Identification of Volume of Distribution for 239Pu in Rats.

ABSTRACT: The work within identifies the volume of distribution (VD) of plutonium using data from studies in which rats were administered an intravenous bolus injection of 239Pu4+-citrate. The research investigated two separate datasets. Data published by Durbin and colleagues in "Plutonium Deposition Kinetics in Rats" and studies conducted by Lovelace Respiratory Research Institute (LRRI) were examined. The goal of this research was to identify a value of VD consistent with the known biological behavior of plutonium. The identified VD is necessary to develop a physiologically-based pharmacokinetic (PBPK) model. The creation of a PBPK model describing the behavior of plutonium in the body enables the comparison of transfer rates to validate the biokinetic models currently in use for internal dosimetry purposes. The VD of a substance describes the distribution between intracellular and extracellular fluid compartments, providing information such as cellular uptake and protein binding. The VD time profiles and values found using the Durbin data were consistent with known behavior of plutonium. The VD values found using data provided by LRRI were not consistent with known behavior of plutonium; however, the VD time profiles generated may still be of use for PBPK modeling.

137Cs Lake Sediment Depth Profiles and Inventories Within Four Lakes of Idaho's Sawtooth Wilderness.

A total of 68 sediment cores from four freshwater alpine lakes in Idaho's Sawtooth Wilderness were collected during the summer of 2017. The objectives of the study were to determine depth distributions of Cs in the cores using gamma spectrometry and to estimate the sedimentation rates of the lakes from the identified geochronological peaks linked to nuclear fallout. The Cs radioactivity above reference-area values was detected in all studied lakes. The maximum Cs concentrations measured in each lake's sediment ranged from 74.0 ± 6.09 to 255 ± 7.48 Bq kg. Factors such as elevation, latitude, and pH showed no correlation to total Cs deposition. However, the data developed during this investigation suggested that characteristics such as geological location or lake flushing patterns are important factors in the total Cs deposition observed. Three of the lakes had Cs sediment depth distributions that resembled the deposition pattern of weapons testing as a function of time. Mean sedimentation rate estimates ranged from 0.08 ± 0.3 to 0.1 ± 0.05 cm y and decreased with increasing altitude.

Optimization of the ICRP 67 and NCRP 156 Transfer Rates Applied to Nonhuman Primates Intramuscularly Injected With 241Am.

Nonhuman primates intramuscularly injected with Am have been investigated using the International Commission on Radiological Protection Report 67 model coupled with National Council on Radiation Protection and Measurements Report 156 model. Default parameters from these models were input into the Integrated Modules for Bioassay Analysis software to predict the intake and skeleton retention in 20 tested nonhuman primates. The predictions generated were compared to the experimental data from the Durbin nonhuman primate studies. A previous study conducted by Alomairy in 2017 indicated that the early behavior of Am(NO3)3 in wound cases can be explained using the default transfer rates. However, these transfer rates were not able to predict the intake and skeleton retention at the time of sacrifice after 100 d postintake due to differences in the amount of activity translocated or deposited in liver tissue and nonliver tissues (primarily skeleton). This is likely due to the physiological differences between the nonhuman primate and human. The objective of this study was to develop new transfer rate parameters for wound and systemic models in an effort to improve biokinetic predictions. Estimates of new transfer rates appropriate for nonhuman primate data were estimated by employing a companion software program called Integrated Modules for Bioassay Analysis Uncertainty Analyzer. During validation of the suggested transfer rates, it was observed that the optimized parameters predicted the intake in 66% of the tested animals used in this investigation. The activity retained in the skeleton improved in almost all cases where the differences between predicted and measured activity is less than 20%.

Application of the ICRP 67 and NCRP 156 Biokinetic Models to 241 Am Wound Data from Nonhuman Primates.

Distribution, retention, and excretion of intramuscularly injected Am citrate have been investigated in cynomolgus and rhesus nonhuman primates (NHP). Bioassay and retention data, obtained from experiments done by Patricia Durbin and her colleagues at Lawrence Berkeley National Laboratory, were evaluated against the International Commission on Radiological Protection (ICRP 67) Am systemic model coupled with to the National Council on Radiation Protection and Measurement wound model (NCRP 156). The default transfer rates suggested in these models were used with the urine and feces excretion data to predict the intake as well as liver and skeleton tissue contents at the time of death. The default models adequately predict the animals' urine bioassay data, but the injected activities were overpredicted by as much 4.41 times and underpredicted by as much as 0.99 times. Poor prediction has been observed in all cases using fecal excretion. The retained activity in the liver and skeleton were investigated using the same approach. It appears that the models predict the amount of the activity retention in the skeleton more accurately than in the liver. The fraction of predicted to measured activity at the time of death in the skeleton was over 1.0 in most cases, and accurate predictions were obtained in seven cases. The predicted activity in skeleton for these cases ranged from 2.7 to 17% overestimated activity and from 9 to 14% underestimated activity. NHPs' urine data and organ retention were compared with data from previously modeled baboons and beagle dogs. About 6% of the injected activity in baboons and beagle dog was excreted in urine and approximately 0.1% in feces in the first 24 h. The results from NHP are not different from excreta analysis in these other species. Urinary excretion in the cynomolgus, rhesus, and baboon NHP is the dominant pathway of Am clearance; however, fecal excretion is considered dominant in beagle dogs. The comparison between NHPs and humans is difficult due to the differences in the number of activities translocated or deposited in the liver tissue and nonliver tissues (primarily skeleton), in addition to the physiological differences between the NHPs and humans.

A Case Study of the NCRP 156 Wound Model of Embedded DU Using Data From Urine Uranium Concentrations of Wounded Veterans.

Depleted uranium (DU) munitions were initially used by the United States (U.S.) military during the first Persian Gulf War in 1991 in order to penetrate heavily armored vehicles. However, as a result of friendly fire, several U.S. military personnel received intakes from DU munitions. One of the ongoing concerns for these wounded veterans is the potential long-term exposure received from DU embedded fragments. The United States Army Institute of Public Health (AIPH) is the first laboratory that analyzes the urine bioassays from Army Soldiers that are injured with DU fragments. The United States Air Force School of Aerospace Medicine also evaluates bioassays from DU injuries. The urine bioassay data collected by AIPH was evaluated using the NCRP 156 wound model coefficients for the DU-Wafer, Fragment, and Particle models. The maximum likelihood method was used in the Integrated Modules for Bioassay Analysis (IMBA-PPAE) to calculate the estimates of intake and tissue doses. Evaluating the three models for wound retention, the DU-Wafer and Fragment model yielded a credible fit to the bioassay data. Comparing the two models, the DU-Wafer model fits the data better than the Fragment model when comparing their autocorrelation coefficient and chi-squared values of (P 1.73 × 10, c 4.83 × 10), (P 2.01 × 10, c 1.09), respectively. This evaluation supports the validity of both the DU-wafer model as well as the default fragmentation model proposed by NCRP 156.

Investigating Uranium Isotopic Ratios and Activity Ratios in Groundwaters in the State of Idaho.

Analyzing uranium isotopic and activity ratios can give valuable information for hydrologic and environmental studies such as insights to weathering processes, estimating water mixing ratios, and identifying water sources. The authors employed an inductively coupled plasma mass spectrometer (ICP-MS) to perform environmental level concentration measurements of isotopic uranium on 380 groundwater samples from various locations within the state of Idaho. The U:U uranium activity ratios (UAR) for these samples range between 0.91 and 6.21, which suggests that the parent U is not in equilibrium with its decay product U. The U:U isotopic ratio was also measured for each sample to confirm that there was no depleted or enriched uranium present. All 380 samples exhibited the natural isotopic ratios of U and U isotopes. Therefore, it was concluded that the U:U UARs reflect natural variations in the Idaho groundwater systems.

Plasma Retention and Systemic Kinetics of 90Sr Intramuscularly Injected in Female Nonhuman Primates.

Thirteen female Rhesus macaques were intramuscularly injected with Sr(NO3)2 diluted in sodium citrate solution. The biokinetic data from these animals were compared against the predictions of the NCRP 156 wound models combined with the ICRP systemic models. It was observed that the activities measured in plasma of these nonhuman primates (NHPs) were consistently lower than those predicted by the default human biokinetic models. The urinary excretion from the NHPs at times immediately after injection was much greater than that in humans. The fecal excretion rates were found to be in relatively better agreement with humans. Similarly, the activities retained in the skeleton of the NHPs were lower than those in humans. These differences were attributed to the higher calcium diet of the NHPs (0.03 to 0.12 g d kg body weight) compared to that of humans. These observations were consistent with the early animal and human studies that showed the effect of calcium on strontium metabolism, specifically urinary excretion. Strontium is preferentially filtered at a much higher rate in kidneys than calcium because it is less completely bound to protein than is calcium. These differences, along with large inter-animal variability, should be considered when estimating the behavior of strontium in humans from the metabolic data in animals or vice versa.

Behavior of Americium in Simulated Wounds in Nonhuman Primates.

An americium solution injected intramuscularly into several nonhuman primates (NHPs) was found to behave differently than predicted by the wound models described in the NCRP Report 156. This was because the injection was made along with a citrate solution, which is known to be more soluble than chlorides, oxides, or nitrates on which the NCRP Report was based. A multi-exponential wound model specific to the injected americium solution was developed based on the retention in the intramuscular sites. The model was coupled with the americium systemic model to interpret the urinary excretion data and assess the intake, and it was determined that the models were adequate to predict early urinary excretion in most cases but unable to predict late urinary excretion. This was attributed to the differences in the systemic handling of americium between humans and nonhuman primates. Information on the type of wounds, solubility, particle size, mass, chemical form, etc., should always be considered when performing wound dosimetry.

ICRP 67 Biokinetic Models for AM-241 Applied to Nonhuman Primates.

Between 1960 and 1985, Patricia Durbin and colleagues performed studies on the distribution of intravenously and intramuscularly injected Am citrate with dosages ranging from 16 to 32 kBq kg in 30 male and female non-human primates (NHP). Dr. Durbin died unexpectedly in March of 2009, leaving much of the extensive serial blood, bioassay, and autopsy data from these NHP studies unanalyzed. As part of the experimental design, serial blood samples were taken, and urine and feces samples were collected separately for the duration of the study. The measurements of urine, fecal excretion, blood samples, and organ burden data obtained from the animals were used to evaluate the transfer rates of the ICRP 67 biokinetic model for Am. Seven cases, in which the primates were administered Am citrate by intravenous injection, were evaluated using the ICRP 67 systemic model. There were differences ranging from 51.4% underestimated to 102.7% overestimated activity between the predicted intake, which was calculated using IMBA Professional Plus software and based upon the urine bioassay data and the actual activity. The difference between the predicted activity at the time of death in the liver and skeleton using IMBA professional software and the value of the measured activity at the time of death were also compared. Generally, the ratios of predicted activity in the liver and skeleton at the time of death to the measured activity were consistently more than 1. However, the ratios were less than 1 in the skeleton for animals that were sacrificed 2,199 and 973 d post injection. The posterior probability distributions for model parameters derived using WeLMoS method were inconsistent with the ICRP 67 default parameters. The prediction made based on the posterior probability distributions for model parameters derived using WeLMoS gave the best fit to these data; however, the modified parameters overestimated the activity in almost all cases. The difference between the predicted Am activity and the value of the measured activity may be due to the physiological age-related characteristics relative to the age of the animal at the time of the injection and early and long scarified time.

Investigating Uranium Concentrations in Groundwaters in the State of Idaho Using Kinetic Phosphorescence Analysis and Inductively Coupled Plasma Mass Spectrometry.

The determination of uranium concentrations in natural water samples is of great interest due to the environmental consequences of this radionuclide. In this study, 380 groundwater samples from various locations within the state of Idaho were analyzed using two different techniques. The first method was Kinetic Phosphorescence Analysis (KPA), which gives the total uranium concentrations in water samples. The second analysis method was inductively coupled plasma mass spectrometry (ICP- MS). This method determines the total uranium concentration as well as the separate isotope concentrations of uranium. The U/U isotopic ratio was also measured for each sample to confirm that there was no depleted or enriched uranium present. The results were compared and mapped separately from each other. The study also found that in some areas of the state, natural uranium concentrations are relatively high.

Biokinetics of Plutonium in Nonhuman Primates.

A major source of data on metabolism, excretion and retention of plutonium comes from experimental animal studies. Although old world monkeys are one of the closest living relatives to humans, certain physiological differences do exist between these nonhuman primates and humans. The objective of this paper was to describe the metabolism of plutonium in nonhuman primates using the bioassay and retention data obtained from macaque monkeys injected with plutonium citrate. A biokinetic model for nonhuman primates was developed by adapting the basic model structure and adapting the transfer rates described for metabolism of plutonium in adult humans. Significant changes to the parameters were necessary to explain the shorter retention of plutonium in liver and skeleton of the nonhuman primates, differences in liver to bone partitioning ratio, and significantly higher excretion of plutonium in feces compared to that in humans.

Application of NCRP 156 Wound Model and ICRP 67 Systemic Plutonium Model for Analysis of Urine Data from Simulated Wounds in Nonhuman Primates.

The predictions of the wound model described in NCRP Report No. 156, coupled with the systemic model described in ICRP 67, were compared with the actual urinary excretion data and wound retention data from nonhuman primates injected intramuscularly or subcutaneously with Pu(IV) citrate. The results indicated that the early behavior of Pu(IV) citrate in wounds can be adequately described by the default retention parameters for moderately retained radionuclides suggested by the report. The urinary excretion rates after 200 d post intake could not be described well by the parameters of any of the default wound models because of the differences in the systemic handling of plutonium by humans compared to nonhuman primates.

Biokinetics of 90Sr in Male Nonhuman Primates.

The current study tests the hypothesis that the biokinetics of Sr can be represented by simplification of the ICRP publication 78 Sr model. Default and proposed models were evaluated by their ability to predict injected activity and more thoroughly define the activity residing in the skeleton of rhesus monkeys. The data obtained from studies done by Patricia Durbin and her colleagues at the Lawrence Berkley National Laboratory were used to create a profile of the activity residing in the skeleton at the time of sacrifice. Post mortem data along with periodic whole body count data were used to optimize the biokinetic parameters using the Integrated Modules for Bioassay Analysis (IMBA), Weighted Likelihood Monte-Carlo Sampling (WeLMoS) program to better predict the intake and fit of the bioassay data. Analysis of the default ICRP 78 parameters resulted in an overprediction of activity in the skeleton for a male cohort by as much as 180%. Using Monte Carlo sampling methods, three models were developed and optimized for a composite cohort of male monkeys. Of the three developed models, one model proved to have the best predictive capabilities. The optimized model C obtained for the male cohort was then tested on a validation cohort to test predictive capabilities. Using the optimized model C parameters, the ability to predict activity in the skeleton was improved in comparison to ICRP 78. Prediction of the intake from bioassay data was also improved by a factor of 2 in comparison to ICRP 78. The results suggest that the modified transfer rates of model C could be used as default parameters for biokinetic nonhuman primate modeling and potentially extrapolated to humans.

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.

Strontium-90 Biokinetics from Simulated Wound Intakes in Non-human Primates Compared with Combined Model Predictions from National Council on Radiation Protection and Measurements Report 156 and International Commission on Radiological Protection Publication 67.

This study had a goal to evaluate the predictive capabilities of the National Council on Radiation Protection and Measurements (NCRP) wound model coupled to the International Commission on Radiological Protection (ICRP) systemic model for 90Sr-contaminated wounds using non-human primate data. Studies were conducted on 13 macaque (Macaca mulatta) monkeys, each receiving one-time intramuscular injections of 90Sr solution. Urine and feces samples were collected up to 28 d post-injection and analyzed for 90Sr activity. Integrated Modules for Bioassay Analysis (IMBA) software was configured with default NCRP and ICRP model transfer coefficients to calculate predicted 90Sr intake via the wound based on the radioactivity measured in bioassay samples. The default parameters of the combined models produced adequate fits of the bioassay data, but maximum likelihood predictions of intake were overestimated by a factor of 1.0 to 2.9 when bioassay data were used as predictors. Skeletal retention was also over-predicted, suggesting an underestimation of the excretion fraction. Bayesian statistics and Monte Carlo sampling were applied using IMBA to vary the default parameters, producing updated transfer coefficients for individual monkeys that improved model fit and predicted intake and skeletal retention. The geometric means of the optimized transfer rates for the 11 cases were computed, and these optimized sample population parameters were tested on two independent monkey cases and on the 11 monkeys from which the optimized parameters were derived. The optimized model parameters did not improve the model fit in most cases, and the predicted skeletal activity produced improvements in three of the 11 cases. The optimized parameters improved the predicted intake in all cases but still over-predicted the intake by an average of 50%. The results suggest that the modified transfer rates were not always an improvement over the default NCRP and ICRP model values.

Plutonium-DTPA Model Application with USTUR Case 0269.

A plutonium-DTPA (Pu-DTPA) biokinetic model was introduced that had originated from the study of a plutonium-contaminated wound. This work evaluated the extension of the Pu-DTPA model to United States Transuranium and Uranium Registry (USTUR) Case 0269 involving an acute inhalation of a plutonium nitrate aerosol. Chelation was administered intermittently for the first 7 mo as Ca-EDTA, mostly through intravenous injection, with Ca-DTPA treatments administered approximately 2.5 y post intake. Urine and fecal bioassays were collected following intake for several years. Tissues were collected and analyzed for plutonium content approximately 38 y post intake. This work employed the Pu-DTPA model for predicting the urine and fecal bioassay and final tissue quantity at autopsy. The Pu-DTPA model was integrated with two separate plutonium systemic models (i.e., ICRP Publication 67 and its proposed modification). This work illustrated that the Pu-DTPA model was useful for predicting urine and fecal bioassay, including final tissue quantity, 38 y post intake.

Selective inhibitory effects of 50-nm gold nanoparticles on mouse macrophage and spleen cells.

Nanoparticles (NP) are significant to multiple industrial processes, consumer products and medical applications today. The health effects of many different types of NP, however, are largely unknown. The purpose of this study was to test the effects of 50-nm gold NP coated with poly-N-vinylpyrrolidone (PVP) on mouse macrophage and spleen cells with and without lipopolysaccharide (LPS), testing the hypothesis that the NP would modulate immune responses without being overtly toxic. Gold NP had no effect on macrophage viability and, in the absence of LPS, they had no effect on tumor necrosis factor (TNF)-α production as measured by ELISA. The presence of LPS significantly increased the release of TNFα from the macrophages above no-treatment controls, but increasing gold NP concentration led to decreasing release of TNFα. The reactive oxygen species (ROS) produced by exposed macrophages were also reduced compared to untreated controls, both with and without LPS, suggesting some kind of oxygen radical scavenging. In splenocyte cultures, gold NP had no effect alone, but significantly reduced the release of interleukin (IL)-17 and TNFα triggered by LPS. These results suggest that the gold NP used here are not cytotoxic to immune cells at these concentrations, but may affect cellular responses to infection or inflammation by altering the balance of cytokines.

Proposed Modification to the Plutonium Systemic Model.

The currently accepted biokinetic model for plutonium distribution within the human body was recommended by the International Commission on Radiological Protection in publication 67. This model was developed from human and animal studies and behavioral knowledge acquired from other known bone-seeking radionuclides. The biokinetic model provides a mathematical means of predicting the distribution, retention, and clearance of plutonium within the human body that may be used in deriving organ, tissue, and whole body dose. This work proposed a modification to the ICRP 67 systemic model for plutonium that incorporated the latest knowledge acquired from recent human injection studies with physiologically based improvements. In summary, the changes included a separation of the liver compartments, removed the intermediate soft tissue-to-bladder pathway, and added pathways from the blood compartment to both the cortical and trabecular bone volumes. The proposed model provided improved predictions for several bioassay indicators compared to the ICRP 67 model while also maintaining its basic structure. Additionally, the proposed model incorporated physiologically based improvements for the liver and skeleton and continued to ensure efficient coupling with intake biokinetic models.

Development of the Plutonium-DTPA Biokinetic Model.

Estimating radionuclide intakes from bioassays following chelation treatment presents a challenge to the dosimetrist due to the observed excretion enhancement of the particular radionuclide of concern where no standard biokinetic model exists. This document provides a Pu-DTPA biokinetic model that may be used for making such determination for plutonium intakes. The Pu-DTPA biokinetic model is intended to supplement the standard recommended biokinetic models. The model was used to evaluate several chelation strategies that resulted in providing recommendations for effective treatment. These recommendations supported early treatment for soluble particle inhalations and an initial 3-day series of DTPA treatments for wounds. Several late chelation strategies were also compared where reduced treatment frequencies proved to be as effective as multiple treatments. The Pu-DTPA biokinetic model can be used to assist in estimating initial intakes of transuranic radionuclides and for studying the effects of different treatment strategies.

Early blood plutonium retention in nonhuman primates compared to the NCRP 156 wound biokinetic model.

Data from animal experiments are relied upon for understanding the biokinetics of contaminant retention and excretion where insufficient human data exist. Records involving nonhuman primate experiments performed from 1973 to 1987 were collected and compiled by researchers at the Lawrence Berkeley Laboratory. These records included early blood samples that were taken after soluble plutonium was administered via intramuscular, subcutaneous, or intravenous injection. Samples were collected as early as 5 min post injection with several samples collected during the first few weeks. The NCRP 156 biokinetic model was developed primarily from animal experiments due to insufficient human data not influenced by chelation therapy. This work compared the NCRP 156 biokinetic model default transfer rate constants to the early blood excretion data from nonhuman primate experiments for 238Pu. These results indicated that the blood content of nonhuman primates exhibited "moderate" retention properties for simulated wound conditions. Additionally, there was no evidence of long-term retention of plutonium in the whole blood samples, confirming that plutonium was not incorporated within blood cells. Particle solubility characteristics should be considered for wounds when using the NCRP 156 wound biokinetic model.