Lauriston S. Taylor Lecture: the quest for therapeutic actinide chelators.

All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

Practical action levels for chelation therapy in plutonium inhalation using nose swab.

The aim of this study is to propose action levels for chelation therapy in the case of inhalation of plutonium compounds using nose swabs. The relationship between the activity found in the nose swabs and early faecal excretion was investigated using actual cases at JAEA-NFCEL. The ratio was found to be in log-normal distribution. The action levels based on the activity of nose swab corresponding to 10 ALI (=200 mSv) are determined for the facilities at JAEA-NFCEL by using the relationship and specific information such as isotopic ratio and physicochemical characteristics of plutonium compounds.

Efficacy of 3,4,3-LI(1,2-HOPO) for decorporation of Pu, Am and U from rats injected intramuscularly with high-fired particles of MOX.

This study aimed to assess the efficacy of 3,4,3-LI(1,2-HOPO) for reducing uranium, plutonium and americium in rats after intramuscular injection of (U-Pu)O2 particles (MOX). Sixteen rats were contaminated by intramuscular injection of a 1 mg MOX suspension and then treated daily for 7 d with LIHOPO (30 or 200 micromol kg(-1)) or DTPA (30 micromol kg(-1)). LIHOPO was inefficient for removing Pu, Am and U from the wound site. However, it reduced Pu retention in carcass and liver by factors of 2 and 6 respectively, and Am retention in carcass and liver by factors of 10 and 30. In contrast, the effect of LIHOPO on U was to decrease the retention in kidneys by a factor of 75. These results confirm that LIHOPO is a good candidate for use after contamination with MOX, in combination with localised wound lavage or surgical treatment aimed at removing most of the contaminant at the wound site.

Octadentate hydroxypyridinonate (HOPO) ligands for plutonium (i.v.): pharmacokinetics and oral efficacy.

Linear octadentate spermine based 3,4,3-LI(1,2-HOPO) and the mixed ligand, 3,4,3-LI(1,2-Me-3,2-HOPO), are the most effective agents for decorporation of Pu prepared so far; they are effective at low dosage, orally active, and of low toxicity at effective injected dosage. Their pharmacological properties are favourable for in vivo Pu chelation--penetration of extracellular water, useful residence in the circulation, substantial hepato-biliary excretion, low but useful GI absorption, and transitory residence in the kidneys. Reductions of body Pu were significant, compared with controls, when oral administration to normally fed mice (30 or 100 micromol kg(-1)) was delayed as long as 24 h after i.v. Pu injection. The HOPO ligands (10-100 micromol kg(-1)) or CaNa3-DTPA (100 or 300 micromol kg(-1)) were given orally to normally fed mice starting at 4 h after an i.v. Pu injection and continued 5 d per week for 3 weeks. 3,4,3-LI(1,2-HOPO) (100 micromol kg(-1)) reduced Pu in skeleton, liver, and body, to 44 +/- 9, 18 +/- 8, and 38 +/- 7% of controls, respectively, reductions significantly greater than with the mixed HOPO ligand or with three times more CaNa3-DTPA.

Comparative decorporation efficacy of 3,4,3-LIHOPO, 4,4,4-LIHOPO and DTPA after contamination of rats with soluble forms of 238Pu and 233U.

The aim of this study was to compare the efficacies of DTPA, 3,4,3-LIHOPO and a newly synthesised molecule, 4,4,4-LIHOPO, in removing 233U and 238Pu after internal contamination by soluble forms of those nuclides. For this purpose, intravenous injections of DTPA (30 micromol kg(-1)) or 3,4,3-LIHOPO or 4,4,4-LIHOPO at dosages of 0.3 or 30 micromol kg(-1) were performed 1, 6 and 24 h after contamination of rats by intravenously injected 238Pu citrate and 1 h after intravenous injection of 233U nitrate. Actinide content in the main retention organs and cumulated excretion were measured 48 h after contamination. These experiments show similar decorporation efficacies of 4,4,4-LIHOPO and 3,4,3-LIHOPO for Pu, which are much higher than that of DTPA. At a dosage of 0.3 micromol kg(-1), the two LIHOPO analogues were as efficient as DTPA at a dosage of 30 micromol kg(-1). After U contamination, a 20% decorporation efficacy was obtained for either 3,4,3-LIHOPO or 4,4,4-LIHOPO at a dosage of 30 micromol kg(-1).

[Study of the effect of a food additive Medetopect on metabolic kinetics of transuranic radionuclides in animal body]. / Izuchenie vliianiia pishchevoi dobavki "Medetopekt" na kinetiku obmena transuranovykh radionuklidov v organizme zhivotnykh.

The effect of Medetopect, a food additive, on the metabolic kinetics of transuranics (239Pu and 241Am) has been studied experimentally in white mongrel rats following chronic intake by ingestion. The Medetopect application has been shown to be advantageous for reduction of the 239Pu and 241Am absorption from and content of the gastrointestinal tract of the animals.

Circulatory kinetics of intravenously injected 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: comparison with rat, dog, and reference man.

New ligands for in vivo chelation of Pu(IV) are being synthesized and evaluated in mice for efficacy and toxicity. Biokinetic studies of the new ligands, CaNa3-DTPA, and Pu(IV) are major components of those investigations. Young adult female mice were injected intravenously (iv) with 3H-inulin, 14C-CaNa3-DTPA, or 238Pu(IV) citrate to provide baseline data for plasma clearance, tissue uptake, and excretion rates and to determine the dilution volume (VOD) and renal clearance rate (RC) of filterable substances. Published plasma clearance data for iv-injected 14C-CaNa3-DTPA and Pu(IV) citrate in Reference Man, dog, and rat were collected. Based on combined data for 3H-inulin and 14C-CaNa3-DTPA, VOD = 17% of body weight and RC = 18 mL kg(-1) min(-1) for mice. Retention of 14C-CaNa3-DTPA in the four species is proportional to body weight and inversely proportional to RC: Integrals of the retention of 14C-CaNa3-DTPA from R(t) = 1.0 to R(t) = 0.05 are 108, 43, 28, and 10 DF min, respectively, for Reference Man, dog, rat, and mouse. Clearances of iv-injected Pu(IV) citrate from plasma are in the same order: The plasma curve integrals from injection to 1440 min are 840, 640, 280, and 67 DF min, respectively, for Reference Man, dog, rat, and mouse. In mice, a large fraction of newly injected Pu(IV) is rapidly transferred to the interstitial water of bulk soft tissue (excluding liver and kidneys), from which it is cleared at the same rate as from the plasma. Rapid plasma clearance, escape into interstitial water (22%ID at 20 min), significant early urinary excretion (8%ID in 12 h), and prompt deposition in liver and skeleton (complete in 12 h) are evidence of inefficient binding to plasma protein (mainly transferrin) of newly injected Pu(IV) in mice. Conversely, slow plasma clearance, little early urinary excretion, and delayed deposition in liver and skeleton reflect more efficient binding by transferrin of newly injected Pu(IV) in Reference Man and dog. Pharmacokinetic parameters (effective dosage, effective concentration) of CaNa3-DTPA, alone or combined with plasma Pu(IV) integrals, yielded only qualitative predictions of the relative efficacies of CaNa3-DTPA therapy in four species. The need for improved models of Pu(IV) and ligand biokinetics and the suitability of the three animals for predicting chelation therapy outcomes in humans are discussed.

Early chelation therapy for injected Pu-238 and Am-241 in the rat: comparison of 3,4,3-LIHOPO, DFO-HOPO, DTPA-DX, DTPA and DFOA.

Chelating agents were tested for removal of simultaneously injected Pu-238 and Am-241 from the rat. The effectiveness of early single chelate injections of Pu-238 retention in tissues decreased in the order 3,4,3-LIHOPO > DFO-HOPO > DTPA > DTPA-DX, and for Am-241 in the order 3,4,3-LIHOPO > DTPA-DX > DTPA >> DFO-HOPO. DTPA-DX showed a special ability to remove Am-241 from the liver. Injected 3,4,3-LIHOPO decreased the contents of Pu-238 in bone and liver to 9 and 3%, respectively, of those in untreated controls. Corresponding values for Am-241 in bone and liver were 30 and 6%, respectively, which indicates that 3,4,3-LIHOPO (unlike DFO-HOPO) is not a plutonium-specific chelator. The effectiveness of prompt single oral treatment with 3,4,3-LIHOPO and DFO-HOPO in reducing retention of actinides was comparable with that of those chelators injected with 1 h delay and at one-third of the oral dose. When 3,4,3-LIHOPO was administered by continuous infusion, a superior effect was achieved with total chelate amounts only slightly exceeding that given as single injection. The retention of PU-238 and Am-241 in bones was reduced to < 5 and 10% of controls, respectively; the contents in the liver were < 2% of controls.

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.

[238Pu body distribution in dogs after intravenous administration and early complexon therapy]. / Raspredelenie 238Pu v organizme sobak posle vnutrivennogo vvedeniia i rannei kompleksonoterapii.

The paper is concerned with the assessment of the level and concentration of 238Pu in different organs and tissues of dogs after iv injection of 238Pu-citrate at the amount of 92.5 kBq.kg-1 and during early complexon therapy. Ninety per cent of Pu detected in the body was shown to be deposited in the skeleton and liver in the ratio 4.5:1. The concentration of 238Pu in per cent to 1 g of tissue in the critical organs (the skeleton, liver, bone marrow) was (28.7--46.9) X 10(-3)%. The concentration of the radionuclide in the organs and tissues regarded as uncritical, was 1-2 orders lower: the endocrine organs--(0.7--7.5) X 10(-3)%, the lymph nodes--(3.8--5.4) X 10(-3)%, the G. I. tract portions--(1.05--1.5) X 10(-3)%, the CNS portions--(0.1--2.0) X 10(-3)%; the kidneys, muscles, heart, spleen and lungs--(0.63--8.8) X 10(-3)%. Early use of octacine or pentacine decreased Pu concentration in all investigated organs and tissues 2 +/- 0.06 times on an average. The efficacy of octacine was no inferior to that of pentacine.

Behaviour of spherical and irregular (U,Pu)O2 particles after inhalation or intratracheal instillation in rat lung and during in vitro culture with bovine alveolar macrophages.

Spherical and irregularly shaped mixed (U,Pu) oxide particles were administered to rats by inhalation and by intratracheal instillation. The lung retention of the particles was independent of particle shape and of the route of administration. Only a small percentage of the administered radioactivity was found in other organs. Detailed electron microscopic studies showed particles within membrane-enclosed vacuoles as well as lying free in the cytoplasm.

Is the beagle dog an appropriate experimental animal for extrapolating data to humans on organ distribution patterns of U, Th, and Pu?

Concentrations and organ distribution patterns of alpha-emitting isotopes of U (238U and 234U), Th (232Th, 230Th, and 228Th), and Pu (239,240Pu) were determined for beagle dogs of our colony. The dogs were exposed to environmental levels of U and Th isotopes through ingestion (food and water) and inhalation to stimulate environmental exposures of the general human population. The organ distribution patterns of these radionuclides in beagles are compared to patterns in humans to determine if it is appropriate to extrapolate organ content data from beagles to humans. The results indicated that approximately 80% of the U and Th accumulated in bone in both species. The organ content percentages of these radionuclides in soft tissues such as liver, kidney, etc. of both species were comparable. The human lung contained higher percentages of U and Th than the beagle lung, perhaps because the longer life span of humans resulted in a longer exposure time. If the U and Th content of dog lung is normalized to an exposure time of 58 y and 63 y, median ages of the U and Th study populations, respectively, the lung content for both species is comparable. The organ content of 239,240Pu in humans and beagles differed slightly. In the beagle, the liver contained more than 60%, and the skeleton contained less than 40% of the Pu body content. In humans, the liver contained approximately 37%, and the skeleton contained approximately 58% of the body content. This difference may have been due to differences in the mode of intake of Pu in each species or to differences in the chemical form of Pu. In general, the results suggest that the beagle may be an appropriate experimental animal from which to extrapolate data to humans with reference to the percentage of U, Th, and Pu found in the organs.

Distribution, retention and dosimetry of plutonium and americium in the rat, dog and monkey after inhalation of an industrial-mixed uranium and plutonium oxide aerosol.

This study provides information on patterns of radiation dose in laboratory animals after inhalation exposure to an aerosol of one form of mixed uranium and plutonium oxide. The aerosol contained a mixture of UO2 and 750 degrees C heat-treated PuO2 obtained from the ball milling operation in a mixed-oxide fuel fabrication process. Americium-241 from the decay of 241Pu was also present in the PuO2 matrix. Fischer-344 rats, Beagle dogs, and Cynomolgus and Rhesus monkeys inhaled aerosols re-generated from dry mixed oxide powders with particle size distribution characteristics similar to those observed in samples collected at the industrial site. Clearance from the lung and distribution in other tissues of the plutonium from this UO2 + PuO2 admixture was similar to what has been observed for PuO2 from laboratory-produced aerosols. The UO2-PuO2 aerosol was relatively insoluble in the lungs of all species. Monkeys and rats cleared plutonium and americium from their lungs faster than dogs. Very little plutonium or americium translocated within the first 2 yr after exposure to tissues other than tracheobronchial lymph nodes. The greater accumulation of plutonium and americium in the tracheobronchial lymph nodes of dogs as compared to monkeys and rats combined with the more rapid initial clearance of these radionuclides from the lungs of rats and monkeys suggests that errors could result from using data from a single animal species to estimate risk to humans from inhalation of these industrial aerosols.