Removal of Pu and am from beagles and mice by 3,4,3-LICAM(C) or 3,4,3-LICAM(S)

Decorporation of Pu and Am by tetrameric catechoylamide (CAM) ligands has been investigated in beagles and mice. Eight dogs were injected intravenously (iv) with 237 + 239Pu(IV) + 241Am(III) citrate, and 30 min later, pairs of dogs were injected iv with 30 mumole/kg of 3,4,3-LICAM(C) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-5-sulfobenzoyl)tetr aazatetradecane, tetrasodium salt], 3,4,3-LICAM(S) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-4-carboxybenzoyl)te traazatetradecane, tetrasodium salt], CaNa3-DTPA, or each of the latter two ligands. Blood was sampled, and excreta were collected for 7 days, at which time the dogs were sacrificed and nuclide retention in liver and nonliver tissue was measured. Groups of five mice were each given 238Pu(IV) or 241Am(III) citrate iv; 3 min later 30 mumole/kg of a CAM ligand was injected intraperitoneally, mice were killed at 24 hr, and separated excreta and tissues were analyzed. In the dogs, average retention at 7 days of the injected Pu and Am, respectively, was as follows: 12 and 70% after treatment with a CAM ligand alone; 30 and 20% after DTPA; 12 and 20% after LICAM(S) plus DTPA; 90 and 89% without a ligand. In the mice, mean retention of the injected Pu and Am, respectively, was as follows: 14 and 66% after treatment with LICAM(C); 21 and 54% after LICAM(S); 91 and 87% without a ligand. In both species, about 99% of net Pu excretion (excretion with ligand - excretion without ligand) promoted in 24 hr by DTPA or LICAM(S) was in the urine, whereas about 10% of net Pu excretion promoted by the less hydrophilic LICAM(C) was in feces. Delayed excretion of both Am and Pu was significant in all ligand-treated dogs. Comparison of the nuclide content of tissues of ligand-treated mice with those of mice killed 3 min after nuclide injection indicated that the CAM ligands chelated circulating Pu and Am and prevented further deposition. In addition, the CAM ligands removed much of the presumably loosely bound Pu present in liver and skeleton at the time of ligand injection. LICAM(C) was more effective in removing Pu from liver and LICAM(S) was more effective in the skeleton. Moderate to severe uremia and histological evidence of cell killing in the distal tubules of the kidney were observed in the four dogs injected once with 30 mumole/kg of LICAM(S).(ABSTRACT TRUNCATED AT 400 WORDS)     

228Th retention and dosimetry in beagles

Total-body and skeletal retention of 228Th were determined in a group of 104 young adult male and female beagles for about the first 7 years after the injection of 0.00159 to 2.76 muCi/kg. Ratios of 224Ra / 228Th , 212Pb / 228Th , and 212Bi / 228Th in the skeleton and in soft tissues of 20 beagles were measured as a function of time after injection. A humerus, femur, and ulna from 20 dogs dying 7 to 554 days after injection were sectioned, and the 228Th concentration was obtained for each piece. Percentage biological retention in the skeleton of 228Th at t days after injection could be described as 68.1 e-0. 000180t . Ratios of daughter-to-parent activity in soft tissue showed no definite trend with dose level or time and averaged Ra/Th = 0.56, Pb/Th = 0.83, and Bi/Th = 0.91, whereas the ratios for the skeleton varied with both dose level and time. Ratios of activity in the skeleton from lowest to highest dose level after 2 years following injection ranged between Ra/Th = 0.88 to 0.95, Pb/Th = 0.78 to 0.92, and Bi/Th = 0.77 to 0.90. Retained 228Th was deposited most heavily in parts of the skeleton with much trabecular bone, much bone surface area, and high bone remodeling rates. No changes in this deposition pattern could be discerned during the 554 days over which the measurements of sectioned long bones were made.     

Toxicity of 241Am in male C57BL mice: relative risk versus 226Ra

A life-span study on male C57BL mice after injection of various doses of 241Am was conducted. The effects on life span were evaluated and the incidence of tumors was determined by procedures that take competing risks into account. Bone tumors were induced in the mice by injections of 22 and 58 Bq 241Am per g. The mice died early from nonneoplastic diseases at the higher dose levels (190, 373, and 1197 Bq 241Am/g). Additionally, spontaneously occurring tumors such as liver carcinomas, lymphosarcomas, and lymphoreticulosarcomas occurred at an enhanced rate with increasing dose level. The data for survival time after 241Am injection and death with bone tumor were compared to data collected previously for 226Ra-injected mice of the same C57BL strain. This enabled direct comparison in the same strain of the effects of the bone-surface seeker 241Am to the effects of the bone-volume seeker 226Ra. The proportional hazards model was applied and the rate of death with bone tumor was 12.9 +/- 5.2 times higher after 241Am injection than after 226Ra injection if the regression covariate was the average dose to the skeleton. The relative risk was 3.5 +/- 1.7 if regressed on the injected radioactivity. The mortality rate after 241Am injection was 20.4 +/- 3.6 times higher than after 226Ra injection if regressed on average dose to the skeleton.     

Effect of age on the efficacy of Zn-diethylenetriaminepentaacetic acid therapy for removal of Am and Pu from beagles

Decorporation of intravenously injected monomeric 241Am and 237+239Pu by the administration of 30 mumole Zn-diethylenetriaminepentaacetic acid (DTPA)/kg each day beginning 2 weeks after radionuclide injection was compared in beagles entered into the experiment when 3 months (juveniles). 1.9 years (young adults), or 10 years (mature adults) old and studied for about 5 months. DTPA therapy was most effective in the juvenile dogs and least effective in the mature adults. Retention of 241Am in the liver decreased from a pretreatment value for adults of about 50% of the injected activity to about 10% in the mature adults and less than 1% in the young adults at 140 days of treatment, while the liver retention of juveniles decreased from pretreatment values of about 16% to undetectable levels by 28 days of treatment. Plutonium retention in the liver decreased from adult pretreatment levels of about 30% of the injected activity (corrected for radioactive decay) to near 10% in the mature adults and 6% in the young adults at 140 days of treatment, while juvenile liver retention decreased from pretreatment values near 15% to undetectable levels by 56 days of treatment. Nonliver Am retention (mainly skeleton) decreased in mature adults from pretreatment values of about 45% of the injected activity to near 25%, in young adults from 35 to 20%, and in juveniles from roughly 70 to 9% by 140 days of DTPA administration. Nonliver Pu retention decreased from pretreatment values of about 50% of the injected activity (corrected for radioactive decay) for mature and young adults to about 30% by 140 days and from 75 to 16% in juveniles over the time period.     

243,244Cm studies in C57BL/Do mice

Three groups of C57BL/Do mice were injected with different activities of 243,244Cm so that the long-term biological effects could be evaluated. The biological retention, R, of injected curium in the skeleton at t days after injection could be represented by the equations R = 0.245e-0.000379t and R = 0.208e-0.000494t for male and female mice, respectively. Effective skeletal retention equations were used to calculate the cumulative mean skeletal dose in rad at 140 days before death in each group of mice. The primary objective of this study was to determine the relative biological effectiveness (RBE) of 243,244Cm compared to 226Ra, using bone sarcoma induction as the end point. Combined data (bone sarcomas per 10(6) mouse-rad) for male and female mice permitted the RBE value +/- SD for 243,244Cm to be calculated as 4.4 +/- 1.8 compared to 1.0 for 226Ra. A comparison of RBE values form a previous study in this mouse strain and the value for 243,244Cm from this study suggests that the trivalent actinides 241Am, 243,244Cm, and 249Cf are about three times less effective for bone sarcoma induction than 239Pu.     

Cytogenetic effects of 241Am in the Allium test

The purpose of this study was to elucidate the genome damage induced by 241Am-irradiation using different parameters of cytogenetic evaluation in Allium-test. The root tip cells test-system for the cytogenetic effects studying was used. 241AmCl3 of different concentrations was used (1.5 x 10(-9)-1.5 x 10(-7) g/l). Water solution-to-plant transfer factor for 241Am was found to be 0.18 +/- 0.04. The internal doses of 241Am accumulated during germination were 0.37-37.00 cGy. The impact of 241Am-irradiation was evaluated on the mitotic index (MI), the yield of aberrant anaphases (AA), the distribution of chromosome aberrations number in cells and the average level of lesion of aberrant cell (LAC). Probably all these parameters are differ in sensitivity to damage factor, but only some changes in MI was revealed. It is supposed, that the absence of any changes in the distribution of chromosome aberrations number in cells and the average level of LAC in 241Am-irradiated cells confirm the absence of significant 241Am-impact on chromosomes, as the alpha-irradiation should cause significant damages in chromosomes. Although solutions of 241Am were high-concentrated, the seedlings didn't accumulate high internal doses. It appears the distribution of 241Am is a significantly heterogeneous hence it is possible the absorbed doses in nuclei can't reach the level necessary for revealing of cytogenetic effects.     

Effect of gavaged chemical form of 241Am on its retention in mice

The retention of 241Am in mice 48 h after administration by gavage is reported here. The 241Am was given to mice in the form of either 241Am nitrate or 241Am citrate. The 241Am was also injected into rats in the same form. The homogenized livers of those rats were subsequently administered by gavage to another group of mice. The retention of 241Am citrate was 1.5 X 10(-2)% of the original dose and was the highest among the compounds examined. The retention of biologically incorporated 241Am into the liver as 241Am nitrate and as 241Am citrate was 2.4 X 10(-3) and 2.6 X 10(-3)%, respectively, and was similar to the retention of 241Am nitrate, which was 2.8 X 10(-3)%. The ratio of the retention in the carcass to that in the liver for the 241Am citrate was lower than that of the 241Am nitrate and the biologically incorporated 241Am. This difference indicates that the distribution of 241Am in the animal body depends on the chemical form administered. The retention of liver-incorporated 241Am as citrate after autolysis of the liver is similar to that of fresh liver-incorporated 241Am citrate.     

Effects of vasomotor- and mediator-induced hypotension on bronchomotor tone in swine

We studied the sympathetic neural response on airways to hypotensive stimuli in 19 swine in vivo. The effects of pharmacologically induced hypotension with nitroprusside (NTP) and hypotension elicited by intravenous compound 48/80 (48/80), a mast cell degranulating agent, were compared after equivalent reductions in mean arterial blood pressure (MAP). Reduction of the MAP to 60% of base line with NTP in six swine caused an increase in plasma epinephrine (E) from 60 +/- 28 to 705 +/- 276 pg/ml (P = 0.032) and plasma norepinephrine (NE) from 270 +/- 46 to 796 +/- 131 pg/ml (P = 0.032). Comparable reduction in MAP elicited with 48/80 in six other swine caused a substantially greater increase in both plasma E (9,581 +/- 4,147 pg/ml; P = 0.012 vs. NTP group) and plasma NE (2,239 +/- 637 pg/ml; P = 0.041 vs. NTP group). Catecholamine secretion attenuated mediator-induced changes in lung resistance (RL). In animals receiving 48/80, RL increased from 2.97 +/- 0.31 to 7.44 +/- 0.56 cmH2O.l-1.s. In animals having ganglionic blockade with 7.5 mg/kg iv hexamethonium and beta-adrenergic blockade with propranolol (4.0 mg/kg iv followed by 40 micrograms/kg-1.min-1), comparable doses of 48/80 caused an increase in RL to 18.6 +/- 4.55 cmH2O.l-1.s (P less than 0.04 vs. swine receiving neither hexamethonium nor propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone structural parameters, dosimetry, and relative radiation risk in the beagle skeleton

A variety of morphometric and histomorphometric parameters such as the mass of bone and marrow, bone surface areas, percentage of bone volume, percentage of the surface that is trabecular, and percentage of surfaces that are forming and resting are calculated for all major parts of the beagle skeleton. The total bone surface of the beagle is estimated at 2.9 m2 with 53.7% of the surface area being associated with trabecular bone. There are about 4.5 x 10(9) bone-lining cells and about 1 x 10(9) osteoblasts. From the fractional retention in each part of the skeleton, the initial surface concentration of 239Pu after a single injection of 592 Bq/kg body wt (0.016 microCi/kg) on resting surfaces and at sites of bone formation is calculated for various values of the affinity ratios of trabecular/cortical and forming/resting surfaces. These estimated concentrations then yield dose rates as well as cumulative and collective doses to bone-lining cells and osteoblasts in the different parts of the skeleton. On the assumption that the relative risk of tumor induction is proportional to the collective dose to either bone-lining cells or osteoblasts, the frequency of tumor occurrence is calculated and compared to observed frequencies. Both hypotheses yield approximate agreement with experimental data for different ratios of trabecular/cortical radiation sensitivity, although the differences between some bones are statistically significant.     

Chelation therapy of incorporated plutonium-238 and americium-241: comparison of LICAM(C), DTPA and DFOA in rats, hamsters and mice

The carboxylated catechoylamide 3,4,3-LICAM(C) was tested for removal of 238Pu and 241Am from small laboratory rodents. The effectiveness of treatment was compared with that of two ligand preparations approved for clinical use: calcium-trisodium diethylenetriaminepentaacetate (DTPA) and desferrioxamine (DFOA). With early treatment and at the dosage used clinically for the decorporation of actinides with DTPA (30 mumol/kg body weight) LICAM(C) was superior to DFOA but when compared with DTPA, the effect of LICAM(C) on 238Pu was greater only in bone; as little as 1 mumol LICAM(C)/kg was as effective as 30 mumol DTPA/kg. However, in all animals treated with LICAM(C) there was a large increase in the 238Pu content of the kidney. With 241Am the effect of DTPA was always superior to that of LICAM(C). The best overall results early (1 day) after injection of 238Pu and 241Am were achieved by a combination of a single injection of LICAM(C) and DTPA with subsequent continuous administration of DTPA in drinking water. LICAM(C) affected the retention of 238Pu even if given orally; the data suggested that about 3 per cent of ingested LICAM(C) was absorbed. When the beginning of treatment was delayed, LICAM(C) became equally effective or less effective than DTPA even as far as 238Pu retention in bone was concerned, but it still increased the accumulation of 238Pu in the kidneys.     

Microdistribution and localized dosimetry of 241Am in bones of beagle dogs

The microdistribution of 241Am in selected bones of seven beagle dogs was analysed using a computer controlled microscope photometer. Four of the animals receiving between 102.5 and 165 kBq/kg were killed between 7 and 20 days after injection, and three animals receiving 32.9-34.0 kBq/kg were killed between 1300 and 1569 days. Using the photometric scanning technique, the concentrations of 241Am in several anatomical regions, as well as the specific surface activities and their variations, dose rates, accumulated radiation doses, burial depths and morphometric parameters, were derived. Dose rates to the 0-10 micron marrow band adjacent to surfaces were found to be between 8.6 and 15.7 times higher than the average skeletal dose. Accumulated radiation doses from initial deposits to lining cells were estimated to be between 87 and 252 Gy. The average burial depth in the animals killed at later times was around 8 micron. Morphometric parameters showed that radiation damage occurred in these animals, resulting in abnormal trabecular architecture. A positive correlation between specific surface activity and local turnover rates was established.     

Study of the influence of peroral zincacin on the removing of ingested Americium

Effect of different cincacine doses was studied in rats ingesting americium citrate during 2 weeks. As a result new data showing the possibility and efficacy of per oral cincacine administration at americium intake into digestive tract have been obtained. Dose dependence of cincacine efficacy has been stated for per oral 241Am intake. Preparation administration at a dose of 25 mumol/kg reduces amount of 241Am in skeleton, liver and kidney by 93, 90 and 33%, respectively and is optimum for radionuclide removal from the body and for the prevention of its deposition in organs. Digestive system organs and kidney structure at cincacine administration at a dose of 150 and 300 mumol/kg) to the rats ingesting 241Am have been studied.     

Chronic bronchial allergic inflammation increases alveolar liquid clearance by TNF-alpha -dependent mechanism

Bronchial inflammation in allergic asthma is associated with active exudation from the bronchial tree into the interstitial space of both mucosa and submucosa. The aim of this study was to evaluate epithelial and endothelial permeability as well as alveolar fluid movement in a model of chronic allergic inflammation in Brown-Norway rats sensitized and challenged with ovalbumin (OA). Control groups were challenged with saline solution (C), and rats were immunized by OA but not challenged (Se). Lung sections showed a marked inflammatory infiltrate associated with perivascular and peribronchiolar edema in OA. To measure alveolar liquid clearance, a 5% bovine albumin solution with 1 microCi of (125)I-labeled human albumin was instilled into the air spaces. Alveolar-capillary barrier permeability was evaluated by intravascular injection of 1 microCi of (131)I-labeled albumin. Endothelial permeability was significantly increased in OA, from 0.08 +/- 0.01 in the C group to 0.19 +/- 0.03 in OA group (P < 0.05). Final-to-initial protein ratio was also statistically higher in OA (1.6 +/- 0.05) compared with C (1.38 +/- 0.03, P = 0.01) and Se groups (1.42 +/- 0.03, P = 0.04). Administration of anti-tumor necrosis factor-alpha antibodies within the instillate significantly decreased this ratio (1.32 +/- 0.08, P = 0.003 vs. OA). To conclude, we demonstrated a tumor necrosis factor-alpha-dependent increase in alveolar fluid movement in a model of severe bronchial allergic inflammation associated with endothelial and epithelial leakage.     

Long-term distribution of 239-Pu, 241-Am,and 233-U in the various bones of the skeleton of adult rats

Conclusions The macrodistribution of the bone surface seekers plutonium and americium and of the bone volume seeker uranium has been analysed in different bones of the skeleton of adult male and female rats under identical laboratory conditions. Whereas the relative concentration differs in a wide range between the different bones and the different nuclides there is the general tendency with time to reach a mean concentration for the whole skeleton. Whereas the retention of 239-Pu and 241-Am is similar in the skeleton with a biological half-life of more than 1 year, 233-U shows a rapid decrease of the nuclide content with a biological half-life of 80 days in male and 140 days in female rats, respectively.     

Flumequine in Atlantic salmon Salmo salar: disposition in fish held in sea water versus fresh water

14C-labeled flumequine was administered as a single oral (5 mg kg(-1), 86 microCi kg(-1)) or intravenous (5 mg kg(-1), 82 microCi kg(-1)) dose to Atlantic salmon Salmo salar held in sea water or in fresh water. The absorption, tissue distribution and elimination were determined by means of liquid scintillation counting and whole-body autoradiography. The drug was rapidly absorbed and extensively distributed in all groups of fish. Radiolabeled compound was present in blood and muscle for more than 8 wk in the freshwater groups. In the seawater groups, however, no radioactivity was detected in the blood and muscle after 4 d and 2 wk, respectively. It was concluded that flumequine was eliminated at a substantially higher rate from Atlantic salmon in sea water than in fresh water.     

The effect of age on the distribution of 241Am in the rat body

In experiments with albino mongrel rats aged from 2 weeks to 1.5-2 years, the kinetics of 241Am distribution was studied after single intraperitoneal administration thereof. The content of 241Am in the skeleton was shown to decrease and in the liver to increase with age.     

Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway surface.

The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.     

Determining liver retention of transuranium elements in living beagles

Summary A method has been developed whereby the liver content of photon-emitting transuranium elements can be determined in living beagles by a combination of total-body and partial-body counting. Calibration of the system was accomplished through the photon counting of intact dogs and also of the parts of the same animals following autopsy. A determination of the calibration factors for²⁵²Cf,²⁴⁷Cf,²⁴³Cm,²³⁷Pu, and²⁴¹Am has been made. The special case of²⁵²Cf was treated in which a significant fraction of the high energy fission gamma-ray spectrum penetrates the Pb shield employed in partial-body counting, and methods were developed which allow for this effect in the calculation of liver content. Some uniformity of response in the system was evident for all of the emitters which were considered. It is proposed that similar techniques could be applied in the determination of selected organ radioactivity in other species including man.Supported by ERDA Contract E (11-1)-119.     

Radiosensitivity and proliferative activity of vertebral CFU-S surviving in mice injected with oncogenic activities of 239Pu or 241Am

Survival, radiosensitivity and capability to produce differentiated progeny were followed in CFU-S from lumbar vertebrae of mice injected with 198.6 kBq 239Pu/kg or 208.6 kBq 241Am/kg. The CFU-S assay and 59Fe uptake into spleen colonies were used. The number of CFU-S from treated mice was significantly lower than in controls. Higher radiosensitivity of CFU-S from 239Pu- or 241Am-treated mice was demonstrated using additional exposure to 0.5 Gy X-rays 1, 24, 48, 72 hrs after cell transplantation and expressed more precisely by survival curves obtained 1 hr after the marrow cell injection. The effect of 239Pu on CFU-S was characterized by Do 0.58 Gy (n = 0.91) and that of 241Am by Do 0.64 Gy (n = 0.91); corresponding control values were Do 0.89 Gy, n = 1.11. Lower iron utilization due not only to the decreased CFU-S numbers, but also to the defective production of erythroid cells per one CFU-S was found. Complexity of radiation effect on hemopoietic stem cells was demonstrated by the present study.     

Potency of peroral and parenteral administration of Zinc-DTPA for decorporation of 241Am from the gastrointestinal tract

An effect of cincacine at three doses (25, 150 and 300 mumol/kg) has been studied in rats receiving 241Am citrate intragastrically. The radionuclide was introduced every other day for 2 weeks. The total content was 925 kBq/kg. A cincacine administration leads to limitation of radionuclide accumulation in the major organs of deposition independent of the modes of intake. At gastrointestinal 241Am intake peroral cincacine administration is more effective in limiting this radionuclide accumulation in skeleton but less effective in reduction of its accumulation in liver compared to parenteral cincacine. No reliable dependence of cincacine efficacy on dosage has been revealed. A morphology study of organs has shown that cincacine ingestion at a dose of 150 mumol/kg for 4 weeks and at a dose of 300 mumol/kg for 2 weeks produces a toxic effect on the small intestine mucosa. 25 mumol/kg is the optimum dose and per os administration of higher doses is not expedient.