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Diethylenetriaminepentaacetic acid (DTPA) is an FDA-approved chelating agent for enhancing the elimination of transuranic elements such as americium from the body. Early access to therapy minimizes deposition of these radionuclides in tissues such as the bone. Due to its poor oral bioavailability, DTPA is administered as an IV injection, delaying access. Therefore, a diethyl-ester analog of DTPA, named C2E2, was synthesized as a means to increase oral absorption. As a hexadentate ligand, it was hypothesized that C2E2 was capable of binding americium directly. Therefore, the protonation constants and americium stability constant for C2E2 were determined by potentiometric titration and a solvent extraction method, respectively. C2E2 was shown to bind americium with a log K of 19.6. The concentrations of C2E2, its metabolite C2E1, and DTPA required to achieve effective binding in rat, beagle, and human plasma were studied in vitro. Dose response curves for each ligand were established, and the 50% maximal effective concentrations were determined for each species. As expected, higher concentrations of C2E2 were required to achieve the same degree of binding as DTPA. The results indicated that chelation in beagle plasma is more representative of the human response than rats. Finally, the pharmacokinetics of C2E2 were investigated in beagles, and the data was fit to a two-compartment model with elimination from the central compartment, along with first-order absorption. Based on the in vitro data, a 100 mg kg dose of C2E2 can be expected to have an effective duration of action of 3.8 h in beagles.

One of the features of 241Am metabolism in the beagle dog is a relatively high selective deposition in the thyroid glands, equal to approximately 0.06% of the injected dosage per gram. Retention is prolonged and principally in the interstitial connective tissue. The resulting average dose to the thyroid glands is about 1.42 and 0.76 times that delivered to the skeleton and the liver, respectively. This thyroid dose is much higher than has been reported in people. Although significant morphological changes and reductions in serum thyroxine occurred in this experiment, a significant increase in thyroid neoplasia was not observed.

A model useful for predicting lung retention and tissue distribution following human inhalation exposure to 241AmO2 has been formulated. The model is based on inhalation studies in beagles exposed to either monodisperse or polydisperse aerosols of 241AmO2. It also describes lung retention for several cases of accidental human inhalation exposure to 241Am adequately. The model incorporates an expression for solubilization of 241AmO2 deposited in lung which is based on physicochemical characteristics of the inhaled particles. Comparison of predictions from this model and those of the International Commission of Radiological Protection in ICRP Publication 30 shows some important differences. Lung retention patterns of inhaled 241Am in dogs and humans after inhalation of 241AmO2 are very similar and do not conform with predictions of the ICRP 30 model. Although use of the ICRP 30 model for calculation of annual limits of intake produces similar values to predictions made from our model, a more complete assessment of accidental human exposures to 241AmO2 and the risk to individual organs can be made using the retention and dosimetry model formulated from these studies in dogs.

Accidental intakes of 241AmO2 and 241Am(NO3)3 can be treated with some success by inhalation of ZnDTPA . The main advantage of this method of treatment is that it can be self-administered very soon after an accidental intake, and it is effective for reducing the lung content of Am at doses about 10 times less than those usually used intravenously. Otherwise the efficacy of injected ZnDTPA is superior since in addition to removing 241Am from the lungs it can deplete appreciably the systemic deposit of the nuclide. There appears to be no advantage in using the lipophilic form of DTPA code-named Puchel , since following the inhalation or injection of the compound decorporation is not significantly increased relative to ZnDTPA .

A Hanford worker received an intake of 241Am by skin absorption and inhalation which was later evaluated to be in excess of 1 mCi. The skin was the main pathway for introduction of 241Am into the body; however inhalation was also a significant pathway. Intensive DTPA therapy prevented 99% of 241Am which entered the blood stream from being deposited in the internal organs. Retention and distribution of 241Am in various internal organs and tissues was determined from sequential measurements in vivo using several arrangements of externally located scintillation detectors. The organ and tissue retention and distribution have been followed for longer than 5 yr. Excretion patterns and estimates of radiation dose to the lung, liver, bone and skin are described.

Haemopoietic stem cell assays allow investigation of local radiation damage at any time after contamination. These techniques were used to determine the relative effectiveness of 241Am and 226Ra in inducing damage in various cortical and trabecular bone marrow sites. Male Balb/c mice were injected with either 230 or 660 kBq 226RaCl2/kg body weight or with one of three doses of monomeric 241Am citrate at 138, 552 or 768 kBq 241Am/kg body weight. At 7 time intervals after injection (from 4 hr to 100 days) the colony-forming capacity of pluripotent stem cells (= CFU-s) and macrophage-granulocyte committed stem cells (CFU-c) was assayed in sternal marrow, marrow of lumbar vertebrae, of the trabecular distal end of the femur and of the femoral shaft (in which were distinguished axial marrow and marrow situated peripherally near the cortical bone). 226Ra retention and 241Am retention were measured in these bone sites. Skeletal doses and doses to the bone marrow sites were calculated. On the base of injected activity, 241Am was more effective than 226Ra in reducing the number of CFU-s and CFU-c but the effectiveness varied in the various bone marrow sites. CFU-s and CFU-c response is considered in relation to the retained radioactivity in the surrounding bone matrix and in relation to the mean marrow dose.

Intake of 241Am was reported in a young female technologist. External monitoring, whole body counting, urinalysis and fecal analysis were performed to determine the subsequent fate of the contaminant. Five days later, more than 99.5% of the radioactivity was voided in a fecal sample. A single particle, containing 2.85 microCi of 241AmO2 incorporated in a ceramic matrix, was isolated from the fecal sample. Brief descriptions of the radioanalytical results and dosimetry implications are presented. A shadow shield whole body counter was conveniently used to make an early estimate of the intake. This initial estimate enabled staff to decide that it was not necessary to artifically remove the contaminant. It was estimated that the lower large intestine was the organ which received the highest dose due to the passage of the ceramic particle. Systemic uptake of 241Am was indicated by urinalysis. The fractional transfer of 241Am from the GI tract to the blood was estimated to be less than 6 X 10(-5). This maximum estimate is limited by the MDA of the analytical procedures used. The fractional transfer of the 241Am from the GI tract to blood in this case is about an order of magnitude less than recent ICRP recommendations for "all compounds of americium".

Two models of the metabolism of inhaled 241AmO2 in Beagles have been formulated. these models differ in their description of lung retention; the empirical dissolution model uses an empirically derived function to describe dissolution of inhaled 241AmO2 while the surface area model uses a dissolution function based on physical and chemical characteristics of the inhaled aerosol. Both models provide more accurate descriptions of retention data for 241Am from several studies in Beagles than does the model published by the ICRP. The surface area model is extended to describe several cases of inhalation of 241Am in humans. This latter model is employed to calculate Annual Limits of Intake for comparison with results based on the current ICRP model.

External X- and gamma-ray counting techniques have been used to study the retention of 238PuO2 and 241AmO2 in the lungs of a worker between 7 and 869 days after simultaneous exposure to aerosols of both oxides. From these data and measurements of early faecal excretion, it is concluded that approx. 50% of the amount of each nuclide initially deposited in the subject was removed during the first few days by ciliary clearance mechanisms. The lung clearance patterns of the other 50% differed for the two nuclides. The 238Pu was apparently cleared with a biological half-life of approximately 800 days, predominantly by systemic or lymphatic uptake, with at least part of the translocated material being subsequently deposited in bone. There was no evidence for the presence of a 30-day component of lung clearance, such as has been suggested elsewhere. In contrast, most of the residual 241Am was cleared relatively quickly, with a half-life of approximately 11 days, although a small proportion was apparently subject to long-term retention, with a half-life of approximately 900 days. The data for both oxides conflict in important respects with the patterns of lung clearance postulated by the ICRP.

Absorption of 233U, 238Pu, 241Am, and 244Cm from the gastrointestinal (GI) tract was measured in rats, fed ad libitum or fasted, that were gavaged with solutions containing ferric iron, ferrous iron, iron powder, quinhydrone or ascorbic acid. Absorption and retention of all of these actinides was increased substantially by fasting and by the addition of mild oxidizing agents, ferric iron and quinhydrone. In contrast, absorption and retention were decreased to below the fasted level by all the reducing agents except ascorbic acid, which caused diarrhea and an increase in absorption. Absorption of the lanthanide element 147Pm from the intestine of fasted rats was also increased by ferric iron. Some of these actinide elements are polyvalent and are, in some cases, known to be absorbed from the GI tract more readily in their higher oxidation states. This suggested an oxidation-reduction mechanism for the effect of fasting and the action of the chemical agents used. However, the improbability that either 241Am(III) 244Cm(III) or 147Pm is converted to a different oxidation state under these conditions makes that mechanism unlikely. Other explanations are suggested.

The 241Am measurements on the donor's body, followed by an analysis of each bone of the skeleton, have provided the best available calibration factors for measuring the 241Am content in the skeletons of the living. These calibration factors have already been useful in measuring the skeletal burden of several workers in the nuclear industry. This study has shown that differential linear scanning provides good results on the content of various parts of the skeleton. Previously used methods of head or leg counting for estimating total skeletal content of 241Am were also found to provide good results. These studies confirm previous recommendations that in-vivo measurement of the skull probably provides the best estimate of 241Am in the skeleton; however, other positions such as the knee are also found to be bilaterally symmetrical for identical bones on the right and left sides of the body. A comparison of measurements on the donor's body with those of other people with skeletal burdens of 241Am shows that differences in skeletal distribution do exist and are probably due to the age of the person, the duration of the skeletal 241Am burden,and perhaps the physical activity of the person. Additional measurements and studies are planned on the remaining half of the skeleton and they should further improve the accuracy of in-vivo measurements of 241Am in the human skeleton.

A simple bioassay model for predicting the organ burdens of 241Am from excretion rates is presented for inhalation exposures. The model uses three compartments representing lung, liver and skeleton. The model was developed using data from studies in laboratory animals of inhaled or injected 241Am and was validated for people by comparison to cases of accidental inhalation exposures to 241Am. The data for people have a large amount of variability but indicate that the retention half-time of 241Am in liver is approximately 2 yr and in skeleton is approximately 30 yr. These parameters can be used in the model to estimate body and organ burdens from excretion rates after inhalation of 241Am or the model can be fitted to an individual's measured excretion rates.

Los Alamos National Laboratory has analyzed autopsy tissue for the USTR, as a part of its study of the uptake, distribution and retention of Pu and other transuranic elements in occupationally exposed workers since 1978. In April 1979, Los Alamos received the internal organs and bone samples from the first whole-body donation to the USTR. The donor was known to have an internal deposition of 241Am. All soft tissue, the bones from the right half of the skeleton, and the odd-numbered vertebrae were received at Los Alamos in February 1980. The bones were subdivided along anatomical areas of interest. All soft tissues and bone specimens were analyzed for their 241Am content. A total deposition of 147.4 nCi 241Am was measured. Approximately 18% of the 241Am remaining in the body (disregarding that in the left hand), was found in the soft tissues, and 82% was in the bones and teeth. The soft tissues and organs containing the largest amounts of 241Am were the combined soft tissue (striated muscle, connective tissue and skin) 8.8%; liver, 6.4% and respiratory tract, 1.5%. The remaining organs accounted for 0.9% of the systemic burden.

To investigate the metabolism of 241Am as affected by pregnancy and lactation, female rats were injected with 5 muCi of 241Am intravenously while nulliparous, pregnant or lactating. The females and subsequent litters were killed at various times after injection to determine 241Am distribution and retention. The temporal relationship between injection and pregnancy influenced the tissue retention of 241Am in both dams and progeny. The half-time of 241Am in livers of pregnant or lactating rats was more than twice that of nulliparous rats, although the initial uptake was approximately 50% of the activity in all groups. Both spleen and femur accumulated more 241Am at 7-10 weeks after injection than at earlier times, but this increase could not be related to pregnancy. Approximately 10 times more 241Am was transferred to offspring from dams that were lactating when exposed than was transferred via the placenta when exposure occurred late in gestation. Furthermore, more 241Am was transmitted to the progeny via milk if exposure of the dam occurred during lactation rather than during pregnancy.

Beagle dogs received a single inhalation exposure to a monodisperse or a polydisperse aerosol of 241AmO2 to determine the radiation dose to internal organs. Three monodisperse aerosol sizes (0.75, 1.5 and 3.0 micrometer activity median aerodynamic diameter) and one polydisperse aerosol (1.8 micrometer activity median aerodynamic diameter) were used to assess the role of particle size in clearance of 241AmO2 from the lung and the rate of translocation of 241Am to other tissues. Dogs were sacrificed in groups of two or three at 8, 32, 64, 128, 256, 365 and 730 days after exposure. The clearance rate of 241Am from lung was particle size dependent; this resulted in an increased radiation dose to lung at 2 yr by 70% as particle size increased from 0.75 to 3.0 micrometer aerodynamic diameter. Conversely, the radiation dose to liver and skeleton decreased by 20 and 35% respectively as particle size increased from 0.75 to 3.0 micrometer activity median aerodynamic diameter. When the radiation doses absorbed by lung, liver and skeleton were compared to those predicted by the ICRP 30 model, differences were noted.

The estimated systemic burden of 0.3 muCi 241Am, made by the resident health physicist, has been compared to postmortem measurements using in-vivo counting equipment and radiochemical analysis of the donor's body. The health physicist's estimate was based on in-vivo measurements and urine excretion data obtained while the donor was still working, and it was logically assumed that the intake occurred about 1954 as a result of inhalation of Am-contaminated air. Based on additional data obtained by postmortem analysis, it seems more reasonable to assume for the purpose of scientific study and evaluation that the intake occurred in 1953, primarily as the result of a contaminated wound. Evaluations of the systemic burden using that assumption and three models indicate that the amount initially deposited could have been in the range of 0.2-1.1 muCi 241Am.

Absorption of isotopes of the actinide elements Np, Pu, Am and Cm from various organic media and/or in combination with plant or animal ligands or tissue is compared with their absorption from an inorganic nitrate medium. Gastrointestinal (GI) transport of 238Pu, 239Pu, 241Am and 244Cm at high concentrations from citrate medium by adult rats and/or mice was higher than from nitric acid medium. Neptunium-237 absorption, however, was not increased by citrate; probably because its oxidation state was reduced from 237Np(V) to 237Np(IV) by the medium and by the GI content. Increasing the mass of the 237Np dose resulted in increased absorption. Neither incorporation of 238Pu in rat liver nor retention of 238Pu oxide in rat lungs enhanced absorption when those Pu-containing tissues were administered intragastrically to either adult or neonatal rats. Ranking of GI absorption of the various forms of Pu gavaged in these studies suggests that transport is in the order: Pu citrate greater than Pu phytate greater than biologically incorporated Pu greater than Pu nitrate.

In nutrient media, Escherichia coli and selected strains of marine facultative anaerobes accumulated significant amounts of the transuranic radioisotope 241Am. The pattern of uptake varied among strains and was dependent upon pH, culture media and growth stage of the population. Desorption of 241Am to montmorillonite was significantly less in filtered media from some bacterial cultures than in "unconditioned" control media, suggesting that bacterial exometabolites may form complexes with Am thereby increasing its solubility.

Newborn mice exposed to 241Am or 237Pu during gestation and whose mothers were given Zn-DTPA at various times before parturition contained less radioactivity than comparable newborn mice given identical 241Am or 237Pu exposure without Zn-DTPA treatment of the mothers. There was no net increase in radionuclide transfer from mothers to unborn young as a result of maternal administration of Zn-DTPA, regardless of the pregnancy stage during which the radioactivity and decorporation treatments were given. Administration of 241Am followed after three days by extended Zn-DTPA therapy resulted in lower fetal content of radioactivity in litters conceived long after or soon after maternal exposure to 241Am. These data indicate that the risk from Am and Pu to unborn young can be reduced by Zn-DTPA treatment of the pregnant mother and of the female who becomes pregnant subsequently. This information may prove to be of significance with the increasing probability of Am or Pu exposure to women in the nuclear industry who could be pregnant at the time or who may conceive a child in the future.

Detailed external measurements were made of internally deposited 241Am in a nuclear chemical operator involved in an americium exposure accident at the Hanford plant. Despite some interference from high-level external contamination, quantitative measurements of the 241Am content in the lung, liver and bones were made starting on the third day after the accident. The rate of excretion of 241Am from these organs was determined. The 241Am embedded in the skin of the face and head was carefully mapped. The distribution over the total length of the body was also determined. Linear and rectilinear scanners, gamma cameras, large and small scintillation detectors, proportional counters, and Si(Li) and intrinsic germanium detectors were used to evaluate the internal deposition. Methods of calibration for quantitative measurement included simulation of the 241Am activity in both phantom and cadaver parts.

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.

Plutonium retention was measured after intragastric administration to neonatal rats, dogs and swine. At 1 week after administration, substantially more of the actinide remained in swine and dogs than in rats. The quantity of 238Pu absorbed by piglets was markedly influenced by such factors as compound solubility, mass of plutonium administered, oxidation state of the actinide, and age of the animal at gavage. Cortisone treatment reduced absorption, but was less effective in piglets than in neonatal rats. Measurements of 238Pu transport from ligated segments of the neonatal swine intestine indicated highest absorption from the duodenum, where the actinide was shown, autoradiographically, to be deposited in the epithelial region; in the ileum, deposition was predominantly in the lacteal region. Absorption of actinides by neonatal swine decreased in the order of 233U greater than 238Pu greater than 237Np greater than 244Cm greater than 241Am. Measurements at 1 yr after gavage showed a much higher retention by swine than by rats.