Pu nitrate, early insufflation of the DTPA powder appears twice as more efficient than an i.v injection of DTPA (30 micromol kg(-1)) to reduce Pu retention in the lungs and is as effective as i.v. injection to limit the extrapulmonary deposit. In contrast, a delayed administration of DTPA cannot reduce the lung or extrapulmonary retention. In conclusion, the improvement of aerodynamic properties of DTPA powder leads to an increase of DTPA amount deposited in the lungs and enhances the body decorporation.

Comparison of ICRP 67 and Other Plutonium Systemic Model Predictions with the Biokinetic Data from Nonhuman Primates.

Despite the presence of a relatively large amount of human data available on the metabolism of plutonium, the experimental animal data is still important in constructing and parameterizing the biokinetic models. Recognizing this importance, the biokinetic data obtained from studies done by P.W. Durbin in nonhuman primates (NHP) were evaluated against the ICRP 67 systemic model and the two human models developed thereafter. The default transfer rates recommended for adult humans in these models predict the urinary excretion in NHP to a certain extent. However, they were unable to describe the fecal excretion rates several days post intake and the activities in skeleton and liver at the time of the death. These inconsistencies between the human reference models and the NHP biokinetic data are the result of metabolic and physiological differences between the species, as demonstrated by early biokinetic studies.

Uncertainties analysis of doses resulting from chronic inhalation of plutonium at the Mayak production association.

A method is presented to determine the uncertainties in the reported dose due to incorporated plutonium for the Mayak Worker Cohort. The methodology includes errors generated by both detection methods and modeling methods. To accomplish the task, the method includes classical statistics, Monte Carlo, perturbation, and reliability groupings. Uncertainties are reported in percent of reported dose as a function of total body burden. The cohort was initially sorted into six reliability groups, with "A" being the data set that the investigators are most confident is correct and "G" being the data set with the most ambiguous data. Categories were adjusted based on preliminary calculation of uncertainties using the sorting criteria. Specifically, the impact of transportability (the parameter used to describe the transport of plutonium from the lung to systemic organs) was underestimated, and the structure of the sort was reorganized to reflect the impact of transportability. The finalized categories are designated with Roman numerals I through V, with "I" being the most reliable. Excluding Category V (neither bioassay nor autopsy), the highest uncertainty in lung doses is for individuals from Category IV-which ranged from 90-375% for total body burdens greater than 10 Bq, along with work histories that indicated exposure to more than one transportability class. The smallest estimated uncertainties for lung doses were determined by autopsy. Category I has a 32-38% uncertainty in the lung dose for total body burdens greater than 1 Bq. First, these results provide a further definition and characterization of the cohort and, second, they provide uncertainty estimates for these plutonium exposure categories.

[Combined prophylactic administration of riboxin and algisorbum at 239Pu intake into gastrointestinal tract of rats].

The present study is devoted to the investigation of effectiveness of combined prophylactic administration of riboxin and algisorbum at 239Pu per oral intake and possible mechanisms of their interaction, and also to comparative estimation of effectiveness of combined administration of the preparations at per oral and intra peritoneal methods of riboxin introduction. The experiments have been carried out on white nonlinear rats. Riboxin (per oral and intra peritoneal) and algisorbum (per oral) have been introduced to the rats both separately and combined before per oral 239Pu introduction. Data obtained as a result of the investigation showed that combined riboxin and algisorbum introduction into gastrointestinal tract before 239PU intake lead to greater decrease in the plutonium content in the organs of deposition than single algisorbum administration. Intra peritoneal riboxin introduction reduced effectiveness of per oral algisorbum administration in plutonium binding in GI tract. Efficiency of combined riboxin and algisorbum administration in the reduction of 239Pu accumulation in organs depends on the method of riboxin introduction and develops only at per oral introduction.

Alveolar macrophage kinetics after inhalation of 239PuO2 by CBA/Ca mice: changes in synthesis of DNA.

For workers in the nuclear industry, the primary route for the entry of radioactive materials into the body is by inhalation, and the rate of clearance of particles from the pulmonary region of the lung is an important factor in determining radiation dose. It is the function of alveolar macrophages (AM) to maintain the sterility of the lung and to remove insoluble particles from the respiratory surfaces and airways. The AM population is not static, and under normal conditions the loss of macrophages from the alveoli via the conducting airways is balanced by renewal. Studies of the effects of external irradiation on the kinetics of AM are numerous, but to date little is known about the effects of inhaled radioactive particles. In this investigation the effects of inhaled 239PuO2 (plutonium dioxide) particles on the synthesis of DNA by AM were studied at times up to 77 days after exposure. We also measured the number of cells recovered by bronchoalveolar lavage and the incidence of AM with nuclear aberrations. The latter provides a sensitive indicator of the effects of radiation. One of the earliest effects observed after exposure to 239PuO2 is a reduction in the number of AM recovered by lavage. This reduction is associated with a 3-fold reduction in the proportion of AM undergoing DNA synthesis at early times after exposure. The overall mean pulse labeling index of AM recovered from sham-exposed mice is 1.68%, and no trend is observed with time.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of inhaled alpha-emitting actinides on mouse alveolar macrophages.

The effects of inhaled alpha-emitting actinides on the alveolar macrophage (AM) population of the rodent lung are reviewed and, in particular, of the effects of 239PuO2 on murine AM. The effects discussed include changes the AM pool size, macrophage diameter, mobility, phagocytic competence, and enzyme content. Finally, similarities in the dose-response relationships for the induction of nuclear aberrations by alpha emitters and in the induction of lung tumors by the same materials are noted.

Promotion of pulmonary carcinogenesis by plutonium particle aggregation following inhalation of 239PuO2.

Promotion of lung tumor formation from inhaled 239PuO2 in rats may be associated with aggregation of plutonium particles near bronchioles. The relationship of plutonium particle aggregation in the lung and the development of lung tumors after inhalation of 239PuO2 was studied in 664 life span rats with mean lung doses ranging from 0.35 to 20 Gy. Plutonium particle concentration and aggregation were determined from autoradiographic sections of the left lung lobe. The increase in particles/cm2 and mean number of particles per aggregate up to 20 Gy were directly proportional to lung dose. Aggregates with greater than 25 particles increased linearly with dose from 0.2% at 1.4 Gy to 8.2% at 20 Gy, in a pattern similar to increasing severity of pulmonary fibrosis and incidence of lung tumors. Lung tumor incidence increased from about 6% at 1.4 Gy to 83% at 8 Gy; no further increase in lung tumors was seen at doses greater than 8 Gy. Maximum lung tumor incidence at 8 Gy corresponded to a particle concentration of 130/cm2 and four particles/aggregate with 4% of aggregates having greater than 25 particles. Aggregation of inhaled plutonium particles in clusters of greater than 25 particles resulted in daily doses of only a few centigray to focal tissue regions containing clustered particles, yet these doses appeared sufficient to cause pulmonary fibrosis and promotion of pulmonary carcinogenesis.

Distribution and biological effects of inhaled 239Pu(NO3)4 in cynomolgus monkeys.

Twenty male cynomolgus monkeys were exposed by inhalation either to an aerosol of 239Pu(NO3)4 to produce projected initial lung burdens of either 40, 10, or 4 kBq or to a carrier aerosol as a control. Animals died or were sacrificed at 0.01, 1, 3, 6, 12, 24, 40, and 99 months after inhalation, and the distribution and biological effects of the 239Pu were determined. The 239Pu cleared efficiently from the lungs so that less than 0.05 kBq remained at 99 months after exposure to 40 kBq. Total skeletal 239Pu activity was nearly constant after the first year, but the fraction of the body burden in skeleton at sacrifice increased with time up to 99 months because of clearance from other organs. Plutonium in the liver increased to a peak at 1 year and then decreased to about 10% of the peak value at 99 months. Plutonium in the testes was localized in the interstitial tissue with only 0.01 to 0.002% of the projected lung burden remaining in testes at 99 months after inhalation. Three animals exposed to 40 kBq of 239Pu died of radiation-related pulmonary pneumonitis and fibrosis. A primary papillary adenocarcinoma of the lung was identified in one animal exposed to 40 kBq initial lung burden and sacrificed 99 months after inhalation. The frequency of chromosome aberrations in blood lymphocytes was significantly elevated only in monkeys with projected deposits of 40 kBq of 239Pu. There was no change in aberration frequency in other exposure groups as a function of inhaled activity, time after exposure, or calculated total dose to the lungs. Only in monkeys that had marked radiation-induced pathological changes in the lung did the frequency of chromosome-type aberrations increase significantly, to a value about twice the control level. In cynomolgus monkeys, chromosome aberration frequency in blood lymphocytes is not a good indicator of radiation dose or damage from inhaled soluble plutonium.

Retention of plutonium in the beagle after gastrointestinal absorption.

A 0.01 M bicarbonate solution containing 130 nCi (approximately 5 kBq) of 237Pu (90% hexavalent, 93% ultrafilterable) was administered via gelatin capsule to six adult male beagles following a 21-hr fast. The dogs were sacrificed after 5-6 weeks and the percentage of the administered plutonium retained in the liver plus skeleton and its distribution within the skeleton were determined. The mean amount retained in these tissues was (0.063 +/- 0.006)% of the administered dose. The mean amounts of plutonium in the liver and the skeleton were approximately equal, and the distribution within the skeleton was similar to that observed by other workers following either intravenous injection or inhalation. Our value for plutonium retention by the dog is about a factor of three less than the values we have reported for rodents. It is a factor of 7 greater than the product of the values for gastrointestinal absorption (f1) and fractional retention (f2) recommended by the ICRP for man.

Retention of 239Pu in the mouse lung and estimation of consequent dose following inhalation of sized 239PuO2.

The retention of 239Pu in the lungs of SAS/4 mice following inhalation exposure to sized 239PuO2 particles is described. When the initial alveolar deposition (IAD) was less than 200 Bq, retention of 239Pu could be described by a two-component exponential expression, about 90% being cleared with a half-time of about 40 days and the remainder with a half-time of about 150 days. Similar amounts of 239Pu were retained up to 3 months with IADs greater than 800 Bq, but clearance was impaired thereafter, the half-time of the second component increasing to about 720 days. The retention of 239Pu was independent of the particle size of the administered 239PuO2. Studies of the retention of 239Pu by individual lobes indicated that there were intrinsic interlobar differences which were enhanced at higher IADs. Lung clearance was also studied by the measurement of 239Pu in feces excreted by groups of mice in the period immediately prior to sacrifice. The estimation of radiation dose to lung is discussed.

Proliferation of mouse lung epithelial cells after inhalation exposure to 239PuO2.

The aim of this study was to investigate cell proliferation in mouse lungs up to 12 weeks after exposure to 239PuO2. CBA mice were exposed (nose-only) to 239PuO2 to give an initial alveolar deposit of 500 Bq. The main morphological change observed was hypertrophy of Type II cells. The labeling index (LI) of alveolar cells, which was monitored by immunocytochemical detection of DNA-incorporated 5-bromo-2'-deoxyuridine (BrdU), increased with time after exposure and was eight times that of controls by the end of the study. The LI of the bronchiolar cells was increased markedly after exposure but declined thereafter. The cell proliferation patterns of the alveolar and bronchiolar cells (mainly Type II and Clara cells, respectively) could be related to the distribution and clearance patterns of the deposited particles of 239PuO2 and to the effects of alpha-particle radiation on these cells. This study showed that significant cellular changes, particularly cell proliferation, occurred at early times after exposure of mouse lung to 239PuO2. However, the relevance of these results to the late carcinogenic effects of 239Pu could not be assessed because of the limited duration of this study.