Determining the relative toxicity and RBE of internal emitters in animals.

It is almost impossible to conduct a perfect study of the relative toxicity of the radiations produced by different radionuclides. This is because the results of such studies are commonly confounded by spatial and temporal differences in the distributions of dose produced by the radionuclides employed. In addition, the results of a study designed to overcome these problems (using matched radionuclides incorporated within fused clay particles) revealed additional characteristics of an ideal study. These included the use of sufficient numbers of animals to give the study statistical power; the derivation of all causes of death and of survival for the analysis; the use of relative risk, rather than crude incidence data, to determine toxicity ratios; the cautious use of relative biological effectiveness values derived from fitted curves; and the preferred use of relative toxicity values derived directly from the data.

Dose responses from inhaled monodisperse aerosols of 244Cm2O3 in the lung, liver and skeleton of F344 rats and comparison with 239PuO2.

The purpose of this study was to obtain information on the alpha-particle dose-response relationship of 244Cm in rats. Rats were exposed briefly by inhalation to graded levels of monodisperse aerosols of 244Cm2O3 heat-treated at 1150 degrees C. The initial lung burden (ILB) of each animal was determined by the use of the gamma-ray-emitting radionuclide 243Cm in the aerosols. Seven groups of 84-day-old F344/Crl rats (a total of 637 males and 645 females) were exposed once to 244Cm2O3 or sham-exposed to filtered ambient air. Mean ILBs of all rats per group ranged from 0.51 +/- 0.17 (+/-SD) to 240 +/- 82 kBq kg-1 body weight. Mean lifetime alpha-particle doses to the lungs per group ranged from 0.20 +/- 0.069 (+/-SD) to 36 +/- 6.5 Gy. After death, each rat was radiographed and necropsied. Dose-related increases occurred in incidences of benign and malignant lung neoplasms, except for the groups of rats with higher mean ILBs that were examined histologically (98 +/- 18 and 240 +/- 77 kBq kg-1 body weight) in which survival was markedly decreased. Also, average alpha-particle doses of 0.0014 +/- 0.00058 (+/-SD) to 0.17 +/- 0.091 Gy and 0.18 +/- 0.007 to 1.6 +/- 1.1 Gy were also absorbed by the liver and skeleton, respectively, in the rats in the different exposure groups. Primary liver neoplasms occurred in several rats. However, the incidence of these lesions was not related to dose. Increased incidences of bone neoplasms occurred only in rats receiving higher doses to the skeleton. Excess numbers of rats with lung neoplasms per 10(4) Gy to the lung per group ranged from 760 +/- 430 (+/- SE) at a mean dose of 0.48 Gy to 84 +/- 16 at a mean dose of 37 Gy. Risk factors for the lowest and highest ILB kg-1 body weight groups were not considered reliable because of large errors associated with these calculations and the life-span shortening in the highest ILB kg-1 group. Inhaled 244Cm2O3 appeared to be about 50% less effective as a lung carcinogen in rats compared to 239PuO2 at similar doses.

Effectiveness of continuously infused DTPA therapy in reducing the radiation dose from inhaled 244Cm2O3 aerosols.

Radionuclide decorporation is the only effective method of reducing radiation dose for persons contaminated accidentally. In this study, dogs that had inhaled a moderately soluble aerosol of 244Cm2O3 were treated with either discrete intravenous injections of the chelating agent diethylenetriaminepentaacetic acid (Zn-DTPA) or with subcutaneous infusion of Zn-DTPA at either 30 or 120 mumol kg-1 d-1. Each treatment regimen was continued for 64 d, whereupon all animals were killed, and collected excreta and tissue samples were analyzed for curium. All DTPA treatment methods were effective. A total of 89% of the initial pulmonary burden (IPB) was removed by DTPA injection, whereas 94% IPB was removed by the low dose of infused DTPA and 97% by the high dose treatment. Thus, low and high infused doses of DTPA prevented the translocation of greater than 99.5% of curium to liver and 97-99% to bone and kidney. The resultant dose reductions to these organs were superior to those achieved by intravenous DTPA injections.

Measurements of actinide gut-transfer factors in humans.

Measurements have been made of the gastrointestinal absorption in humans of 239Np and 242Cm administered together in citrate media. Using five volunteers, consistent results of (2.0 +/- 0.2) x 10(-4) and (1.7 +/- 0.3) x 10(-4) were obtained for Np and Cm respectively; the quoted uncertainties are the standard errors of the means. A progress report is given of work to measure the f1 value for Pu in humans. Early work suggests an f1 value of 2 x 10(-4).

Gastrointestinal absorption of neptunium and curium in humans.

The gastrointestinal absorption of Np and Cm has been determined in five male adult volunteers. The Np and Cm, which were in citrate solution, were taken with food. An initial experiment with each individual determined the fraction of each element excreted in the urine following intravenous administration. Subsequently, the results for urinary excretion for the two routes of administration were used to calculate the fractional absorption (f1) of ingested Np and Cm. The mean f1 values were: Np (2.0 +/- 0.2) X 10(-4), range (1.2-2.9) X 10(-4), and Cm (1.7 +/- 0.3) X 10(-4), range (0.95-3.0) X 10(-4), the quoted uncertainties being the standard error of the means. Currently, the International Commission on Radiological Protection recommends a value of 10(-3) for both elements. Cumulative urinary excretion over 1 wk after intravenous injection accounted for about 20%-40% of administered Np and 7%-10% of Cm. At the conclusion of the experiment, the total committed effective dose equivalent for each volunteer was calculated to be in the range 130-250 microSv, based on the individual f1 values, and, in some cases, a knowledge of the rate of clearance of 239Np through the gut as measured by whole-body counting.

Inhalation carcinogenesis of repeated exposures to high-fired 244CmO2 in rats.

Rats were given single or multiple (10 exposures at about 21-d intervals) inhalation exposures to 244CmO2 starting at 70 d of age. Mean lung and bone doses (+/- standard deviation) were 1.4 +/- 1.3 and 0.74 +/- 1.1 Gy, respectively, in the single exposure group, and 1.8 +/- 2.9 and 0.53 +/- 0.74 Gy, respectively, in the multiple exposure group. After cessation of exposure in the multiple exposure group, mean cumulative lifetime radiation doses to lung and skeleton were not significantly different in the two groups. The percentages of rats with lung and bone tumors were 9.1 and 12%, respectively, in the single exposure group, and 20 and 24%, respectively, in the multiple exposure group. However, the multiple exposure regimen did not significantly alter survival times or tumor incidences in lung or bone from a single inhalation exposure to 244CmO2 when survival patterns were taken into account.

A biokinetic model of inhaled Cm compounds in dogs: application to human exposure data.

Curium isotopes are major by-products in irradiated nuclear reactor fuel and comprise a significant fraction of the alpha-emitting radionuclide inventory. Although little use is currently being made of purified Cm sources, such usage is possible if reprocessing of spent fuel becomes feasible. Because little information is available on the biokinetics and dosimetry of inhaled Cm compounds, a study was conducted in which adult beagle dogs received a single inhalation exposure to either a monodisperse aerosol of 244Cm2O3 (1.4 micron activity median aerodynamic diameter [AMAD]; sigma g = 1.16) or a polydisperse aerosol of 244Cm (NO3)3 (1.1 micron AMAD; sigma g = 1.74). At times ranging from 4 h to 2 y after exposure, animals were sacrificed and their tissues analyzed for Cm content. The data describing the uptake and retention of 244Cm in the different organs and tissues and the measured rates of excretion of these dogs formed the basis on which a biokinetic model of Cm metabolism was constructed. This Cm model was based on a previously published model of the biokinetics of 241Am that was shown to be applicable to data from human cases of inhalation exposure to 241Am aerosols. This Cm model was found to be adequate to describe the biological distribution of Cm in dogs and was also applied to the sparse data from humans. Reasonable agreement was found between the model predictions for lung retention of Cm and for urinary excretion patterns in humans.

Biokinetics and dosimetry of inhaled Cm aerosols in beagles: effect of aerosol chemical form.

This study was designed to provide tissue distribution data of 244Cm that was inhaled by beagle dogs. Two chemical forms that were presumed to bracket the solubility of pure Cm compounds in vivo were used: 244Cm2O3 (oxide) and 244Cm(NO3)3 (nitrate). Adult dogs of both sexes received a single brief pernasal exposure to either a monodisperse aerosol of 244Cm2O3 (1.4 micron activity median aerodynamic diameter, AMAD, and 1.16 geometric standard deviation, sigma g) or a polydisperse aerosol of 244Cm(NO3)3 (1.1 micron AMAD, 1.74 sigma g). The resulting initial pulmonary burdens (IPB) were 1.5 and 1.7 kBq kg-1 body mass for the oxide and nitrate groups, respectively. The tissue distribution data obtained from the dogs that were serially sacrificed from 4 h to 2 y after exposure showed that both chemical forms were very soluble in vivo. For the oxide group, 78% IPB was cleared from the lung with a T 1/2 of 7.6 d, whereas for the nitrate group, 42% IPB cleared with a T 1/2 of 0.6 d. The lung retention for each group was described by three-component exponential functions. Most of the Cm that cleared the lung was redeposited in the liver (37% IPB) and skeleton (27% IPB), with lesser amounts in the muscle, fat and connective tissue (3.5% IPB) and kidney (approximately 2% IPB). The only significant difference noted in the biokinetics of Cm for the two exposure groups was a more rapid translocation of Cm from the lung to liver and bone during the first 10-20 d after exposure to the nitrate compared to the oxide chemical form. Extrapolation of these data to obtain estimates of committed dose equivalents for man indicate substantial agreement with the limits for occupational exposure specified by ICRP 30 (1979).

Biokinetics of inhaled 244Cm oxide in the rat: effect of heat treatment at 1150 degrees C.

A study was conducted in rats to determine solubility and subsequent metabolism of an inhaled aerosol of curium treated at high temperatures. Young adult Fischer-344 rats received a single inhalation exposure to one of three monodisperse aerosols of 244Cm2O3 (0.70, 1.3, or 2.6 micron activity median aerodynamic diameter) heat-treated at 1150 degrees C. Animals were maintained individually in metabolism cages for excreta collection and serially sacrificed in groups of two male and two female rats from 2 to 33 days after inhalation exposure. Additionally an injection study with curium citrate was done to define the systemic behavior of Cm in this rat model. The in vivo solubility was inversely related to the aerosol particle size. The relationship of the results of this study to results from other experimental inhalation studies with curium oxide aerosols is discussed, as is the relevance to bioassay interpretation and risk assessment in man.

[Carcinogenic efficacy of the transuranium elements americium-241 and curium-244]. / Kantserogennaia éffektivnosti transuranovykh élementov ameritsiia-241 i kiuriia-244.

Albino female rats were used in the experiments. After a single intraperitoneal administration of 241Am and 244Cm chloride is doses ranging from 0.37 to 185 kBq/kg (14 doses were used) it was established that the doses applied had different effect on the average life of animals. The largest doses shortened and the lowest increased the life span of experimental animals as compared to the controls. The carcinogenic effect of the studied radionuclides and the development of malignant tumors were detected at sufficiently low doses absorbed. Malignant tumors developed in the experimental and control animals were different not only in their incidence but also their localization and spectrum.

Curium excretion studies in man and baboon: a predictive animal model.

A major rationale for performing metabolic research in laboratory animals is to obtain useful information which is applicable to man. Since it is usually impossible to determine many of the kinetic parameters which are responsible for the fate of a contaminant in inadvertently-exposed individuals, it is essential that well-controlled laboratory experimentation in animals be performed. In the present case, we will demonstrate how our experimental protocol, i.e. curium in the adult baboon, can provide a model from which to derive important characteristics of curium in man. To accomplish this goal, we have compared the retention and excretion patterns of curium in several men accidentally exposed via inhalation, burns, or puncture wounds with that of 243,244Cm citrate injected i.v. in nine adult baboons. Although many of the exposure conditions are different in considering the two primate species (human and non-human), biokinetic research in the baboon may serve to estimate tissue burdens and dose commitments in man. Comparison of the excretion rates of the nuclide in the urine of man and the baboon gives similar half times between days 10 and 50 post exposure.

The wound clearance and distribution of plutonium, americium and curium in rodents.

Wound contamination was simulated by the intramuscular injections of either 239Pu, 241Am or 244Cm nitrate in the hamster and by the subcutaneous injection of either 239Pu or 241Am nitrate in the rat. The actinides moved from the hamster muscle at approximately the same rate after injection of 370 Bq of each radionuclide (approximate 80 per cent cleared after 6 months). Similarly, the rates of translocation of 239Pu and 241Am in the rat were the same after injection of 370 Bq of each radionuclide (approximate 80 per cent cleared after 1 month). The clearance of 239Pu in the rat was slower after injection of 14.8 kBq and more rapid after injection of 20 Bq (approximately 40 per cent and 90 per cent moved after 1 month, respectively) while the movement of 241Am showed no dependence on the administered dose over the same range. The mixing of 239Pu and 241Am prior to intramuscular injection appeared to enhance the clearance of both radionuclides. The levels of accumulation of each actinide in the skeleton and liver of both species showed that they reached the circulation predominantly in soluble form. Some uptake of Pu and Am in regional lymph nodes was also observed, indicating that lymphatic clearance of polymeric material also took place.

The mobility of curium-244 dioxide in the bronchially intubated rat.

The mobility of curium dioxide in the rat after pulmonary intubation has been investigated by administering suspensions containing different particle size ranges of the oxide. A major factor influencing the movement of curium from lungs to blood is the formation of hydroxide or hydrous oxide particles about 0.001 micrometer in diameter. This process is sufficiently rapid for the lung clearance kinetics of the dioxide to resemble those of a soluble compound more closely than those of an insoluble one. Filtration of 0.001 micrometer particles through the kidneys results in considerably enhanced excretion of curium relative to administered curium citrate. It is concluded that current metabolic models, which assume that solubility in the lung is a prerequisite for transport in body fluids, do not adequately describe the behaviour of curium fromthe standpoint of radiological protection.