Validation of a system of models for plutonium decorporation therapy

A recently proposed system of models for plutonium decorporation (SPD) was developed using data from an individual occupationally exposed to plutonium via a wound [from United States Transuranium and Uranium Registries (USTUR) Case 0212]. The present study evaluated the SPD using chelation treatment data, urine measurements, and post-mortem plutonium activities in the skeleton and liver from USTUR Case 0269. This individual was occupationally exposed to moderately soluble plutonium via inhalation and extensively treated with chelating agents. The SPD was linked to the International Commission on Radiological Protection (ICRP) Publication 66 Human Respiratory Tract Model (HRTM) and the ICRP Publication 30 Gastrointestinal Tract model to evaluate the goodness-of-fit to the urinary excretion data and the predictions of post-mortem plutonium retention in the skeleton and liver. The goodness-of-fit was also evaluated when the SPD was linked to the ICRP Publication 130 HRTM and the ICRP Publication 100 Human Alimentary Tract Model. The present study showed that the proposed SPD was useful for fitting the entire, chelation-affected and non-affected, urine bioassay data, and for predicting the post-mortem plutonium retention in the skeleton and liver at time of death, 38.5 years after the accident. The results of this work are consistent with the conclusion that Ca-EDTA is less effective than Ca-DTPA for enhancing urinary excretion of plutonium.

     

Activity estimation and biokinetic analysis of 99mTc-DMSA in renal infant patients using a gamma camera

Biokinetic data from the administration of radiopharmaceuticals is essential in nuclear medicine dosimetry. It has particular significance in children, as their metabolism is very different from adults. Biokinetic models for paediatric patients could therefore need to be adapted to better reflect their absorption, retention and excretion functions, when compared to adults. Obtaining quality in vivo infant or paediatric biokinetic data is then essential to improve the available reference models, which in turn can lead to the optimization of paediatric procedures and protocols in clinical practice.This study analyses the biokinetic behaviour of ^99mTc-dimercaptosuccinic acid (DMSA), in 8 infants aged 4 months to 2 years old, through an imaging study using a gamma camera, and compares the obtained values with those obtained with the reference ICRP biokinetic model. The in vivo data was treated using an adapted methodology from the MIRD 16 pamphlet. Activity curves for the liver, the kidney and the whole body, were built, and new effective absorption, retention and excretion half-lives were estimated, and compared with the reference biokinetic parameters of ICRP 128. The obtained residence time in the kidneys of 2.56 h, has a deviation of 30.8% to the ICRP 128 value of 3.70 h. The obtained maximum uptake in the kidneys was of 0.22/A₀, which compares to the value of 0.31/A₀ for ICRP.The obtained biokinetic parameters were used to estimate the absorbed dose. The obtained dose values are smaller than the reference ICRP 128 ones by 32.1% in the kidneys, and 18.4% in the liver.     

Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes

The aim of the study was to demonstrate that decorporation of 238Pu is achieved more efficiently by an optimized liposomal formulation of diethylene triamine pentaacetic acid (DTPA) than by the usual free DTPA treatment. The optimized formulation consisted of polyethylene glycol-coated stealth liposomes with a mean diameter of 100 nm (SL-100 nm). Rats were intravenously injected with various Pu-phytate salt solutions in order to test different contamination conditions (activity and salt concentration) impacting liver kinetics and skeletal uptake of Pu. All treatments were given intravenously 1 h after contamination. Efficiency was evaluated 24 h, 7, 16 or 30 days later through their ability to promote Pu elimination and to reduce Pu burden in the skeleton and liver, the main organs of Pu deposition and radiotoxicological effects. Whatever the conditions of contaminations, a single injection of SL-100 nm (3.2 micromol kg(-1) DTPA) boosted urinary elimination of Pu to above 90% of the injected dose. In addition, liposomes strongly and significantly reduced the Pu burden of the liver and skeleton even 30 days after a single treatment: a dose of 0.3 micromol kg(-1) induced the same skeletal Pu reduction as four injections of free DTPA (30 micromol kg(-1)). A log dose-effect relation was found with SL-100 nm DTPA and Pu excretion in urine or Pu burden in the studied organs (liver, femurs, spleen and kidneys). This efficacy was attributed to an optimized targeting of DTPA to the main Pu retention organs and especially the liver.     

Measured intake and excretion patterns of naturally occurring 234U, 238U, and calcium in humans

The normal dietary and fluid intake and urinary and fecal excretion of 234U and 238U were determined in humans under strictly controlled conditions in the Metabolic Research Ward at Hines Hospital. These values formed the basis of the metabolic balances of these uranium isotopes. The major pathway of 234U and of 238U excretion was via the intestine while the urinary 234U and 238U were very low, averaging 2% of the total excretion. The uranium balances were roughly in equilibrium. These data were used in combination with measurements of tissue concentrations of uranium from nonoccupationally exposed humans to calculate steady-state uptake factors for environmental exposure to uranium isotopes during baseline conditions of a normal dietary intake.     

Influence of human biokinetics of strontium on internal ingestion dose of <Superscript>90</Superscript>Sr and absorbed dose of <Superscript>89</Superscript>Sr to organs and metastases

The objective of the present work is to apply the plasma clearance parameters to strontium, previously determined in our laboratory, to improve the biokinetic and dosimetric models of strontium-90 (⁹⁰Sr) used in radiological protection; and also to apply this data for the estimation of the radiation doses from strontium-89 (⁸⁹Sr) after administration to patients for the treatment of the painful bone metastases. Plasma clearance and urinary excretion of stable strontium tracers of strontium-84 (⁸⁴Sr) and strontium-86 (⁸⁶Sr) were measured in GSF-National Research Center for Environment and Health (GSF) in 13 healthy German adult subjects after intravenous injection and oral administration. The biological half-life of strontium in plasma was evaluated from 49 plasma concentration data sets following intravenous injections. This value was used to determine the transfer rates from plasma to other organs and tissues. At the same time, the long-term retention of strontium in soft tissue and whole body was constrained to be consistent with measured values available. A physiological urinary path was integrated into the biokinetic model of strontium. Parameters were estimated using our own measured urinary excretion values. Retention and excretion of strontium were modeled using compartmental transfer rates published by the International Commission on Radiological Protection (ICRP), the SENES Oak Ridge Inc. (SENES), and the Urals Research Center for Radiation Medicine (TBM). The results were compared with values calculated by applying our GSF parameters (GSF). For the dose estimation of ⁸⁹Sr, a bone metastases model (GSF-M) was developed by adding a compartment, representing the metastases, into the strontium biokinetic model. The related parameters were evaluated based on measured data available in the literature. A set of biokinetic parameters was optimized to represent not only the early plasma kinetics of strontium but also the long-term retention measured in soft tissue and whole body. The ingestion dose coefficients of ⁹⁰Sr were computed and compared with different biokinetic model parameters. The ingestion dose coefficients were calculated as 2.8 × 10⁻⁸, 2.1 × 10⁻⁸, 2.5 × 10⁻⁸ and 3.8 × 10⁻⁸ Sv Bq⁻¹ for ICRP, SENES, TBM and GSF model parameters, respectively. Moreover, organ absorbed dose for the radiopharmaceutical of ⁸⁹Sr in bone metastases therapy was estimated based on the GSF and ICRP biokinetic model parameters. The effective doses were 3.3, 1.8 and 1.2 mSv MBq⁻¹ by GSF, GSF-M, and ICRP Publication 67 model parameters, respectively, compared to the value of 3.1 mSv MBq⁻¹ reported by ICRP Publication 80. The absorbed doses of red bone marrow and bone surface, 17 and 21 mGy MBq⁻¹ calculated by GSF parameters, and 7.1 and 8.8 mGy MBq⁻¹ by GSF-M parameters, are comparable to the clinical results of 3–19 mGy MBq⁻¹ for bone marrow and 16 mGy MBq⁻¹ for bone surface. Based on the GSF-M model, the absorbed dose of ⁸⁹Sr to metastases was estimated to be 434 mGy MBq⁻¹. The strontium clearance half-life of 0.25 h from the plasma obtained in the present study is obviously faster than the value of 1.1 h recommended by ICRP. There are no significant changes for ingestion dose coefficients of ⁹⁰Sr using different model parameters. A model including the metastases was particularly developed for dose estimation of ⁸⁹Sr treatment for the pain of bone metastases.     

In vivo biodistribution and pharmacokinetics of (18)F-labeled human C-peptide: evaluation in monkeys using positron emission tomography

The recently observed beneficial effects exerted by C-peptide in insulin-dependent diabetes patients (IDDM) have instigated research into the mechanisms of C-peptide action as well as the location for it. Here we report in vivo biodistribution studies performed in monkeys using positron emission tomography (PET) and C-peptide labeled in the N-terminal with fluorine-18. Following iv injection of the radiotracer, dynamic decay data were collected over the chest and/or abdomens of the monkeys. The radioactivity distributed mainly to the kidneys, less to the heart and to some extent to the liver. Excretion of radioactivity into the urinary bladder was observed. Brain uptake was not detected in a static emission scan of the head performed at late times. Accumulation of radioactivity in the skeleton as a result of in vivo defluorination was not observed. Pharmacokinetic modeling of the regional concentrations of radioactivity over time resulted, for most organs, in two-compartment models. The organs with the highest radioactivity concentrations have been identified, enabling dose estimations for studies in humans with low or no C-peptide.     

Physiologically based pharmacokinetic modeling of hydrogen cyanide in humans following the oral administration of potassium cyanide and cyanogenic glycosides from food

Abstract

Cyanogenic glycosides (CGs) are commonly found in some edible plants and seeds. After ingestion, CGs can release toxic hydrogen cyanide (HCN) in humans. At present, unfortunately, there is no tool capable of predicting the cyanide concentration in human blood and organs following oral administration of CG-containing food. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of cyanide following the ingestion of CG-containing food in humans. To develop this model, pharmacokinetic data concerning cyanide concentration levels in humans exposed to potassium cyanide (KCN) and CG-containing foods (persipan paste, linseed, cassava, and bitter apricot kernels) were obtained from published data. This study created a model structure consisting of four organ compartments including the lungs, kidneys, liver, and slowly perfused tissues by employing Berkeley Madonna software to extract three unknown parameters including the maximum velocity of rhodanese, the absorption rate constant, and the bioavailability for oral administration of KCN and the four CG-containing foods (equivalent a 6.8?mg dose of cyanide). The model was then validated by comparing the simulated results for the concentration-time courses of cyanide levels in venous blood with data from two clinical studies covering the oral administration of KCN and linseed at three other doses.     

Comparison of Prussian blue and apple-pectin efficacy on 137Cs decorporation in rats

Cesium-137 (137Cs) is one of the most important nuclear fission elements that contaminated the environment after the explosion of the Chernobyl nuclear power plant in Ukraine (1986). The aim of the study was to compare the efficacy of two chelating agent, Prussian blue and apple-pectin on 137cesium decorporation in rats. Rats were intravenously injected with a solution of 137cesium (5 kBq per rat). Chelating agents, Prussian blue or apple-pectin were given immediately after Cs contamination and during 11 days by addition of each chelating agent in drinking water at a concentration corresponding to 400 mg kg(-1) day(-1). Efficiency was evaluated 11 days after contamination (at the end of treatment) through their ability to promote Cs excretion and to reduce the radionuclide accumulation in some retention compartments (blood, liver, kidneys, spleen, skeleton and in the remaining carcass). In these conditions after treatment with Prussian blue a fivefold increase in fecal excretion of Cs was observed and was associated with a reduction in the radionuclide retention in the main organs measured. In contrast, no significant differences were observed between untreated rats and rats treated with apple-pectin. These observations were discussed in terms of ability of pectins to bind Cs and compared to recently published results obtained after treatment of Cs-contaminated children with this chelate.     

Endogenous excretion and true absorption of cobalt as affected by the oral supply of cobalt

At the end of a 49-d experiment with 32 growing male rats, a period of 8 d was used to determine endogenous excretion and true absorption as well as apparent absorption and retention of cobalt with the aid of the isotope dilution technique. For this purpose, a single im dose of⁵⁸Co was applied at d 35 of the experiment. After that, urine and feces were collected separately from d 8 to 15 after injection of the isotope. The specific cobalt activity of the liver was used as an endogenous reference source. The basal diet provided 5.9 ppb cobalt, the different treatment groups were obtained by supplementing the diet with 0, 10, 50, 250, or 1250 ppb cobalt. The different diets were offered from the beginning of the experiment. In the balance period, apparent and true absorption as well as fecal excretion behaved similar to cobalt intake, whereas urinary excretion increased more rapidly with increasing cobalt supply. Endogenous fecal excretion accounted for 3.5 ng Co/d in the groups fed the diets without and with 10 ppb cobalt. An increase was not observed until supplementing the diet with 50 ppb cobalt. This increase between 250 and 1250 ppb cobalt was higher than the corresponding increase in the dietary cobalt supply. This indicates that endogenous fecal excretion might be more important for homeostatic regulation at a higher dietary cobalt concentration. Endogenous renal excretion as calculated from the results of the isotope dilution technique showed a similar kind of response to increasing cobalt supply as endogenous fecal loss. Nevertheless, the elimination of excessive cobalt mainly took place by adjusting urinary excretion, whereas the variations in true absorption and endogenous fecal excretion had no quantitative importance. Apparent and true absorption were on average 28.0 and 29.8%, respectively, of the cobalt intake. In the case of retention, a marked decline was observed from 19% in the depletion group to 3% with 1250 ppb cobalt, again demonstrating the importance of urinary excretion for controlling the cobalt content of the organism.     

Endogenous iron excretion

The effects of supplemental oral (0, 40, and 400 ppm) and parenteral iron (0 and 2.72 mg Fe iv given initially as a single dose) on iron absorption, excretion, and retention were determined in 30 rats. Endogenous fecal iron excretion was determined by the radioisotope dilution technique after im injection of 80 kBq Fe-59, using blood and certain body tissues as reference sources for the estimation of the specific activity (Bq Fe-59/micrograms Fe) of endogenous iron. The basal diet contained 3.6 ppm Fe. Fe(III)-hydroxide-polymaltose was used as the sole iron source in oral, iv, and im iron treatments. Iron balance as determined from day 14 to 20 of the experiment was not significantly affected by iv iron administration. Nevertheless, a temporarily reduced retention should have occurred, since differences in final body iron contents were lower than 2.72 mg, as compared to the respective untreated groups. Apparent iron absorption and iron retention increased with surplus oral iron, and the efficiency rates were highest with adequate iron supply (40 ppm). True absorption rates of iron were similar without any, and with 40 ppm Fe amounting 40 to 50% of the intake. In the iron deficient rats, half of the actually absorbed iron (about 16 micrograms/d) was lost by endogenous fecal re-excretion, and another 3 micrograms/d by the urinary route. Endogenous loss with feces and with urine increased with further oral iron supply, but at a considerably lower rate as total fecal excretion. Parenterally administered iron did not affect endogenous loss at all. The results indicate that endogenous excretion cannot be regarded as a means to eliminate excessive iron, and might actually be an inevitable loss.     

Internal dose assessment of <Superscript>210</Superscript>Po using biokinetic modeling and urinary excretion measurement

The mysterious death of Mr. Alexander Litvinenko who was most possibly poisoned by Polonium-210 (²¹⁰Po) in November 2006 in London attracted the attention of the public to the kinetics, dosimetry and the risk of this high radiotoxic isotope in the human body. In the present paper, the urinary excretion of seven persons who were possibly exposed to traces of ²¹⁰Po was monitored. The values measured in the GSF Radioanalytical Laboratory are in the range of natural background concentration. To assess the effective dose received by those persons, the time-dependence of the organ equivalent dose and the effective dose after acute ingestion and inhalation of ²¹⁰Po were calculated using the biokinetic model for polonium (Po) recommended by the International Commission on Radiological Protection (ICRP) and the one recently published by Leggett and Eckerman (L&E). The daily urinary excretion to effective dose conversion factors for ingestion and inhalation were evaluated based on the ICRP and L&E models for members of the public. The ingestion (inhalation) effective dose per unit intake integrated over one day is 1.7 × 10⁻⁸ (1.4 × 10⁻⁷) Sv Bq⁻¹, 2.0 × 10⁻⁷ (9.6 × 10⁻⁷) Sv Bq⁻¹ over 10 days, 5.2 × 10⁻⁷ (2.0 × 10⁻⁶) Sv Bq⁻¹ over 30 days and 1.0 × 10⁻⁶ (3.0 × 10⁻⁶) Sv Bq⁻¹ over 100 days. The daily urinary excretions after acute ingestion (inhalation) of 1 Bq of ²¹⁰Po are 1.1 × 10⁻³ (1.0 × 10⁻⁴) on day 1, 2.0 × 10⁻³ (1.9 × 10⁻⁴) on day 10, 1.3 × 10⁻³ (1.7 × 10⁻⁴) on day 30 and 3.6 × 10⁻⁴ (8.3 × 10⁻⁵) Bq d⁻¹ on day 100, respectively. The resulting committed effective doses range from 2.1 × 10⁻³ to 1.7 × 10⁻² mSv by an assumption of ingestion and from 5.5 × 10⁻² to 4.5 × 10⁻¹ mSv by inhalation. For the case of Mr. Litvinenko, the mean organ absorbed dose as a function of time was calculated using both the above stated models. The red bone marrow, the kidneys and the liver were considered as the critical organs. Assuming a value of lethal absorbed dose of 5 Gy to the bone marrow, 6 Gy to the kidneys and 8 Gy to the liver, the amount of ²¹⁰Po which Mr. Litvinenko might have ingested is therefore estimated to range from 27 to 1,408 MBq, i.e 0.2–8.5 μg, depending on the modality of intake and on different assumptions about blood absorption.     

Osteosarcoma development following single inhalation exposure to americium-241 in beagle dogs

Young, mature Beagle dogs underwent single inhalation exposure to respirable aerosols of 241AmO2 to determine the radiation dose distribution to tissues. The dogs were serially sacrificed to assess the clearance of 241Am from the lung, the rate of translocation to internal organs, the pattern of retention in the organs, and the rates and modes of excretion. Americium dioxide was relatively soluble in the lung, leading to the translocation of significant quantities of 241Am to bone and liver, thus delivering radiation doses to these tissues nearly equal to that received by the lung. Osteoblastic osteosarcomas developed in four dogs surviving more than 1000 days after exposure. Histologically, all of the osteosarcomas were associated with areas of radiation osteodystrophy characterized by bone infarction, peritrabecular new bone formation, marrow fibrosis, and microresorptive cavities. The retention and translocation of inhaled 241Am in dogs is similar to that of man, indicating that 241Am inhaled by humans may potentially result in significant risk of bone tumor development.     

Demonstration of N-acetyldopamine in human kidney and urine

Free and conjugated dopamine and N-acetyldopamine concentrations were measured in human urine and kidneys by reversed phase high performance liquid chromatography with single-electrode electrochemical detection. Conjugated N-acetyldopamine was found to occur in urine from six normal humans and in four out of six human kidneys. Unconjugated N-acetyldopamine was detected in only one urine sample and in three of seven kidneys. Urinary excretion of total N-acetyldopamine averaged 0.485 micromoles/day. This compares to a total dopamine excretion of 4.69 micromoles/day in the same subjects. In the kidneys, total N-acetyldopamine concentration averaged 1.46 nanomoles/gram. Total dopamine in the same tissues averaged 5.48 nanomoles/gram. N-acetyldopamine was not detected in human caudate nucleus, mouse whole brain, or liver from Rhesus monkey. When daily urinary excretion rates of N-acetyldopamine were determined in six individuals by both single-and dual-electrode electrochemical detection, the results were highly correlated for both free and total N-acetyldopamine (r>0.97,p<0.001). Using dual-electrode electrochemical detection, conjugated N-acetyldopamine accounted for 96.4% of the total N-acetyldopamine excretion. This value was 95.8% in the same individuals using single-electrode detection.     

Metabolism of N-(3′,5′-Dichlorophenyl)succinimide in Rats and Dogs

When N-(3′,5′-dichlorophenyl)succinimide (DSI)-carbonyI-¹⁴C and –pheny-³H were each orally administered to rats, regardless of the label site, most of the dose was readily eliminated. There was no difference in the excretion rate between male and female rats. No radioactive residues were detected in tissues and organs 24 hr after dosing. Urinary metabolites consisted of N-(3′,5′-dichlorophenyl) succinamic acid (DSA), N-(3′,5′-dichlorophe-nyl) malonamic acid (DMA), N-(3′5’-dichlorophenyl)-2-hydroxysuccinamic acid (2-OH-DSA) and 2-OH-DSA derivatives. In dogs, most of the administered dose was excreted in equal amounts in urine and feces. 2-OH-DSA derivatives were main urinary metabolites and most of fecal radiocarbon was due to intact DSL. The results of this study indicate that DSI is a biodegradable compound which is unlikely to leave any persistent residues in animals.

The degradation of DSI to DSA was mediated by an arylamidase-type hydrolase, which was present in the microsomal fraction of rabbit liver. The enzyme activity was found in livers and kidneys of four animal species tested. Depending on the animal species, the enzyme appears to be important for the metabolism of DSI.     

Chronic uranium exposure dose-dependently induces glutathione in rats without any nephrotoxicity

Abstract

Uranium is a heavy metal naturally found in the earth's crust that can contaminate the general public population when ingested. The acute effect and notably the uranium nephrotoxicity are well known but knowledge about the effect of chronic uranium exposure is less clear. In a dose-response study we sought to determine if a chronic exposure to uranium is toxic to the kidneys and the liver, and what the anti-oxidative system plays in these effects. Rats were contaminated for 3 or 9 months by uranium in drinking water at different concentrations (0, 1, 40, 120, 400, or 600 mg/L). Uranium tissue content in the liver, kidneys, and bones was linear and proportional to uranium intake after 3 and 9 months of contamination; it reached 6 μg per gram of kidney tissues for the highest uranium level in drinking water. Nevertheless, no histological lesions of the kidney were observed, nor any modification of kidney biomarkers such as creatinine or KIM-1. After 9 months of contamination at and above the 120-mg/L concentration of uranium, lipid peroxidation levels decreased in plasma, liver, and kidneys. Glutathione concentration increased in the liver for the 600-mg/L group, in the kidney it increased dose dependently, up to 10-fold, after 9 months of contamination. Conversely, chronic uranium exposure irregularly modified gene expression of antioxidant enzymes and activities in the liver and kidneys. In conclusion, chronic uranium exposure did not induce nephrotoxic effects under our experimental conditions, but instead reinforced the antioxidant system, especially by increasing glutathione levels in the kidneys.     

Studies on the Utilization of Levulinic Acid

The single injection of levulinic acid oxime (250 mg/rat) or α-ketoglutaric acid oxime (250 mg/rat) on rats, carrying radioactive cesium, promoted both urinary and fecal excretion of this radionuclide. The administration of levulinic acid oxime (sodium salt) decreased the cesium retention by liver. The administration of the oxime did not have influence on the urinary excretion of sodium and potassium in normal rats. The toxicity of the oxime was low. The LD₅₀ of α-ketoglutaric acid oxime was 3500 mg/kg (mice, intraperitoneally). (The LD₅₀ of levulinic acid oxime has already been indicated as 2040 mg/kg (mice, intravenously).     

The Retention of Cadmium and Selenium Influence in Fowl and Chickens of F1 Generation

The retention of cadmium and selenium influence on Cd retention in the muscle, liver and kidneys of hens, chickens and in eggs was studied. Cadmium (Cd) as cadmium chloride (CdCl(2)) and selenium (Se) as sodium selenite (Na(2)SeO(3)) were added to feed at dosages: group 0-control, group 1-20 mg/kg Cd, group 2-30 mg/kg Cd + 4 mg/kg Se. The birds were exposed to Cd for 8 weeks. Cadmium level in hens and cocks was found highest in the kidneys, followed by the liver and muscle. Se supplementation resulted in Cd increase in the muscle tissue and in the reduction of Cd content in the liver and in significant decrease in the kidneys (p < 0.05). A higher Cd level in the yolk and lower in the white was noted in both experimental groups. Nonsignificant increase of Cd in eggs was noted in experimental groups with Se supplementation. Level of cadmium in organs of 7-day-old chicks hatched from Cd-treated hens in both experimental groups was low but the tendency to accumulate preferentially the Cd in the liver and kidneys was recorded. Supplementation of selenium in hens and cocks was not reflected in the decrease of Cd in these two organs of F(1) chickens but was reflected in increase in the muscle. In spite of relatively high Cd levels in the organs of layers no layer-egg-chickens transfer was observed. It was confirm that kidneys and liver are organs more attacked by dietary cadmium than muscle. Supplementation of low dose of Se resulted in decrease of cadmium deposition in analyzed organs.     

Biokinetic measurements and modelling of urinary excretion of cerium citrate in humans

Tracer kinetics in healthy human volunteers was studied applying stable isotopes of cerium citrate to obtain biokinetic human data for the urinary excretion of cerium. These data were then used to compare and validate the biokinetic model for lanthanides (cerium) proposed by Taylor and Leggett (Radiat Prot Dosim 105:193–198, 2003), which is substantially improved and more realistic than the biokinetic model currently recommended by the International Commission on Radiological Protection (ICRP Publication 67, 1993); both models are primarily based on animal data. In the present study, 16 adults were investigated and two cerium tracers were simultaneously administered, both intravenously and/or orally. The cerium concentrations in urine were determined by inductively coupled plasma mass spectrometry. Ingested cerium citrate was poorly absorbed, and its low excretion was similar to the prediction of the biokinetic model of Taylor and Leggett. In contrast, after injection of cerium citrate its urinary excretion was rapidly increased, and the model underestimated the experimental results. These results suggest that urinary excretion of cerium may be dependent on the administered chemical form of cerium (speciation).     

Effect of dietary selenium and tumor status on the retention of75Se by tissues and mammary tumors of DMBA-treated rats

The effects of the presence of mammary tumors on 75Se retention was examined in DMBA-treated rats. Tumor bearing rats fed varying amounts of Se exhibited an inverse linear dose response between dietary Se intake and tissue retention of 75Se in whole body, heart, lungs, ovaries, adrenals, spleen, and muscle. Tumor 75Se retention, however, was independent of the dietary intake of Se. Tumor bearing rats excreted more 75 Se label in the urine compared to both control rats fed the same amount of Se and DMBA-treated animals that remained tumor free. In the short term, no significant differences were seen in tissue retention of 75Se. By 7 d, the increased urinary excretion of the label resulted in significantly decreased retention of 75Se in blood, spleen, liver, lungs, and kidneys of tumor-bearing rats compared to tumor-free animals. The presence of tumors, however, did not affect the liver distribution of the label among cytosolic proteins. These results suggest that tumor bearing animals have an accelerated urinary excretion of Se compared to animals without tumors and that tumors either have a very slow turnover of Se or a low priority for the element.     

Dietary oxidized linoleic acid enhances liver cholesterol biosynthesis and secretion in rats

Based on studies showing that excretion of cholesterol is elevated in rats fed oxidized linoleic acid, we hypothesized that cholesterol metabolism is enhanced under such oxidative stress. Liver cholesterol biosynthesis and secretion and fecal cholesterol excretion were studied in rats fed for 4 weeks diets containing 10% oxidized linoleic acid. Incubation of liver slices with 1-(14)C acetate and intraperitoneal injection of 5-(3)H-mevalonate showed the occurrence of enhanced hepatic cholesterol biosynthesis and elevated liver cholesterol secretion in animals subjected to oxidative stress. In addition, impaired liver cholesterol uptake was suggested. Higher levels of excreted cholesterol observed in the experimental animals were accompanied by augmented levels of liver phospholipids, primarily phosphatidylcholine, which most likely increased to enable the excessive cholesterol excretion. This study thus demonstrates that ingestion of oxidized lipids causes profound alterations in cholesterol metabolism.