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PubMed1987

Acute lesions induced by alpha-irradiation of intestine after plutonium gavage of neonatal rats.

After gavage of two-day-old rats with 238Pu(IV)-citrate at 17.4 MBq/kg (122 kBq per animal), 45 per cent of the animals died during the second week following ingestion. Histological analysis showed that death was due to acute intestinal lesions caused by alpha-radiation that resulted in denudation of the ileum. Under these experimental conditions, the total alpha-dose delivered to the ileal wall and its contents was estimated at 150 Gy. No acute lesions were observed after gavage of two-day-old rats with Pu-citrate at 5.3 MBq/kg.

Acute Disease↗

PubMed1988

Localization of plutonium retention in the small intestine of the neonatal rat, guinea pig, baboon and macaca after Pu-citrate ingestion.

The retention of Pu-citrate in the gastrointestinal wall was compared at similar post ingestion times after ingestion at 2 days of age by rats and guinea pigs and at 1 to 34 days by neonatal primates. The small intestine was the main site of the Pu retention in all species. In rats and primates, most of the Pu was retained in the distal ileum, whereas in guinea pigs it was more homogeneously distributed. In the rats, Pu was retained in the epithelial cells on villi, but in the guinea pigs and primates it was confined to the macrophages under the epithelial cells in the lacteal region.

Animals↗

PubMed1989

The efficacies of pure LICAM(C) and DTPA on the retention of plutonium-238 and americium-241 in rats after their inhalation as nitrate and intravenous injection as citrate.

The pure carboxylated catechoyl amide LICAM(C) and the calcium and zinc salts of diethylenetriaminepenta-acetic acid (DTPA), were tested for efficacy for removing 238Pu and 241Am from rats after inhalation of the nitrate or intravenous injection of the citrate. The results were compared with the efficacy of methylated LICAM(C) used in previous experiments. It was shown that: (1) after inhalation of 238Pu nitrate, DTPA was far superior to pure LICAM(C); (2) after intravenous injection of 238Pu citrate, the infusion of DTPA plus LICAM(C) was only marginally more effective than DTPA alone; and (3) after inhalation or intravenous injection of 238Pu plus 241Am, the efficacy of pure LICAM(C) was only marginally more effective than the methylated form and neither form was effective for the decorporation of 241Am. It was concluded that DTPA, at present, remains the chelating agent of choice for treating persons accidentally contaminated with transportable forms of Pu and Am.

Aerosols↗

PubMed1991

A versatile plutonium-238 irradiator for radiobiological studies with alpha-particles.

A versatile irradiator has been constructed for in vitro irradiation of mammalian cells with alpha-particles of well-defined energy, LET, direction, dose and dose rate. It is based on approximately 1.2 x 10(9) Bq of 238Pu (on a platinum disc) contained in a He-filled chamber. In a standard configuration, monolayers of cells grown in 10 Hostaphan-based dishes are irradiated with 3.26 +/- 0.22 MeV alpha-particles (LET 121 keV microns-1) at selectable dose rates from approximately 2 Gy min-1 down to less than 10(-4) Gy min-1 (i.e. fluence rates of 1 x 10(7) cm-2 min-1 to 3 x 10(2) cm-2 min-1). Single dishes can be irradiated at dose rates up to 24 Gy min-1 (fluence rate 1 x 10(8) cm-2 min-1). Incident energy and LET can be varied from 0.8 to 4.2 MeV and 266 to 102 keV microns-1, respectively. The irradiator has full incubation and gassing facilities for protracted irradiations. The irradiator is particularly suitable for in vitro analytical studies of the biological effects of alpha-particles of energies and LETs similar to those which cells may receive in vivo from radionuclides such as radon and the actinides. It has been used successfully for investigations of a variety of alpha-particle-induced effects in different cell types irradiated either as attached monolayers or as very thin suspensions.

Alpha Particles↗

PubMed1991

The efficacy of DFO-HOPO, DTPA-DX and DTPA for enhancing the excretion of plutonium and ameriicum from the rat.

A hydroxypridinone derivative of desferrioxamine (Na-DFO-HOPO), a dihydroxamic derivative of diethylenetriaminepenta-acetic acid (ZnNa-DTPA-DX), and DTPA (CaNa3- and ZnNa3-DTPA) were tested at dosages of 30 mumol kg-1 for their ability to remove 238Pu or 241Am from rats after their intravenous injection as citrate or inhalation as nitrate. The most effective treatment regimen for injected Pu was the repeated administration of DFO-HOPO; by 7 days the body content was reduced to 8% of that in untreated animals. Repeated dosages of 3 mumol kg-1 DFO-HOPO were as effective as those of 30 mumol kg-1 DTPA. After inhalation of Pu nitrate, repeated treatment with DTPA, DTPA-DX or DFO-HOPO reduced the body content by 7 days to, respectively, 10, 15 and 31% of those in untreated animals. After inhalation of Am, DTPA-DX and DTPA were equally effective, the body contents being reduced to 7% of control values with repeated treatment. Injection of DFO-HOPO was ineffective for enhancing the elimination of inhaled or injected Am. The results confirm the strategy of examining the use of siderophore analogues for the decorporation of Pu or Am. However, at present DTPA should remain the agent of choice, particularly after inhalation.

Administration, Inhalation↗

PubMed1991

The incorporation of plutonium by the embryo and fetus of rats and guinea-pigs.

The transfer of 238Pu from the maternal circulation to the developing embryo and fetus was studied in rats and guinea-pigs to provide data for the development of dosimetric models for the human embryo and fetus. Following administration at different stages of gestation, measurements were made after 3 days in the rat and 7 days in guinea-pigs. The amount transferred was greater after administration at later stages of gestation, up to a maximum of about 0.8-0.9% of the injected activity per fetoplacental unit (FPU) and about 0.2% per fetus in both species. In advanced gestation the yolk sac, the initial site of haemopoietic stem cells, contained up to 80% of the total activity in the FPU in rats, compared with about 25% for the guinea-pig; retention in placental trophoblast was greater in the guinea-pig. The concentrations of 238Pu in the yolk sac were generally about two to three orders of magnitude greater than fetal concentrations and of the same order as in maternal liver and bone. In both species, concentrations in the embryo and fetus were greatest after injection early in gestation, reached their lowest around mid-organogenesis and increased again in later gestation. The fetus:mother whole-body concentration ratios in late gestation were about 0.1 and 0.05 in rats and guinea-pigs, respectively. Measurements were also made of the 238Pu retention in neonates at birth. In guinea-pigs the liver accounted for about 6-9% of retained activity; similar values for femora indicated skeletal retention of about 60-80%. For administration at each stage of gestation, and particularly at early stages, transfer of 238Pu to the fetus continued throughout gestation but concentrations decreased due to fetal growth.

Animals↗

PubMed1991

Effectiveness of DTPA treatments following the injection of particulate plutonium.

A limited long-term experiment has been completed in which the chronic toxicity resulting from a single intravenous injection of 31.4 kBq of a poly-disperse 239Pu colloid sol per kg of body weight was tested in Beagle dogs. The Pu deposited mostly in the phagocytic cells of liver, spleen and to a lesser degree in lung and bone marrow. Slow solubilization of the Pu particles by endogenous ligands caused translocation of the nuclide and redeposition mostly as monomeric Pu in the skeleton and in liver hepatocytes. Thus, the deposit behaved as expected from a pulmonary or wound contamination in humans with a moderately soluble depot of Pu such as Class W hot particles. Therefore, this type of deposit provided the basis for a practical model to study the ensuing radiation effects under various experimental conditions. The dogs were divided into three groups of four animals each, and the following conditions were applied: (a) no further treatment was given, allowing free translocation of the Pu to its secondary deposition sites; (b) interception of the Pu translocation by weekly injections of 30 mumol of Ca-DTPA/kg of body weight (Ca-chelate of diethylene-triaminepentaacetic acid); and (c) interception of translocation by daily injections of 30 mumol/kg body weight of Zn-DTPA. For each of the groups (b) and (c), three dogs were used in a lifetime study, and one was sacrificed for nuclide distribution studies. Free translocation and subsequent deposition in the skeleton resulted in the death of each of the non-chelated dogs from osteosarcoma between 1267 and 1594 days after injection. Weekly treatment with Ca-DTPA reduced the total Pu burden significantly, but these dogs also died with osteosarcoma between 1462 and 1783 days. Daily injections with Zn-DTPA reduced the total Pu burden more efficiently than Ca-DTPA and prevented continuous deposition of solubilized Pu on bone surfaces. The mean post-injection survival of these dogs was 3520 days or about 2.1 times that of the animals receiving Ca-DTPA, while the latent period for bone tumour induction was about 2.6 times longer. This treatment reduced the severity of liver lesions and eliminated the occurrence of persistent leukopenia, but it did not prevent the formation of bone cancer.

Animals↗

PubMed1992

The efficacies of 3,4,3-LIHOPO and DTPA for enhancing the excretion of plutonium and americium from the rat: comparison with other siderophore analogues.

With DTPA as a comparison, the siderophore analogue code named 3,4,3-LIHOPO has been tested for its ability to remove 238Pu and 241Am from rats after their inhalation or intravenous injection as nitrate. The most effective treatment regimen for inhaled Pu was the repeated administration of 30 mumol kg-1 3,4,3-LIHOPO. By 7 days after exposure, the Pu contents of the lungs and total body were reduced respectively to 2 and 4% of those in untreated animals. These values were six and three times less than when DTPA was administered using the same protocol. For inhaled Am, 3,4,3-LIHOPO and DTPA were considered equally effective, the lung and total body contents being reduced respectively to 13 and 10% of those in controls. Some animals showed slight degenerative changes in the liver and proximal tubules of the kidneys after the repeated administration of 30 mumol kg-1 of 3,4,3-LIHOPO; however these changes were less marked than after DTPA treatment. After the intravenous injection of Pu, the most effective regimen was the single administration of 3 mumol kg-1 3,4,3-LIHOPO. The body content at 7 days was reduced to 7% controls compared with 19% after the repeated administration of 30 mumol kg-1 DTPA. At a dosage of 30 mumol kg-1, 3,4,3-LIHOPO was less effective owing to the higher retention of Pu in the liver. With repeated dosages of 30 mumol kg-1 3,4,3-LIHOPO was more effective than DTPA for the decorporation of Am; the body contents were 16 and 31% of those in controls respectively. Importantly, the body content was still reduced to 28% of control after a single administration of 3 mumol kg-1. The ligand 3,4,3-LIHOPO, which is also superior to other siderophore analogues, could represent a most significant development in the decorporation of Pu and Am.

Administration, Inhalation↗

PubMed1993

Decorporation therapy for inhaled plutonium nitrate using repeatedly and continuously administered DTPA.

Decorporation therapy is the only known effective method of reducing the radiation dose to persons accidentally contaminated internally with radionuclides. Deposition of actinides in bone must be minimized because osteosarcoma appears to be the most likely pathological effect arising from systemic exposure. In previous studies, beagle dogs inhaled moderately soluble Am and Cm oxide aerosols and were then treated with diethylenetriaminepentaacetic acid (DTPA), either by repeated intravenous injection or by continuous infusion. The latter therapy was more effective in removing the actinides from the body. In this complementary study, dogs inhaled a polydisperse aerosol of 238Pu(NO3)4 and were treated as before using a single initial injection of CaDTPA (30 mumol kg-1) followed with either repeated intravenous injections of ZnDTPA (30 mumol kg-1 injection) or with subcutaneous infusion of ZnDTPA (30 or 120 mumol kg-1 day-1). Each treatment regimen commenced at 1 h after exposure and continued throughout 64 days, whereupon all animals were killed, and tissue samples and collected excreta samples were analysed radiochemically for their Pu contents. Unlike the results of previous studies with Am and Cm, in which the actinide dissolved in vivo over periods of many days to weeks, no significant differences in decorporation efficiency of 238Pu were noted for the three different DTPA-treated groups. All treatments removed about 85% of the initial pulmonary burden (IPB) of 238Pu compared with 24% IPB excreted by the saline-treated control dogs. The lack of additional effectiveness of the continuously infused DTPA was attributed to the high, initial in vivo solubility of the Pu nitrate aerosol used in this study. This resulted in a relatively rapid systemic uptake of Pu and translocation to liver, skeleton, and muscle/connective tissue, where it was less available to the longer-term action of DTPA.

Administration, Inhalation↗

PubMed1993

Comparative efficacies of 3,4,3-LIHOPO and DTPA for enhancing the excretion of plutonium and americium from the rat after simulated wound contamination as nitrates.

With DTPA as a comparison, the siderophore analogue 3,4,3-LIHOPO has been examined for its ability to remove 238Pu and 241Am from the rat after subcutaneous (s.c.) and intramuscular (i.m.) injection of about 200 Bq of each actinide (0.3 ng Pu, 1.6 ng Am). After the s.c. deposition of 238Pu and 241Am, both ligands were more effective after local administration than (in decreasing order) their repeated interperitoneal (i.p.) injection, single i.p. injection and continuous infusion. Dosages of 3 mumol kg-1 of 3,4,3-LIHOPO were at least as effective as 30 mumol kg-1 DTPA after each mode of administration. The most effective regimen of those investigated for s.c. 238Pu and 241Am involved local administration of 30 mumol kg-1 of 3,4,3-LIHOPO at 30 min followed by i.p. injections at 6 h, 1, 2 and 3 day. By day 7 after exposure, the amounts of 238Pu and 241Am retained in the body were 2 and 7% of those in controls, respectively and 10 and four times less than when DTPA was administered using the same regimen. The ligand 3,4,3-LIHOPO was more effective for 238Pu and 241Am after their i.m. injection. This was attributed to the greater retention of these actinides at the wound site (97 versus 67%) when treatment commenced. After a single local injection of 30 mumol kg-1 at 30 min, the amounts of 238Pu and 241Am retained in the body at 7 day were 0.9 and 0.8% of controls. These values were 34 and 27 times less than after local and repeated i.p. injections of DTPA at dosages of 30 mumol kg-1. It is concluded that the administration of 3,4,3-LIHOPO represents potentially a most significant advance in the treatment of wound contamination by 238Pu and 241Am by chelating agents.

Americium↗

PubMed1995

Efficacy of 3,4,3-LIHOPO for enhancing the excretion of plutonium from rat after simulated wound contamination as a tributyl-n-phosphate complex.

The siderophone analogue 3,4,3-LIHOPO, referred to hereafter as LIHOPO, has been examined for its ability to remove 238Pu in a tributyl-n-phosphate (TBP) complex from rat after intramuscular (i.m.) or subcutaneous (s.c.) contamination. The chelating agent was administered at a dosage of 30 mumol.kg-1, 30 min after the contamination, either by intravenous (i.v.) or local injection. By day 7 after exposure, local (i.m.) administration of LIHOPO reduced the amounts of i.m.-injected 238Pu in the would site, skeleton and liver to 75, 20 and 25% respectively of those in untreated animals. At the i.m. Pu would site, local treatment was superior to i.v. treatment; both ligands were equally effective. At the s.c. Pu would site, local and systemic treatments were equally effective and LIHOPO was superior to DTPA. After translocation, LIHOPO was the most effective treatment for enhancing Pu excretion, whatever the route of contamination and treatment: the administration of LIHOPO and DTPA reduced whole-body Pu retention by a factor of 1.8 and 1.4 respectively. All these results are encouraging for the use of LIHOPO in the future but more studies are needed, concerning both the toxicity of the compound and its use in man.

Animals↗

PubMed1996

Treatment with 3,4,3-LIHOPO of simulated wounds contaminated with plutonium and americium in rat.

The effect of a siderophore analogue 3,4,3-LIHOPO has been investigated in rat after intramuscular injection of 238Pu, 239Pu and 241Am simulating puncture wounds. Various treatment regimens were used to remove the radioactivity from its injection site and to reduce its retention in body tissues. The local deposits could be reduced to 9% of that in untreated controls by a single local injection of 30 mumol kg-1 3,4,3-LIHOPO administered 1 day after the actinides. Tissue retention of radioactivity was most effectively reduced (to 3% of controls) by continuous subcutaneous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting immediately after the injection of actinides and continuing for 2 weeks. The administration of 3,4,3-LIHOPO in drinking water was least effective. Treatment efficacy was substantially higher with 238Pu than with an equal activity of 239Pu (the 238Pu mass, however, was almost 300 times lower than that of 239Pu). Accordingly, the biokinetics and removal of 241Am changed when it was injected with 239Pu instead of 238Pu. Continuous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting 4 and 30 days after intramuscular injection of 238Pu and 241Am reduced their femoral retention after 1 month to 20 and 60% of controls respectively; whole-body retention of 241Am was reduced to 20 and 70% of controls respectively.

Americium↗

PubMed1999

Effect of oral ZnDTPA on late effects of injected plutonium in rat.

PURPOSE: To reduce the long-term toxicity of 239Pu in rats by lifetime drinking of ZnDTPA solution and to investigate possible side-effects of the drug. MATERIALS AND METHODS: Male Sprague-Dawley rats received a single injection of 239Pu citrate, alone or plus oral ZnDTPA. Additional groups were administered only ZnDTPA. Late tissue changes were evaluated by post-mortem examination, X-rays and histologically. RESULTS: The incidence of rat bearing osteosarcoma decreased after treatment to 35% as compared with 53% in untreated controls. The proportional incidence of osteosarcomas was reduced after ZnDTPA by more than the corresponding removal of 239Pu. Unexpectedly in the male rat, mammary tumours, mostly malignant, developed in 20% of rats that received 239Pu as compared with 0.5% in the untreated controls. After a lifetime drinking solely 3 x 10(-3) M ZnDTPA the incidence of diffuse glomerulosclerosis reached 29% as compared with 10% in controls. CONCLUSIONS: In rat, protracted oral administration of ZnDTPA reduced the incidence of osteosarcomas after injection of 239Pu, even if treatment started with a delay of 1 month. In the latter case, however, more soft tissue damage was found than after treatment beginning at 4 days post-239Pu. An increased incidence of diffuse glomerulosclerosis was observed as a side effect of oral ZnDTPA only when given continuously, alone and in high amounts.

Administration, Oral↗

PubMed1980

Influence of cadmium and copper on the distribution pattern of plutonium in the rat.

The results of pilot experiments on metal interactions in vivo are presented. In rats pretreated with a single injection of Cd, substantially less Pu accumulated in the liver, while significantly more was found after pretreatment with Cu. In bone, somewhat more Pu was detected after Cd and less after Cu administration. Both metals increased the retention of Pu in the kidneys and spleen. The changes were similar with 238Pu and 239Pu and were still present 1 wk after Pu administration; in the case of Cu they were dependent on the amount administered. All the changes described concern solely the tissue distribution pattern of Pu; the total amount of Pu retained in the organs studied remained the same. The possible relation of Pu uptake to induced synthesis of Cd-thionein and Cu-chelatin is discussed.

Animals↗

PubMed1967