Raymond A. Guilmette

COMPUTATIONAL FLUID DYNAMICS SIMULATIONS OF INSPIRATORY AIRFLOW IN THE HUMAN NOSE AND NASOPHARYNX

Extrapolation of the regional dose of an inhaled xenobiotic from laboratory animals to humans for purposes of assessing human health risk is problematic because of large interspecies differences in nasal respiratory physiology and airway anatomy. There is a need for dosimetry models that can adjust for these differences in the upper respiratory tract. The present work extends previous efforts in this laboratory and elsewhere to simulate nasal airflow profiles numerically in laboratory animals and humans. A three-dimensional, anatomically accurate representation of an adult human nasal cavity and nasopharynx was constructed. The Navier-Stokes and continuity equations for airflow were solved using the finite-element method under steady-state, inspiratory conditions simulating rest and light exercise (steady-state inspiratory flow rates: 15 L/min and 26 L/min, respectively) with the fluid dynamics software package FIDAP. Simulated airflow was streamlined in the main nasal passages and complex in the vestibul...

Toxicity of inhaled plutonium dioxide in beagle dogs.

This study was conducted to determine the biological effects of inhaled 238PuO2 over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of 238PuO2 to achieve graded levels of initial lung burden (ILB). The aerosols also contained 169Yb to provide a gamma-ray-emitting label for the 238Pu inhaled by each dog. Excreta were collected periodically over each dogs life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest alpha-particle doses, ranging from 0.16-68 Gy for the lung, 0.08-8.7 Gy for the skeleton and 0.18-19 for the liver. At death all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. Bone tumors found in 93 dogs were the most common cause of death. Lung tumors found in 46 dogs were the second most common cause of death. Liver tumors, which were found in 20 dogs but were the cause of death in only two dogs, occurred later than the tumors in bone and lung. Tumors in these three organs often occurred in the same animal and were competing causes of death. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to 238PuO2.

Biokinetics of Inhaled 239PuO2 in the Beagle Dog: Effect of Aerosol Particle Size

This study was designed to measure the effect of aerosol particle size on the deposition, retention, excretion and translocation of 239Pu inhaled as the dioxide by Beagle dogs. To address these questions, young adult male and female Beagle dogs received single brief inhalation exposures to one of three monodisperse aerosols of 239PuO2 having sizes of 0.72, 1.4 or 2.8 microns activity median aerodynamic diameter (AMAD). Periodic collections of urine and faeces were made for each dog until sacrifice at times ranging from 4 hours to 2 years after exposure. The results indicate long term retention of a substantial percentage of the initial pulmonary burden (IPB), and that the retention was affected by particle size. The percentage of the initial pulmonary lung burden retained in the long term component and its effective half time (TE) were 90 per cent with TE = 680 days for the 0.72 micron AMAD aerosol, 68 per cent with TE = 1400 days for the 1.4 microns AMAD aerosol and 82 per cent with TE = 1800 days for the 2.8 microns AMAD aerosol. The major route of elimination of 239Pu from lung was via the faeces, but significant amounts were also translocated to thoracic lymph nodes (approximately 15 per cent IPB by 2 years). Small amounts were translocated to liver (0.2 per cent IPB) and skeleton (0.1 per cent IPB) by 2 years after exposure. The average alpha-radiation dose to the lung was projected to be twice as large for the 2.8 microns AMAD group as for the 0.72 micron AMAD group at 10 years after exposure.

Metabolomic and lipidomic analysis of serum from mice exposed to an internal emitter, cesium-137, using a shotgun LC-MS(E) approach.

In this study ultra performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry in the MSE mode was used for rapid and comprehensive analysis of metabolites in the serum of mice exposed to internal exposure by Cesium-137 (137Cs). The effects of exposure to 137Cs were studied at several time points after injection of 137CsCl in mice. Over 1800 spectral features were detected in the serum of mice in positive and negative electrospray ionization modes combined. Detailed statistical analysis revealed that several metabolites associated with amino acid metabolism, fatty acid metabolism, and the TCA cycle were significantly perturbed in the serum of 137Cs-exposed mice compared with that of control mice. While metabolites associated with the TCA cycle and glycolysis increased in their serum abundances, fatty acids such as linoleic acid and palmitic acid were detected at lower levels in serum after 137Cs exposure. Furthermore, phosphatidylcholines (PCs) were among the most perturbed ions in the serum of 137Cs-exposed mice. This is the first study on the effects of exposure by an internal emitter in serum using a UPLC–MSE approach. The results have put forth a panel of metabolites, which may serve as potential serum markers to 137Cs exposure.

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

Cesium-137 is a fission product of uranium and plutonium in nuclear reactors and is released in large quantities during nuclear explosions or detonation of an improvised device containing this isotope. This environmentally persistent radionuclide undergoes radioactive decay with the emission of beta particles as well as gamma radiation. Exposure to 137Cs at high doses can cause acute radiation sickness and increase risk for cancer and death. The serious health risks associated with 137Cs exposure makes it critical to understand how it affects human metabolism and whether minimally invasive and easily accessible samples such as urine and serum can be used to triage patients in case of a nuclear disaster or a radiologic event. In this study, we have focused on establishing a time-dependent metabolomic profile for urine collected from mice injected with 137CsCl. The samples were collected from control and exposed mice on days 2, 5, 20 and 30 after injection. The samples were then analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC/TOFMS) and processed by an array of informatics and statistical tools. A total of 1,412 features were identified in ESI+ and ESI– modes from which 200 were determined to contribute significantly to the separation of metabolomic profiles of controls from those of the different treatment time points. The results of this study highlight the ease of use of the UPLC/TOFMS platform in finding urinary biomarkers for 137Cs exposure. Pathway analysis of the statistically significant metabolites suggests perturbations in several amino acid and fatty acid metabolism pathways. The results also indicate that 137Cs exposure causes: similar changes in the urinary excretion levels of taurine and citrate as seen with external-beam gamma radiation; causes no attenuation in the levels of hexanoylglycine and N-acetylspermidine; and has unique effects on the levels of isovalerylglycine and tiglylglycine.

Dosimetry of /sup 239/Pu in dogs that inhaled monodisperse aerosols of /sup 239/PuO2

Existing data from human exposure cases and experimental animal studies on the fate and dosimetry of inhaled insoluble Pu particles are inadequate to provide a comprehensive description and evaluation of the tissues at risk from the alpha radiations of Pu. To improve our knowledge of the dosimetry of inhaled insoluble 239PuO2, this paper describes the uptake and retention of 239Pu in the tissues of dogs that received single inhalation exposures to monodisperse aerosols of 239PuO2. These data include times through 3 years after exposure. Using analytical functions fitted to each tissue data set, 1100-day radiation doses were calculated for lung, liver, skeleton, kidney, spleen, and tracheobronchial, mediastinal, sternal, hepatic, mandibular, and retropharyngeal lymph nodes. The dosimetry results suggest that the lung and lymph nodes associated with lymphatic drainage of the respiratory tract are the principal sites of alpha irradiation. However, the doses for the different respiratory tract lymph nodes vary by a factor of 2000, suggesting that assuming equivalent doses to respiratory tract lymph nodes is not appropriate. Other tissues receive radiation doses also but at levels one to three orders of magnitude less than the lung. Particle size dependence on uptake and retention was noted for the skeleton, mediastinal lymph nodes, hepatic lymph nodes, retropharyngeal lymph nodes, and mandibular lymph nodes.

OVERVIEW OF THE CAPSTONE DEPLETED URANIUM STUDY OF AEROSOLS FROM IMPACT WITH ARMORED VEHICLES : TEST SETUP AND AEROSOL GENERATION, CHARACTERIZATION, AND APPLICATION IN ASSESSING DOSE AND RISK

The Capstone Depleted Uranium (DU) Aerosol Characterization and Risk Assessment Study was conducted to generate data about DU aerosols generated during the perforation of armored combat vehicles with large-caliber DU penetrators, and to apply the data in assessments of human health risks to personnel exposed to these aerosols, primarily through inhalation, during the 1991 Gulf War or in future military operations. The Capstone study consisted of two components: 1) generating, sampling, and characterizing DU aerosols by firing at and perforating combat vehicles, and 2) applying the source-term quantities and characteristics of the aerosols to the evaluation of doses and risks. This paper reviews the background of the study including the bases for the study, previous reviews of DU particles and health assessments from DU used by the U.S. military, the objectives of the study components, the participants and oversight teams, and the types of exposures it was intended to evaluate. It then discusses exposure scenarios used in the dose and risk assessment and provides an overview of how the field tests and dose and risk assessments were conducted.

A biokinetic model for 137Cs.

An improved biokinetic model for 137Cs in humans was developed based on an analysis of data obtained from individuals internally contaminated during an accident in Goiania, Brazil, and other data. Seventeen children (ten girls and seven boys 1-10 y old), ten adolescents (four females and six males), and thirty adults, (fifteen females and fifteen males contaminated in the accident in Goiânia contributed to this study. 137Cs retention was determined through periodic measurements in a whole-body counter. In addition to the data on 137Cs retention from these individuals, data from a study on the metabolism of 137Cs in immature, adult, and aged Beagle dogs and data from the literature were used in the formulation of the 137Cs biokinetic model presented. Mathematically, the retention of cesium is described by three exponential terms, and the retention model is based on a step function of body weight. When the ICRP Publication 56 model for cesium was compared to the model suggested in this paper, it was determined that the ICRP model predicts lower effective doses in 5-y-old children and higher effective doses in infants, adolescents, and adults.

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.

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.