Biokinetic Method on Simultaneous Intake of Radionuclides from Multiple Intake Scenarios for Application in Internal Exposures.

Biokinetics underlies the basis for assessment of internal exposures. This paper develops a biokinetic method on simultaneous intake of radionuclides from multiple intake scenarios in internal exposures. With numerical techniques that transform the whole biokinetics between the coupled and decoupled representations of the same problem, this method applies to coupled biokinetics with complex structures and has no restrictions of practical importance on the number of intake scenarios, the number of intake parent radionuclides and decay products, and the complexity of decay relationships between parent and progeny nuclides. For illustration, this method is applied to an assumed case of mixed inhalation and ingestion of weapon-grade plutonium material for reference workers that is focused on Pu and Am. Due to coupled biokinetics between the direct intake and ingrowth parts in different intake pathways, the multiple intake results (the contents of lungs, daily excretions, and cumulative contents) display richer behaviors as compared to single intake cases. This method benefits both the prospective and retrospective assessment of internal exposures for complex intake cases in actual applications.

Monte Carlo evaluation of the dose sparing and dose enhancement by combination of Gd-infused tumor and 241Am source for an endocavitary brachytherapy geometry.

In this work, the benefits in terms of dose enhancement and dose sparing via radiation shielding are evaluated, for a combined irradiation scheme with sources of 241Am and tumor-infused with Gd agents, regarding conventional 192Ir treatment. Monte Carlo simulations using PENELOPE code were implemented for endocavitary brachytherapy geometries, configuring a pelvis phantom of 15 cm radius and 30 cm length. Inside, it was defined cylindrical tumor phantoms of 2 cm radius and 4 cm-6 cm length (simulating initial stages) as well as tumors of extensive volume (2.5 and 3.0 cm radius) and difficult coverage. Tumor phantoms were doped with 68 mM and 138 mM of Gd in order to assess the effects of enhancement and protection based on the concentration and emission energy of the isotope. Obtained results for the first tumor group, shown the feasibility of achieving dose enhancements of 94.3%-117% and 160%-194% for 68 mM and 138 mM of Gd infused into the tumor and irradiation with 241Am, respectively. Similarly, reduced dose enhancements of 3.5-5.7% y 8.9%-11.2% for 68 mM and 138 mM of Gd are attained with 192Ir. In terms of dose sparing outer the tumor, the radiation shielding and dose enhancement allowed a higher reduction in the dose by 241Am of 17%-24% for 68 mM and 21%-32% for 138 mM of Gd, and non-negligible dose sparing are produced too by 192Ir of 2% and 5% for the same concentration of Gd. For the second tumors group, the combined use of 241Am and Gd agents simultaneously allowed to improve coverage and reduce the healthy tissue dose, showing the obtained results the possibility of achieving coverage of 95% of the prescribed dose in 100% of tumor volume together with dose sparing factor of 6-21% reduction in isodose of the studied point and dose enhancements of 75%-158% at the prescription point.

COMPARING LUNGS, LIVER AND KNEE MEASUREMENT GEOMETRIES AT VARIOUS TIMES POST INHALATION OF 239Pu AND 241Am.

In-vivo measurement of Pu/241Am in workers is carried out by placing suitable detector above lungs, liver and skeleton, as major fraction of Pu/Am is transferred to liver and skeleton, after its retention in entry organ. In this work, committed effective dose (CED) corresponding to minimum detectable activity for Type M and Type S 239Pu/241Am deposited in these organs are presented and a monitoring protocol of organ measurement giving lowest CED at different time intervals post inhalation is described. We have observed, for Type M compounds, lung measurement is most sensitive method during initial days after exposure. Liver measurement yields lowest CED between 100 and 5000 d and beyond that bone measurement gives lowest CED. For Type S compounds lung measurement remains most sensitive method even up to 10 000 d post inhalation. This study will be useful for the assessment of CED due to internally deposited 239Pu/241Am in the workers.

Behavior of Americium in Simulated Wounds in Nonhuman Primates.

An americium solution injected intramuscularly into several nonhuman primates (NHPs) was found to behave differently than predicted by the wound models described in the NCRP Report 156. This was because the injection was made along with a citrate solution, which is known to be more soluble than chlorides, oxides, or nitrates on which the NCRP Report was based. A multi-exponential wound model specific to the injected americium solution was developed based on the retention in the intramuscular sites. The model was coupled with the americium systemic model to interpret the urinary excretion data and assess the intake, and it was determined that the models were adequate to predict early urinary excretion in most cases but unable to predict late urinary excretion. This was attributed to the differences in the systemic handling of americium between humans and nonhuman primates. Information on the type of wounds, solubility, particle size, mass, chemical form, etc., should always be considered when performing wound dosimetry.

Synthesis and Physicochemical Characterization of a Diethyl Ester Prodrug of DTPA and Its Investigation as an Oral Decorporation Agent in Rats.

The increasing threats of nuclear terrorism have made the development of medical countermeasures a priority for international security. Injectable formulations of diethylenetriaminepentaacetic acid (DTPA) have been approved by the FDA; however, an oral formulation is more amenable in a mass casualty situation. Here, the diethyl ester of DTPA, named C2E2, is investigated for potential as an oral treatment for internal radionuclide contamination. C2E2 was synthesized and characterized using NMR, MS, and elemental analysis. The physiochemical properties of solubility, lipophilicity, and stability were investigated in order to predict its oral bioavailability. Finally, an animal efficacy study was conducted in Sprague Dawley rats pre-contaminated by intramuscular injection with (241)Am(NO3)3 to establish effectiveness of the therapy via the oral route. Synthesis of C2E2 yielded a crystalline powder with high solubility and improved lipophilicity over DTPA. The ester was stable in both simulated gastric and intestinal fluids over the anticipated time course of absorption. Capsules containing C2E2 were demonstrated to be stable for 12 months under accelerated stability conditions. After a single dose, C2E2 enhanced the elimination of (241)Am in a dose-dependent manner. Significant improvement was seen in both total (241)Am decorporation and reduction of (241)Am liver and skeletal burden. C2E2 was concluded to be effective when orally administered to (241)Am-contaminated rats. It may therefore have potential for medical countermeasure in treating humans contaminated with (241)Am or other transuranic elements. An oral capsule or powder for reconstitution may be suitable formulations for future development based on the physiochemical properties and anticipated dose required for efficacy.

[Study of effectiveness of long-term per oral and parenteral cincacine administration at parenteral 241Am incorporation into the organism].

Effect of long-term (during 4 weeks) cincacine administration following single parenteral 241Am intake has been studied on rats depending on method (per oral or parenteral), dosage and time of treatment initiation. Cincacine administration leads to limitation of radionuclide incorporation in the major organs of deposition for the both methods of introduction. At the parenteral 241Am intake in the organism parenteral cincacine administration was found to be more effective compared to per oral cincacine administration even in case of its dose increase by a factor of 6 and 12. At the parenteral introduction of the preparation, time of treatment beginning is more significant than at per oral administration.

Skull counting in late stages after internal contamination by actinides.

Monitoring preparation for internal contamination with actinides (e.g. Pu and Am) is required to assess internal doses at nuclear fuel cycle-related facilities. In this paper, the authors focus on skull counting in case of single-incident inhalation of (241)Am and propose an effective procedure for skull counting with an existing system, taking into account the biokinetic behaviour of (241)Am in the human body. The predicted response of the system to skull counting under a certain counting geometry was found to be only ∼1.0 × 10(-5) cps Bq(-1) 1y after intake. However, this disadvantage could be remedied by repeated measurements of the skull during the late stage of the intake due to the predicted response reaching a plateau at about the 1000th day after exposure and exceeding that in the lung counting. Further studies are needed for the development of a new detection system with higher sensitivity to perform reliable internal dose estimations based on direct measurements.

Development of a shielded 241Am applicator for continuous low dose rate irradiation of rat rectum.

This paper describes the development of sources, applicators, and techniques that can be used to irradiate rat rectums with continuous irradiation at dose rates of interest in brachytherapy, either with the full circumference of the rectum irradiated, or with half of the circumference shielded from the radiation. The system uses encapsulated 241Am sources, to irradiate rat rectum with 60 keV photons continuously at a dose rate of up to 50 cGy/hr. Details of the design and fabrication of the 241Am sources, the rectal applicator, the dosimetry of the system, and the protocols for preparing and irradiating the rats, and for detecting early rectal injury using histological examination of irradiated rectum are presented. Highly effective shielding (attenuation factors as low as 0.04) of half of the circumference of the rat rectum was achievable. Unidirectional 241Am irradiators for intracavitary brachytherapy offer a unique tool for examining the effects of shielding a portion of the circumference of the rat rectum, on the radiation tolerance of the rectum.

Gastrointestinal absorption of americium-241 by orally exposed swine: comparison of experimental results with predictions of metabolic models.

Two groups of 11-week-old swine (40 miniature and 40 domestic swine) received a single oral administration of 1.9 X 10(8) Bq (5.2 mCi) of 241Am citrate, and groups of eight animals, four of each type, were killed and sampled at 1, 2, 4, 8, 16, 24, 48, 72, and 96 h and 30 days later. Uptake and excretion patterns of the radioactivity appeared to occur in three phases: rapid uptake, rapid excretion, and then a slower excretion. All animals were systematically dissected, and the eviscerated carcasses were autoclaved for separation of bone and muscle. The predominant site of deposition was bone, and autoclaving had little effect on releasing 241Am from either bone or muscle. The maximum fractional gastrointestinal absorption of 1.1 X 10(-3) occurred 8 h after radionuclide administration. The tissue distribution data suggest partitions of 50, 20, and 30%, for bone, liver, and other soft tissues, respectively. Two metabolic models were evaluated: a modified Mewhinney-Griffith model and the ICRP 30 model to compare the biological data with model predictions. All models underestimated the actual early time data, but the fits to the experimental results were better at later times.

Retention and dosimetry of injected 241Am in beagles.

Equations have been derived, from the results of total-body and partial-body counting and gamma-ray counting of individual bones and soft tissues, which describe the retention of injected 241Am in the liver, in the nonliver tissue (including skeleton), and in the skeleton of young adult beagles. Retention was found to be dependent upon injection level, and different sets of equations were developed for dogs given about (a) 2.8 microCi/kg (b) 0.9 microCi/kg (c) 0.3 microCi/kg, and (d) 0.1 microCi/kg and less. Liver rention, RL, was characterized by a single exponential equation of the form RL = ce-beta t, with c = 0.49 +/- 0.04 and beta = a function of injection level. Nonliver tissue was assigned a retention equation of the form RNL = d + alpha + J(l - e-mt), with d = 0.102 +/- 0.024 e-1.22t, alpha = 0.41 +/- 0.04, and both J and m as a function of injection level. Skeletal retention was found to be about 0.885 +/- 0.037 of nonliver retention with no significant dependence upon either injection level or time after 241Am injection. Dosimetry equations based on these retention expressions were derived. Individual bones of 55 beagles were assayed at death for their 241Am content for a determination of 241Am distribution within the skeleton.

Comparative studies on the lysosomal association of monomeric 239Pu and 241Am in rat and Chinese hamster liver: analysis with sucrose, metrizamide, and Percoll density gradients of subcellular binding as dependent on time.

The binding of 239Pu and 241Am in the livers of Chinese hamsters and rats was analyzed by centrifugation of a mitochondrial-lysosomal fraction in sucrose, metrizamide, and Percoll density gradients at intervals between 4 and 70 days after nuclide injection. The behavior of 239Pu and 241Am during the centrifugation experiments was very similar. In contrast to the results for rats, the median densities of the nuclide profiles from hamsters decrease with time in hyperosmolar sucrose gradients, as does the nuclide fraction liberated by addition of Triton X-100, and the nuclide profiles do not respond typically to Triton WR 1339 treatment of the animals. The results with nearly iso- osmolar metrizamide gradients, together with those for Percoll, agree with the assumption that there is an initial lysosomal association of the transuranium elements. It was concluded from the results that the major fraction of 239Pu and 241Am remained bound to typical lysosomes in rat liver, whereas those in hamster liver may be transformed into telolysosomes . Possibly, a vesicular biliary transport system for certain heavy metals, for which evidence exists in rat liver, does not occur in Chinese hamster liver.

Effect of inhaled alpha-emitting nuclides on mouse alveolar macrophages.

The effects of inhaled alpha emitters on the free cell population of the mouse lung were investigated up to 100 days after exposure. Groups of mice inhaled aerosols of 238PuO2, 239PuO2, or 241Am(NO3)3 to give alveolar deposits resulting in lung-averaged cumulative absorbed doses of about 20 Gy by the end of the study. Initially, with 238Pu most of the activity was associated with relatively few pulmonary alveolar macrophages (PAM), whereas with 241Am, all pulmonary alveolar macrophages were labeled and a substantial fraction was extracellular. The free cell population of the lung was sampled using bronchoalveolar lavage. The main parameters investigated were (a) the recovery and total numbers of free cells, including PAM, lymphocytes, and neutrophils; (b) the incidence of nuclear abnormalities in PAM (cells with more than one nucleus or with micronuclei); and (c) metabolic activation of PAM from measurements of their size and associated beta-glucuronidase activity. All three actinides produced depletions in total numbers of PAM, increased incidences of nuclear abnormalities, and metabolic activation of PAM, without a marked infiltration of inflammatory cells. Americium-241, which is distributed relatively uniformly in PAM, produced the most marked changes in that population and 238Pu, which gave the most inhomogeneous distribution of activity, produced the least.

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.

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.

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.

High radiosensitivity of the mineralization capacity of adult murine bone marrow in vitro to continuous alpha-irradiation compared to acute X-irradiation.

Adult BALB/c mice, injected with osteosarcomogenic amounts of 241Am (between 40 and 500 Bq/g mouse) showed an impaired mineralization capacity of their femoral bone marrow. This effect persisted until at least 1 year after 241Am injection and was expressed after incubation of bone marrow cells in vitro in conditions allowing osteogenic differentiation. The mineralization capacity of marrow in vitro was evaluated by measurement of 85Sr uptake from the tissue culture medium. Two osteogenic assays were used: in marrow cultured as an intact organ (marrow organ cultures), reduced mineralization was observed in mice given 149 Bq 241Am/g mouse or more (skeletal dose rate of 25 mGy/day), in stromal marrow cells cultured from adherent cell layers and subsequently brought into a three-dimensional (3D) mineralizing condition (stromal 3D cultures), reduced 85Sr uptake was observed from the lowest dose level tested (42 Bq 241Am/g mouse, skeletal dose rate of 7 mGy/day). Taking into account that only a fraction of the skeletal alpha-dose reached the marrow of the femoral diaphyses, marrow organ cultures and stromal 3D cultures exhibited high radiosensitivity to alpha-irradiation in vivo. However, after acute X-irradiation of marrow in vivo or in vitro prior to initiation of the marrow organ cultures, X-ray doses of 4 Gy or higher were needed to significantly impair the mineralization capacity of marrow organ cultures in vitro. Our data demonstrated that the osteogenic cells from the bone marrow are subjected to long-term damage after low doses of continuous alpha-irradiation in vivo.

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.

The gastrointestinal absorption of plutonium and americium in the hamster.

Plutonium-239 and americium-241 were administered to adult hamsters in various chemical forms and their absorption from the gut was measured. The results have been compared with published data on other species in order to derive values for the estimated absorption of these actinides in man. On the basis of current knowledge, the best values for adults would appear to be: 0.05% for americium, 0.01% for plutonium ingested in soluble form, and 0.0001% for plutonium ingested as the dioxide. Plutonium dioxide should be considered as soluble if a significant proportion (greater than 5%) of the activity is in particles less than 25 nm in diameter.

The gastrointestinal absorption of neptunium, plutonium and americium in a primate (C. jacchus).

Mixtures of Np, Pu and Am were administered to primates (C. jacchus) by gastric intubation to measure their fractional gastrointestinal absorption (f1 values). The values obtained were about 2 x 10(-3) and 1 x 10(-3), respectively, for Np and Pu administered as the citrate, and 2 x 10(-3) and 6 x 10(-4), respectively, for Pu and Am in potato. The significance of these values in terms of absorption in humans is discussed.

Measurements of the gastrointestinal absorption and tissue distribution of plutonium, americium and polonium in experimental animals.

In order to set limits on environmental and occupational intakes of radionuclides, information is needed on their uptake and metabolism in man. Human data are very limited, particularly for long-lived alpha-emitting isotopes such as those of the actinides. Animal experiments are therefore an important source of data on the distribution of radionuclides in tissues, and the effects of factors such as subject age and the chemical form of elements on gastrointestinal absorption. The NRPB performs experimental programs using mainly rats and guinea pigs. In order to study the gastrointestinal absorption and tissue distribution of plutonium, americium and polonium, a variety of analytical techniques are employed. These include ion exchange and solvent extraction leading to alpha spectrometry and liquid scintillation counting. The investigation of low specific-activity environmental or industrial materials, and the very low bioavailability of elements such as the actinides, means that very low levels of activity have to be measured. Contamination at the dissection and tissue separation stage, as well as during the radiochemistry, has to be rigorously avoided. Where very detailed information is needed on the location of radionuclides within tissues, such as in the study of alpha-emitter distribution in the intestine, autoradiography is used. The application and relevance of different measurement techniques to animal studies will be discussed and examples of the results presented.