Treatment of accidental intakes of plutonium and americium: guidance notes.

The scientific basis for the treatment of the contamination of the human body by plutonium, americium and other actinides is reviewed. Guidance Notes are presented for the assistance of physicians and others who may be called upon to treat workers or members of the public who may become contaminated internally with inhaled plutonium nitrate, plutonium tributyl phosphate, americium nitrate or americium oxide.

Influence of heavy metals upon the retention and mobilization of polonium-210 in rats.

PURPOSE: To provide information about the tissue retention and mobilization of the alpha-emitting radionuclide, polonium-210 (210Po), in rats under combined exposure to heavy metal ions and the chelating agent, 2, 3-dimercaptopropane-1-sulfonate (DMPS). MATERIALS AND METHODS: Rats were pre-exposed intraperitoneally to either CdCl2 or Pb(CH3COO)2. 9 or 15 h later they received 210Po nitrate intravenously. The retention and excretion of 210Po via the urine and faeces of pre-exposed rats, as well as in pre-exposed rats treated with DMPS, were followed. The radioactivity due to 210Po in a broad spectrum of body tissues and excreta was measured by the liquid scintillation counting after sample digestion in a mixture of perchloric acid and hydrogen peroxide. The immunohistochemical localization of metallothioneins (MT) was studied using a mixture of murine monoclonal antibodies directed against MT I+II. RESULTS: The present study revealed different tissue distributions of polonium-210 in the rats pre-exposed to lead or cadmium ions when compared with that in 210Po only controls. Under combined exposure to Pb or Cd, the spontaneous excretion of 210Po was enhanced and could be further enhanced by treatment with DMPS. Treatment with this chelator was efficient even when its start was postponed until 24h after internal contamination of the body with 210Po. CONCLUSIONS: Polonium-210 is bound in vivo to binding sites on various biomolecules, among them erythrocytic enzymes and MT. This phenomenon explains the different affinity and overall distribution of 210Po in control body tissues. When the appropriate binding sites are occupied by lead or cadmium, enhanced natural excretion of polonium-210 occurs.

Improved chelation therapy of intramuscularly deposited thorium by CaDTPA in the rat.

Comparative studies on the translocation and retention of intramuscularly (i.m.) injected thorium nitrate (234Th 46 ng + 232Th 5 microg per rat) in solutions of citrate, CaDTPA or citrate + CaDTPA in rats have been conducted. Results showed that only thorium in mixed-ligand solution was entirely translocated from the muscle, with the greatest part being excreted from the body. In this case, the whole-body retention of thorium decreased to 16% of the injected radioactivity within 2 d, 13% being retained in the skeleton. Studies on the decorporation of 234Th + 232Th nitrates from a rat wound simulated with i.m. injection have also been carried out. The greatest translocation of thorium and its excretion was achieved with a single local injection of the mixed-ligand (citrate + CaDTPA) solution when compared with those of citrate or CaDTPA alone. The efficiency of mixed-ligand treatment decreased with its delay. On day 2 post-therapy, the whole-body content of thorium decreased to 30, 37 and 55% of injected radioactivity when the local treatment started immediately, postponed to 1 h or 24 h, after i.m. injection of thorium, respectively. In control rats without treatment, there was only a slight decrease in the content of thorium in the whole body.

Mobilization and detoxification of polonium-210 in rats by 2,3-dimercaptosuccinic acid and its derivatives.

PURPOSE: To reduce retention and toxicity of the alpha particle emitter polonium-210 in rats by newly developed chelating agents. MATERIALS AND METHODS: Repeated subcutaneous chelation was conducted after intravenous injection of 210Po nitrate. For reduction of 210Po retention the treatment with vicinal dithiols meso-and rac-2,3-dimercaptosuccinic acid (DMSA), mono-i-amylmeso-2,3-dimercapto succinate (Mi-ADMS) and mono-N-(i-butyl)-meso-2,3-dimercapto succinamide (Mi-BDMA) were used. For the reduction of toxic effects of 210Po, treatment effectiveness of Mi-BDMA was compared with that of N,N'-di(2-hydroxyethyl)ethylenediamine-N,N'-biscarbodithioate (HOEtTTC, reference compound). RESULTS: Treatment with meso-DMSA and rac-DMSA altered the main excretion route of 210Po, reduced its contents in the liver but increased its deposition in the kidneys. Treatment with Mi-ADMS or Mi-BDMA increased total excretion of 210Po, mainly via the faeces. Only Mi-BDMA decreased 210Po levels in the kidneys. The effectiveness of all chelators decreased with delay in the start of treatment. In a survival study, the lives of rats treated early with Mi-BDMA or delayed with HOEtTTC were prolonged three-fold when compared with rats receiving a lethal amount of 210Po only. CONCLUSIONS: Of the vicinal dithiols examined, Mi-BDMA was the best mobilizing chelating agent for 210Po and it reduced 210Po toxicity when the treatment started immediately. However, the detoxification efficacy of the immediate treatment with HOEtTTC, observed in our previous study, was superior to that of the present result with Mi-BDMA.

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.

Reduction of subacute lethal radiotoxicity of polonium-210 in rats by chelating agents.

The protective effect of N,N'-di(2-hydroxyethyl)ethylene-diamine-N,N'-biscarbodithioate (HOEtTTC) against the subacute lethal radiotoxicity of polonium-210 was investigated in a survival study and by histopathological and haematological examinations of some organs and tissues in Sprague-Dawley rats. This effect was compared with that of N,N'-diethylamine-N-carbodithioate (diethy dithiocarbamate, DDTC). In the survival study, rats injected in intravenously solely with a lethal amount of 210Po (1.45 MBq kg-1 body mass) died within 14-44 days while 90% of rats treated with HOEtTTC survived for 5 months until sacrificed. When treated with DDTC all rats died within 36-93 days. In the histopathological examination, relevant changes resulting from incorporation of 210Po were found in lymph nodes, thymus and humeral bone marrow. After the treatment with HOEtTTC no pathological changes were observed. In the haematological examination, severe reduction in blood and femoral bone marrow (BM) cell counts was revealed in rats injected with 210Po. This reduction was reversed by treatment with HOEtTTC. Treatment with DDTC led only to partial recovery of blood and BM cell count. In conclusion, under the conditions of the experiment only HOEtTTC was fully effective in reducing subacute lethal radiotoxicity of 210Po.

Effect of 50-Hz electromagnetic field on the retention of toxic radionuclides in rat tissues.

The effect of electromagnetic field (EMF) 50 Hz, 10 mT, on the tissue retention of radiotoxic polonium-210 and thorium-234 was studied in a rat model. Regarding 210Po in the ionic state, small but significant effects were obtained by exposure of rats to EMF either before the intravenous injection of 210Po (pre-exposure) or after the rats had already been injected with 210Po (post-exposure). When compared with control values, pre-exposure to EMF caused a significant 28% decrease in the retention of 210Po in the skin and a 10% decrease in total 210Po retention in the investigated tissues. Relative to controls, post-exposure resulted in a 131% increase in 210Po retention only in the thymus. Regarding carrier-free 234Th in the ionic state, both types of EMF exposure caused a substantial increase in 234Th retention in the liver and spleen and a decrease of 234Th in the bones. A different effect of EMF on the retention of 234Th in the body was obtained when the mass of thorium was increased by adding as carrier 232Th (50 micrograms kg-1 body mass). With pre-exposure, a significant 10% decrease in the high retention of 234Th in the liver (77% of injected radioactivity) was observed. On the other hand, with post-exposure no significant changes in retention of 234Th were found in the tissues.

Combined chelation treatment for polonium after simulated wound contamination in rat.

Contaminated puncture wounds were simulated in rat by intramuscular injection of 210Po. The aim of the study was to determine the effectiveness of chelation treatment as a function of time, dosage, and route of chelate administration. Ten newly synthesized substances containing vicinal sulphydryl and carbodithioate groups were used and their effect was compared with that of chelators clinically applicable in man--BAL (2,3-dimercaptopropane-1-ol), DMPS (2,3-dimercaptopropane-1-sulphonate), DMSA (meso-2,3-dimercaptosuccinic acid), and DDTC (sodium diethylamine-N-carbodithioate). The results indicate first that complete removal of 210Po from the injection site is achieved by only two local injections of DMPS, beginning as late as 2 h after injection of 210Po. Second, many of the substances used merely induce translocation of 210Po from the injection site into other tissues. Third, a combined local treatment at the injection site with DMPS plus repeated systemic, subcutaneous, treatments with HOEtTTC (N,N'-di-(2-hydroxyethyl)ethylenediamine-N,N-biscarbodithioate), a derivative of DDTC, results after 2 weeks in a reduction of the estimated total body retention of 210Po to about one-third of that in untreated controls. In the latter case the cumulative excretion of 210Po increased from 8 to 54%, mainly via the faeces.

Bis-dithiocarbamates: effective chelating agents for mobilization of polonium-210 from rat.

The time dependence of organ distribution and excretion of intravenously (iv) injected 210Po was investigated after the single or repeated administration of N,N'-diethylamine-N-carbodithioate (diethyldithiocarbamate, DDTC) and three bis-dithiocarbamates: N,N'-dimethylethylenediamine-N,N'-biscarbodithioate (MeTTC), N,N'-diethylethylenediamine-N,N'-biscarbodithioate (EtTTC), and N,N'-di)20hydroxyethyl)ethylenediamine-N,N'-biscarbodithioate++ + (HOEtTTC). The biokinetics of iv injected 210Po was used as a model for the behaviour of 210Po absorbed into the blood from any other site of entry into the body. The most effective chelating agent was HOEtTTC, which was not only effective when injected subcutaneously (sc) immediately after 210Po, but also 1 h later. Toxic effects of DDTC were observed in a metabolic study when the effect of HOEtTTC was compared with that of DDTC. DDTC caused accumulation of 210Po in brain and transiently in liver. When HOEtTTC was administered, the faecal excretion of 210Po was increased from the very beginning. MeTTC, EtTTC and N-(2,3-dimercaptopropyl)phtalamidic acid (DMPA) were ineffective when the treatment started 1 h after iv injection of 210Po.

Relative effectiveness of dithiol and dithiocarbamate chelating agents in reducing retention of polonium-210 in rats.

Nine different sulphur-based chelators, including dithiols and dithiocarbamates, were examined for their ability to remove Po-210 from the rat. In general, treatments merely caused a redistribution of Po-210 in the body. Greatest reduction of Po-210 in blood was achieved by 2,3-dimercaptopropanol (BAL), sodium diethyldithiocarbamate (DDTC), and N-(2,3-dimercaptopropyl) phthalamidic acid (DMPA). Nearly all the compounds tested decreased Po-210 in the spleen and muscle. On the other hand, BAL and DDTC substantially increased the accumulation of Po-210 in the brain while DMPA, DMPS (sodium 2,3-dimercaptopropane-1-sulphonate) and DMSA (meso-2,3-dimercaptosuccinic acid) increased by several times the Po-210 in kidneys. A less pronounced increase of Po-210 was sometimes observed in liver (due to DDTC and DMPA) and in muscle (due to BAL and DDTC). Three of the dithiocarbamates (BGDTC, MeOBGDTC and BLDTC) did not increase accumulation of Po-210 in the brain and muscle but they reduced Po-210 in blood to a lesser degree than DDTC. A derivative of DMSA (Mi-ADMS) reduced Po-210 in blood, bone and muscle more than DMSA, but at the same time increased Po-210 in the kidney. When BAL or DDTC were combined with other agents there was a greater reduction in the whole-body burden of Po-210. Removal of Po-210 from the bone, spleen and kidneys by BAL was increased by repeated treatment. However, under similar experimental conditions the effect of a single injection of BAL on Po-210 in blood was less pronounced when the period of observation was prolonged. Total-body retention of Po-210 could not be reduced to less than 85% of the untreated controls by any of the chelators tested. In spite of this some of them (BAL, DMPS, DMSA, DMPA) could still have a useful role in reducing the toxicity of Po-210.

Pseudomonas aeruginosa. II. Experimental acellular vaccine of an endotoxin and anatoxin type.

The results are given of quality evaluation of endotoxin and exotoxin antigens isolated from P. aeruginosa strains. The isolates were tested by both in vitro and in vivo methods. The results of an active protection test on white mice formed the basis for the construction of an experimental Pseudomonas vaccine that protects the immunized animals against infection even by heterologous strains of P. aeruginosa.

Pseudomonas aeruginosa. I. Large-volume cultivation of production strains for vaccination purposes.

A submerged culture technology was used to produce large-volume suspensions of Pseudomonas aeruginosa production strain for the purpose of vaccination. This paper describes the composition of the culture media used and the methods of preparing endotoxin and exotoxin components of the desired immunogenic activity.