Physiologically-based toxicokinetic modeling of soluble hexavalent uranium in the rat
Uranium (U) is a bone-seeking element and a chemical renal toxicant. Prolonged exposure to U may lead to storage of significant quantities in the bone. The extent to which the return of U from bone to blood affects renal toxicity and excretion of uranium is unknown. Changes in susceptibility to U-induced renal toxicity following repeated exposures to U have been reported in the literature. In light of the possibility that previous exposure to U may reduce or enhance toxicity, experiments were designed to test whether slow release of U stored in bone might alter the response to a subsequent acute U dose. A physiologically-based model of U disposition in rats was developed to predict the relationship between the concentration of U in bone and kidney. The model was tested with results in a study in 80 male Long Evans rats. Uranyl nitrate was administered by IP osmotic pump (4.7 [mu]g U/day, 14 days). Urinary clearance of U was measured. The urine was found to be essentially the only route of elimination. Renal toxicity, measured as the ratios of glucose and protein to creatinine in the urine, was detected at a kidney concentration of 1-2 [mu]g U/g wet weight. Postexposure kinetics were followed up to 85 day. Single acute doses of U were given IP (284 [mu] g U/kg bw) at five time points during this postexposure period. Renal toxicity was evaluated at each of these time points. Toxicity was found not to be dependent on skeletal U burdens accumulated during previous exposure by osmotic pump. The model adequately predicts the relationship between the concentrations of U in bone and kidney at low doses, but predictions of total renal U levels after acute injections were not satisfactory. Implications of the differences between the kinetics of uranium at low and high doses are discussed. The results of this study lead to specific recommendations for the risk characterization of U.
- Research Organization:
- Cincinnati Univ., OH (United States)
- OSTI ID:
- 5568679
- Country of Publication:
- United States
- Language:
- English
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551000 -- Physiological Systems
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59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ACTINIDES
ACUTE EXPOSURE
ANIMAL TISSUES
BIOLOGICAL ACCUMULATION
BIOLOGICAL MATERIALS
BIOLOGICAL MODELS
BIOLOGICAL PATHWAYS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
BONE SEEKERS
BONE TISSUES
CHRONIC EXPOSURE
CONNECTIVE TISSUE
ELEMENTS
ISOTOPES
KIDNEYS
MATERIALS
METALS
ORGANS
RADIOISOTOPES
RADIONUCLIDE KINETICS
TISSUES
TOXICITY
URANIUM
URINE
WASTES