Effect of dose on the metabolism of 1,1,2,2-tetrabromoethane in F344/N rats after gavage administration.

1,1,2,2-Tetrabromo[U-14C]ethane ([14C]TBE) was used to study the metabolism of TBE in rats. Three graded doses of TBE (1.17, 13.6, and 123 mg/kg; 1 microCi 14C/rat at each dose) were administered by gavage to three groups of four rats each. Excreta samples were collected at various time intervals up to 96 hr. Following euthanization, 14C activity was measured in the excreta, tissues, and carcass. The fraction of the dose exhaled as volatile metabolites of TBE, excluding 14CO2, was approximately 9-10% higher in rats given the high dose of TBE compared to that in rats given either the low or the medium dose. The fraction excreted in the urine decreased with increasing TBE dosage. 1,2-Dibromoethylene and tribromoethylene were identified as exhaled metabolites at the high dose. Three major urinary metabolites were identified: dibromoacetic acid, glyoxylic acid, and oxalic acid. The results of this study indicate that the metabolism of TBE was linear up to a dose of 13.6 mg/kg, but the contribution of various TBE metabolic pathways was different at a dose of 123 mg/kg.

A model for scaling the results of U excretion rate studies in beagle dogs to man.

A biokinetic model was used to simulate retention and excretion of two forms of U: ammonium diuranate (ADU), a relatively soluble form, and U3O8, a relatively insoluble form. These two U forms represent those most likely to be encountered in the U milling industry. The simulation model was compared with results from a study of aerosols of commercial refined U ore inhaled by laboratory animals. Beagle dogs were exposed by inhalation to ADU aerosols to achieve a median initial body burden of 0.058 mg U kg-1 body weight (within a range of 0.016 to 0.64 mg U kg-1), or to U3O8 aerosols to achieve a median retained body burden of 0.28 mg U kg-1 (0.030-0.81 mg U kg-1). The simulation model accurately described the accumulation of nephrotoxic concentrations of U in kidneys of animals exposed to ADU. Very small fractions of the initial body burden of U3O8 were translocated to kidney, and these fractions were overestimated by the model. The model showed general agreement with results of other laboratory animal studies and with available information from human exposures to ADU, UF6, or U3O8.

Effect of wet and dry cycles on dissolution of relatively insoluble particles containing Pu.

Dissolution of gross alpha emitter radioactivity from particles composed of mixed uranium and plutonium oxides or of plutonium dioxide continually immersed in solvent typically display at least a two-phase dissolution pattern. Rapid dissolution of a small fraction of the total particulate mass is followed by much slower dissolution for the majority of the particulate mass. In this study, respirable particles of (U, Pu)O2 and PuO2 were subjected to dissolution using an alternate wetting and drying cycle. Particles were continuously immersed in solvent for 4 d and then dried in air for 3 d. This cycle was repeated weekly for 7 wk. Four solvents were used to represent a range of potential environmental conditions and a fifth solvent was used for comparison to other continuous immersion studies. In contrast to dissolution studies involving continuous immersion over periods of two or more weeks that exhibit a three-phase dissolution process, the alternate wet-dry cycling resulted in repetition of the first two phases of the dissolution pattern for each cycle. This led to significantly enhanced dissolution of both particulate materials. The enhancement in total dissolution ranged from two to ten times larger during each wet-dry cycle compared to studies involving continuous immersion. The results indicate a potential need to re-evaluate environmental models of actinide element bioavailability for particulate materials released to environments where wet-dry cycling may be routine, i.e. intermittent rainfall in an otherwise arid climate or in stream beds with intermittent flow.

Effect of acclimation to caging on nephrotoxic response of rats to uranium.

Animal studies of the toxicity and metabolism of radionuclides and chemicals often require housing of rats in metabolism cages for excreta collection. Response of rats to toxic substances may be affected by environmental factors such as the type of cage used. Dose-response studies were conducted to assess the effects of two types of cages on the nephrotoxic response of rats to uranium from implanted refined uranium ore (yellowcake). The LD50/21 days was 6 mg of uranium ore per kilogram body weight (6 mg U/kg). The 95% confidence limit (C.L.) was 3-8 mg U/kg for rats housed in metabolism cages beginning on the day of implantation (naive rats). However, for rats housed in metabolism cages for 21 days before implantation (acclimated rats) the LD50/21 days was 360 mg U/kg (95% C.L. = 220-650 mg U/kg), which was the same value obtained for rats housed continuously in polycarbonate cages. This significant difference (P less than 0.01) in response of naive rats compared to response of acclimated rats appeared related to a significantly lower water consumption by the naive rats.

Comparison of early lung clearance of yellowcake aerosols in rats with in vitro dissolution and IR analysis.

The lung retention of uranium was determined in rats that inhaled aerosols of commercial yellowcake powders obtained from two mills (Mill A and Mill D) and whose chemical composition and solubilities in vitro were significantly different. Analysis by IR absorption indicated Mill A yellowcake contained 82% ammonium diuranate (ADU) and 18% U3O8. The Mill D powder contained 25% ADU and 75% U3O8. In vitro dissolution studies indicated for the Mill A sample, approximately 85% of the uranium had a dissolution half-time (T 1/2) of less than one day, with the remainder dissolving with a half-time of 500 days. For the Mill D sample, 25% had T 1/2 less than one day and 75% had T 1/2 of 300 days. Groups of 50 rats were exposed by nose-only inhalation to aerosols of either the Mill A or the Mill D yellowcake. Rats were sacrificed in groups of five at intervals through six months after exposure. Selected tissues and excreta samples were assayed by fluorometry to determine their uranium contents. For the Mill A yellowcake, 78% initial lung (broncho-alveolar) burden cleared with T 1/2 of 0.5 days, and 22% with T 1/2 of 240 days. For the Mill D yellowcake, 25% initial lung burden cleared with T 1/2 of 3.5 days and 75% with T 1/2 of 110 days. Thus, the lung clearance of uranium in the rat mimicked the in vitro dissolution data and supported the contention that ADU should be considered as a Class D compound (T 1/2 = 0.5 days) and U3O8 behaves in the lung as a Class Y (T 1/2 greater than 100 days) material.

Techniques for yellowcake dissolution studies in vitro and their use in bioassay interpretation.

The high variability in solubility of yellowcake produced by different mills complicates the interpretation of routine bioassay data. A simple in vitro dissolution test is needed for yellowcake to improve this interpretation. A series of experiments was designed to evaluate the relative importance of solvent composition, method, pH and temperature in determining yellowcake dissolution according to a model developed from the known composition of a test yellowcake and data from inhalation exposures of humans to UO3 or U3O8. Useful in vitro dissolution results can be obtained using either simulated serum ultrafiltrate or simulated lung fluid as the solvent if dissolved and undissolved yellowcake are separated by a membrane filter. In vitro dissolution experiments estimated the soluble portion of the test yellowcake within +/- 6% (mean +/- 2 S.E.) and showed that the dissolution rates of the more soluble and less soluble portions corresponded to Class D and Class Y compounds, respectively. It was not necessary to maintain physiological pH or temperature conditions to approximate the "human" model. The greatest utility of in vitro dissolution results was in the estimation of the more soluble fraction of the yellowcake and to indicate whether prior excretion of a Class D uranium compound and possible kidney damage could have occurred before detection of an exposure. Some guidelines for the use of in vitro dissolution data in biassay interpretation are suggested based on ICRP Publication 30 recommendations.

Predicted deposition rates of uranium yellowcake aerosols sampled in uranium mills.

Uranium aerosols generated during normal yellowcake packaging operations were sampled at four uranium mills. Samplers located in the packaging area were operated before, during and after drums of yellowcake were filled and sealed. Median aerosol concentrations in the packaging areas ranged from 0.04 micrograms U/1 to 0.34 micrograms U/1. The aerosols were heterogeneous and included a broad range of particle sizes such that 14% to 76% (by weight) of the airborne uranium was in particles with aerodynamic diameters greater than 12 micron. Air concentrations and particle-size distributions varied with time as larger particles settled or more aerosols were suspended. Aerosol characteristics could often be related to individual packaging steps. The results show that appreciable amounts of airborne uranium would be expected to deposit in the nasopharyngeal compartment of the respiratory tract if inhaled by a worker not wearing respiratory protection.

In vitro dissolution of respirable aerosols of industrial uranium and plutonium mixed-oxide nuclear fuels.

Dissolution characteristics of mixed-oxide nuclear fuels are important considerations for prediction of biological behavior of inhaled particles. Four representative industrial mixed-oxide powders were obtained from fuel fabrication enclosures. Studies of the dissolution of Pu, Am and U from aerosol particles of these materials in a serum simulant solution and in 0.1M HCl showed: (1) dissolution occurred at a rapid rate initially and slowed at longer times, (2) greater percentages of U dissolved than Pu or Am: with the dissolution rates of U and Pu generally reflecting the physical nature of the UO2-PuO2 matrix, (3) the temperature history of industrial mixed-oxides could not be reliably related to Pu dissolution except for a 3-5% increase when incorporated into a solid solution by sintering at 1750 degrees C, and (4) dissolution in the serum simulant agreed with the in vivo UO2 dissolution rate and suggested the dominant role of mechanical processes in PuO2 clearance from the lung. The rapid initial dissolution rate was shown to be related, in part, to an altered surface layer. The advantages and uses of in vitro solubility data for estimation of biological behavior of inhaled industrial mixed oxides, such as assessing the use of chelation therapy and interpretation of urinary excretion data, are discussed. It was concluded that in vitro solubility tests were useful, simple and easily applied to individual materials potentially inhaled by humans.