Abstract  Seventy-three rats were exposed to an aerosol of enriched uranium dioxide (UO2), giving initial lung burdens of 26 to 447 micrograms at 6 days post-inhalation (PI). At 7 days PI 35 of these rats were further exposed to thermalised neutrons at a fluence of 1 x 10(12) neutrons cm-2. There was no significant difference between the two groups in the clearance rate of the UO2 particles from the lung, up to 590 days PI. The particles cleared relatively slowly over this period with a retention half-time in the lung of 160 to 176 days. Transmission electron microscope (TEM) studies of tissue from the alveolar region at 8 days PI showed that inhalation of UO2 particles significantly increased the sizes of macrophage and type II cells, and the number of macrophage and type I cells. There was also a significant increase in the size of lysosomal granules within the macrophages after exposure to the UO2 particles. The exposure to UO2, neutrons and 235U fission fragments had no significant effect on any of the cells above that observed in the animals exposed to UO2 alone. Additional rats were exposed to the same neutron fluence without prior UO2 inhalation. The alveolar cells of neutron-only exposed rats were, in size and number, typically no different from those in the completely unexposed control rats.

Abstract  Two etiologically different models of experimental acute renal failure were induced in rats by administration of either glycerol or uranyl nitrate. Both compounds caused a substantial decrease in the glomerular filtration rate (GFR) and the net tubular secretion of tetraethylammonium bromide (TEAB) and para-aminohippuric acid (PAH). The degree of renal impairment induced by uranyl nitrate and glycerol appeared to be dose related. Deprivation of drinking water 24 hr before the administration of glycerol potentiated the renal damage. In uranyl nitrate-induced renal failure, the decline of the net tubular secretion for TEAB and PAH was not proportional to the decrease in GFR; the secretion process deteriorated faster than the GFR. For example, when 0.5 mg/kg uranyl nitrate was administered, GFR fell to approximately 65% of normal, whereas the net tubular secretion was decreased to 30% of normal. These results suggest that the tubular transport was preferentially affected by uranyl nitrate. In contrast, in glycerol-induced renal failure, the decline of TEAB secretion fell in a parallel fashion with the GFR, suggesting that the glomeruli and the proximal tubules were equally damaged by glycerol. However, in this latter model, the decline of PAH secretion did not parallel the decrease in GFR, contradicting the proposal that glycerol affects equally the glomeruli and the proximal tubules. This discrepancy may be due to the selective competitive inhibition of PAH secretion by the accumulation of naturally occurring organic acids. The results that the secretion of PAH but not TEAB was selectively depressed in azotemic rats induced by the i.v. infusion of fresh urine supported the possibility of selective inhibition. In conclusion, these results suggest that the effects of experimental acute renal failure on the active secretion and passive filtration may be quantitatively different depending on the type of renal failure and the type of drugs (cation or anion) studied.

Abstract  Through radiochemical analysis of voluntary tissue donations, the U.S. Transuranium and Uranium Registries (USTR) are gaining improved understanding of the distribution and biokinetics of actinide elements in occupationally exposed persons. Evaluation of the first two whole-body contributions to the USTR revealed an inverse proportionality between actinide concentration and bone ash. The analysis of a whole body with significant 241Am deposition indicated a significantly shorter half-time in liver and a greater fraction resident in the skeleton than predicted by existing models. Other studies with tissues obtained at autopsy suggest that existing biokinetic models for 238Pu and 241Am and the currently accepted models and limits on intake, which use these models as their basis, may be inaccurately implying that revisions of existing safety standards may be necessary. Other studies of the registries are designed to evaluate in-vivo estimates of actinide deposition with those derived from postmortem tissue analysis, to compare results of animal experiments with human data, and to review histopathologic slides for tissue changes that might be attributable to exposure to transuranic elements. The implications of these recent findings and other work of the registries is discussed from the standpoint of this potential effect on biokinetic modeling, internal dose assessment, and safety standards and operational health physics practices.

Abstract  The pharmacokinetics of phenytoin (DPH) was investigated in rats with uranyl nitrate induced renal failure, and with D-galactosamine induced hepatic failure. The serum disappearance of DPH after 10 mg/kg i.v. dose followed a two-exponential decline in normal and both types of intoxicated rats. The serum disappearance half-life (t1/2) and the volume of distribution (Vd) significantly increased in both types of intoxicated rats, while the total blood clearances (CLb) significantly decreased. The serum unbound fraction (fu) of DPH significantly increased in both types of intoxicated rats. The blood to plasma concentration ratio (RB) of DPH significantly increased in the uranyl nitrate-treated rats, while that of the D-galactosamine-treated rats did not show significant alteration. The tissue to serum concentration ratios (Kp) of most of tissues studied after i.v. bolus injection of DPH increased in both types of intoxicated rats. Except for the lung of the D-galactosamine-treated rats, the tissue to serum unbound concentration ratio (Kpu) of other tissues did not show a significant alteration. This suggested that the tissue uptake and/or binding of DPH is not affected by uranyl nitrate or D-galactosamine intoxication and that the increases in Vd and Kp are due mainly to the decrease in serum protein binding. The hepatic intrinsic clearance of unbound DPH (CLuint,H) also decreased in both types of intoxicated rats. Thus, the uranyl nitrate and D-galactosamine intoxication caused the increase in fu and the decrease in CLuint,H and these results may explain the significant decrease in CLb and increases in Vd and t1/2. The tissue concentration-time courses of DPH were predicted by a physiciologically based pharmacokinetic model and good agreement between the predicted and observed values in normal and in both types of intoxicated rats were obtained for serum, liver, kidney, brain and muscle.

Abstract  Ceramic and non-ceramic forms of uranium dioxide, produced industrially, were administered to rats either by inhalation or as an aqueous suspension which was injected directly into the pulmonary region of the lungs. The results showed that: 1 both materials should be assigned to inhalation class Y as defined by the International Commission on Radiological Protection; 2 whilst the translocation of uranium to the blood for the non-ceramic UO2 was about twice that obtained for the ceramic form, the two dioxides were unlikely to be differentiated on the basis of their lung retention kinetics; 3 the distribution of uranium amongst body tissues and the relationship between systemic content and cumulative urinary excretion indicated that it was transported in the hexavalent form; 4 in addition to air sampling procedures, lung radioactivity counting measurements could be used to advantage for assessing occupational exposures; 5 the exposure limits should be based on radiation dose rather than chemical toxicity.

Abstract  Plasma calcium regulation in uranyl nitrate-treated dogs was studied. A discrete hypercalcemia was observed without significant changes in the level of plasma ionized calcium. Serum phosphate increased markedly following uranyl nitrate treatment. A sharp rise of iPTH was demonstrated. Uranyl nitrate-induced acute renal failure in dogs was found to be a useful model for studying the mechanisms regulating calcium and phosphate metabolism.

Abstract  The acute oral and subcutaneous toxicity of uranium (7440611) was investigated in rats and mice. Male Sprague-Dawley-rats and male Swiss-mice were administered single doses of uranyl-acetate (541093), subcutaneously or intragastrically. The median lethal dose (LD50) 14 days following subcutaneous administration was 8.3 and 20.4mg/kg for rats and mice, respectively; and the oral LD50 for rats was 204mg/kg and for mice was 242mg/kg. Most deaths occurred 5 to 8 days following uranyl-acetate administration. Physical signs of toxicity, usually evident after 6 days and persisting through the 14 day experimental period, included: weight loss, piloerection, rubefaction, tremors, hypotension, pupillary constriction, exophthalmos, and mild hemorrhages in eyes, nose, and legs. In a separate experiment, rats and mice were administered single doses of 210mg/kg uranyl-acetate subcutaneously or 10mg/kg intragastrically. Animals were observed for 14 days and then survivors were sacrificed and examined for pathological changes. Significant weight loss was observed in all treated animals. Food intake and amount of feces excreted were significantly reduced. Water consumption was not changed, but the volumes of urine excreted were significantly increased. Plasma urea and creatinine were significantly increased 7 days following either oral or subcutaneous uranyl-acetate administration. Histopathologic examination of the kidneys and liver revealed minimal lesions in animals administered uranyl-acetate orally, and more severe lesions in animals administered uranyl-acetate subcutaneously. The authors conclude that renal toxicity is the most characteristic response to uranyl-acetate, which is highly toxic when administered subcutaneously and moderately toxic when administered orally.

Abstract  A retrospective cohort mortality study of 995 white males employed more than 30 d at a uranium processing facility in upstate New York between 1943 and 1949 investigated the association between excess observed deaths and long-term occupational exposure via inhalation to uranium compounds. Two comparison groups were used, the white male population of the United States and the white male population in the New York counties of Erie and Niagara. The vital status determination was 94.3% complete through 31 December 1979. With the use of the national comparison group, statistically significantly increased standardized mortality ratio (SMR) values were observed for all causes (SMR 118), laryngeal cancer (SMR 447), all circulatory diseases (SMR 118), arteriosclerotic heart disease (SMR 119), all respiratory diseases (SMR 152), and pneumonia (SMR 217). Site-specific outcomes of special interest with a statistically increased number of deaths above expected were laryngeal cancer (observed 5) and pneumonia (observed 17). No association was found with length of employment or work in the most hazardous areas of the plant. The comparison with regional rates gave similar results.

Abstract  A study was made of the effect of alpha-radiation of 238U solutions and enriched uranium (9.9 X 10(7) Bq/g) on developing Misgurnus fossilis eggs. The incidence of abnormal larvae and the death rate of eggs increased when the latter were incubated in 138 mg/l solution of uranium 238: this was not accompanied by the increase in the yield of the aberrant ana- and telophases in the epithelium cells of 1-day larvae.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM CHICKEN HEPATOTOXICITY NEPHROTOXICITY LD-50

Abstract  To examine the kinetic behaviour of americium, plutonium and uranium in the different organs of male and female rats an extended mammillary model has been developed; the model is composed of 10 compartments connected with 17 linear transfer coefficients. The 10 compartments describe the behaviour of the three nuclides in the blood, skeleton, liver and kidney, whereas the remaining activity is assigned to one residual organ. Each organ is divided into two compartments, a short- and long-term compartment. Morphologically, in the skeleton the short-term compartment has been assumed to be the bone surface and bone marrow and the long-term compartment to be the deep bone, whereas in the liver there is some evidence to suggest that the short-term compartment is physiologically associated with lysosomes and the long-term compartment is identical with telolysosomes. The influence of age, sex and different nuclides on the transfer coefficients and the absorbed radiation dose have been discussed. Additionally, by using the transfer coefficients calculated for intravenous injection, the behaviour of the nuclides in skeleton and liver during continuous intake has been calculated. As a second example of the application of the model the behaviour of the three nuclides in skeleton and liver after intravenous injection has been calculated with the additional assumption that from the fifth day on the animals were treated continuously with a chelating agent.

Abstract  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.

Abstract  Absorption of 233U, 238Pu, 241Am, and 244Cm from the gastrointestinal (GI) tract was measured in rats, fed ad libitum or fasted, that were gavaged with solutions containing ferric iron, ferrous iron, iron powder, quinhydrone or ascorbic acid. Absorption and retention of all of these actinides was increased substantially by fasting and by the addition of mild oxidizing agents, ferric iron and quinhydrone. In contrast, absorption and retention were decreased to below the fasted level by all the reducing agents except ascorbic acid, which caused diarrhea and an increase in absorption. Absorption of the lanthanide element 147Pm from the intestine of fasted rats was also increased by ferric iron. Some of these actinide elements are polyvalent and are, in some cases, known to be absorbed from the GI tract more readily in their higher oxidation states. This suggested an oxidation-reduction mechanism for the effect of fasting and the action of the chemical agents used. However, the improbability that either 241Am(III) 244Cm(III) or 147Pm is converted to a different oxidation state under these conditions makes that mechanism unlikely. Other explanations are suggested.

Abstract  The literature on metabolism of U and Ra for man relevant to deriving drinking water standards has been reviewed and summarized. Radium is well understood, but significant gaps remain in our knowledge about U metabolism. Limits should be based on an equilibrium model where a constant relationship between intake and organ burden is established, using the best and most likely metabolic parameters. For the skeleton we conclude that the best estimate of skeletal burden expressed in days equivalent intake are 25 days for 226Ra, 10 days for 228Ra, and 0.3 days for 224Ra. For long-lived isotopes of U, we chose 11 days, with a range between 1 and 35 days. The committee believes that intake of natural U in water should be limited by considerations of toxicity to the kidney, and we believe that the metabolic model of Spoor and Hursh with a modified gastrointestinal (GI) absorption (1.4%) should be used to infer kidney content. Our review and analysis of the world literature leads us to believe the average human GI absorption of U is most likely 1-2% and is probably reasonably independent of age or the mass of U ingested. Using a safety factor of 50-150, the committee recommends a limit of U in water of 100 micrograms/l in order to limit toxic effects in the kidney. One hundred micrograms/liter is equivalent to 67 pCi/l of long-lived alpha-emitting natural U isotopes. Further research into the distribution of U in the human body is desirable, especially at natural levels in kidney and skeleton, the time-dependent pharmacokinetics of U in animals, the GI absorption of U in man from water and food, toxicological and U distribution studies in animals under conditions of chronic oral U intake, and metabolic model error propagation.

Abstract  From extensive human data on the induction of skeletal cancers (bone sarcomas and carcinomas of the head sinuses) by 226Ra, 228Ra and 224Ra, the cumulative lifetime risk to 1 million people, each ingesting 5 pCi of a Ra isotope per day, was calculated to be nine bone sarcomas plus 12 head carcinomas for 226Ra, 22 bone sarcomas for 228Ra, and 1.6 bone sarcomas for 224Ra. Assuming that the risk per rad of average skeletal dose is equal for 226Ra and the U isotopes with half-lives exceeding 1000 yr and that the equilibrium skeletal content is 25 times the daily ingestion of 226Ra, but 11 times the daily ingestion of long-lived U, the cumulative life-span risk to 1 million persons, each ingesting 5 pCi per day of 233U, 234U, 235U, 236U or 238U, is estimated to be about 1.5 bone sarcomas. The U risk is not well established and additional research is needed on the metabolism of U in humans and its carcinogenicity in laboratory animals. These estimates assume linear dose responses. However, if incidence varies with the square of dose, virtually no induced cancers would be expected from these levels of radioactivity.

Abstract  The alterations in the serum lipolytic activity of mice were studied under Uranyl nitrate (UN) intoxication. The lipemia produced as a result of UN intoxication was probed studying the alterations in the serum triacyl-glycerol-hydrolase (EC 3.1.1.3) activity. After an intraperitoneal injection of UN (10 mg/kg and 25 mg/kg), triacyl-glycerol-hydrolase (TAGH) activity was considerably enhanced. In the initiation phase the elevation in the activity was observed to be higher than the elevation in the maintenance phase of acute UN toxicity. The possible reasons for the elevation in the TAGH activity and its role under such intoxication is discussed.

Abstract  There are substantial animal and epidemiological data related to cigarette smoking and lung cancer among miners exposed to elevated levels of radon daughters that appears to be in disagreement. An hypothesis is advanced that explains most of this disagreement as being derived from temporal differences of cancer expression. The hypothesis is that a given radiation exposure induced a finite number of lung cancers, which have shorter latent periods due to the cancer promotion activity of smoke among cigarette smokers. According to this hypothesis, the life-shortening effect is greater among smoking miners than nonsmoking miners, and the ultimate number of lung cancers among smoking miners will be only a little larger than among nonsmokers. The greater number will derive from the additive effect of radiation and smoking, plus the greater force of competing causes of death among elderly nonsmokers.

Abstract  The study was performed to elucidate the progression and regression of superficial and inner glomerular alterations in uranyl acetate-induced renal failure in rabbits. Fifteen hours after the drug injection, creatinine clearance (CCr) decreased to 55% of controls with slightly elevated plasma creatinine concentration (initiation stage). After 5 days, urine flow and CCr decreased to approximately zero, with severe azotemia (maintenance stage). Scanning electron microscopic observations in these stages revealed a flattening and spreading of podocyte cell bodies associated with loss of epithelial foot processes, and reduction in the density of endothelial fenestrae. These changes were more advanced in the maintenance stage. Glomerular and fenestral diameters did not significantly change in the initiation stage but increased in the maintenance stage. There was no significant difference in these morphologic alterations, however, between the superficial and inner glomeruli. Glomerular alterations reverted to normal within 14 days, with good recovery of glomerular function. The findings show no significant difference in the progression or regression of the glomerular changes between the superficial and deep cortex. These morphologic changes may play a role in the reduction of CCr observed in this model.

Abstract  HEEP COPYRIGHT: BIOL ABS. RRM HUMAN INDUSTRIAL HYGIENE PROGRAMS

Abstract  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.

Abstract  One of the major pathways of radiological exposure to man from uranium milling operations is through the beef/milk food chain. Studies by various investigators have shown the extent of uptake and distribution of 238U, 234U, 230Th, 226Ra, 210Pb, and 210Po in plants and cattle. These long-lived natural radioisotopes, all nuclides of the uranium decay series, are found in concentrated amounts in uranium mill tailings. In this paper, data from these investigations are used to estimate the dose to man from consumption of beef and milk from cattle that have fed on forage contaminated with the tailings. The estimated doses from this technologically enhanced source are compared with those resulting from average dietary intake of these radionuclides from natural sources.