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Beagle dogs injected with 241Am and treated subsequently with DTPA exhibited a reduced occurrence of skeletal malignancies and increased lifespans when compared to corresponding untreated animals also given 241Am. Whereas 92% of dogs given about 11 kBq 241Am kg(-1) and not treated with DTPA developed bone cancer (skeletal dose about 5.9 Gy), skeletal malignancy was seen in only 40% and 27%, respectively, among two groups of DTPA-treated animals injected with 11 kBq kg(-1) (doses of 5.7 and 1.7 Gy). The median lifespan among the untreated dogs was 1,728 d, but the median lifespans in the DTPA-treated groups were 2,478 and 3,654 d, respectively. Untreated dogs with a skeletal dose averaging about 2 Gy had 53% bone cancer occurrence and a median lifespan of 3,227 d. These data did not enable us to address the question of whether the reduction in cancer occurrence was proportional to, greater than, or less than the reduction in skeletal dose, but the third possibility seems unlikely.

Forty young adult grasshopper mice (Onychomys leukogaster) of both genders were injected with either 129 or 44 kBq kg-1 of monomeric 239Pu and were maintained for lifetime observation. Average liver doses to death (mean times +/- standard deviation (SD) from injection to death = 405 +/- 133 and 756 +/- 189 d) were calculated as approximately 16 and 9 Gy, respectively. These animals developed a total of 18 primary liver tumors (neoplasms, malignant, and benign). Comparison of these mice to a previously published study involving 49 control animals of the same species, 70 mice given 241Am, and 73 given Thorotrast, indicated that the liver cancer induction of Thorotrast can be attributed almost exclusively to the effects of the radioactivity and not to its nonradiation properties. This suggests that projected risks of liver cancer induction from 239Pu, 241Am, or other liver-seeking actinides in humans probably can be estimated from the liver cancer experience in Thorotrast patients using the calculated radiation doses to liver. For this species, the linear risk coefficient for induction of liver neoplasia (percent of mice with liver tumor) by 241Am or Thorotrast was estimated to be about 14.6 +/- 5.4 times the average liver dose (in Gy) for groups of animals with average liver doses of 5 Gy or less. The lowest average liver dose among groups of these mice given 239Pu was about 9 Gy, the dose was not in the linear range, and it was too high to yield reliable results for determining a risk coefficient for low dose irradiation. However, the estimates for a risk coefficient were similar for the plutonium and americium mice with liver doses of approximately 9 Gy or 16 Gy.

The risk of americium-induced liver cancer in beagle dogs that received long-term dietary ethanol was two to three times that of their nonalcoholic cohorts, even though the radionuclide retention time in hepatic tissue was shortened by the alcohol treatment. Liver malignancies did not occur in the ethanol-treated, nonirradiated controls. An ethanol-induced tumor-promoting effect was not observed in organs or tissues other than the liver.

Plutonium-239 or 241Am administered intravenously in the monomeric citrate form was initially deposited in beagle livers principally in the hepatocytes and to a much lesser extent in the sinusoidal macrophages and connective tissues. The initial distribution was quite uniform throughout the hepatic parenchyma; however, at later postinjection intervals, depending on the amount of injected activity, the liver burden became increasingly more focal due to: (1) a progressive shift of the radionuclide from the hepatic epithelium to the macrophages; (2) the movement of such macrophages toward the portal or central regions of the lobule; and (3) the displacement of the older more radioactive tissue by regenerating hepatocytes, which generally have a much lower radionuclide content. The hepatic lesions produced by Pu or Am included: (1) necrosis and degenerative changes that were clinically serious or fatal in some of the animals injected with approximately 107 kBq kg-1; (2) marked structural and circulatory changes resulting from necrosis and focal hepatocyte hyperplasia; (3) a significant incidence of both benign and malignant primary liver tumors. In both Pu- and Am-treated dogs, the most frequently appearing neoplasm was the bile duct adenoma, followed by the cholangiocarcinoma. The most obvious difference between Pu- and Am-induced liver neoplasia was the greater frequency of fibrosarcomas and mast cell sarcomas in the Am-treated groups. Hepatomas were of relatively low frequency in animals with Pu or Am burdens. Although the incidence of bone neoplasia was high among the dogs in these studies, the risk of liver tumors, especially in the Am-treated animals, exceeded that of the skeleton in some of the lower dosage levels where the survival times were long. A risk coefficient of approximately 1200 fatal liver malignancies (10(4) beagle Gy)-1, derived from the dosage groups with long survival times, was calculated for combined Pu and Am animals. The prominence of the liver syndromes in beagles with burdens of Pu or Am indicates that humans with body burdens of 239Pu, 241Am, or other actinide elements may be at risk from radiation effects in the liver, including neoplasia development.

Groups of C57BL/Do (black and albino) mice were injected with graded activities of 226Ra, 239Pu, 241Am, 249Cf, or 252Cf and were followed throughout life. Bone sarcoma was the principal radiation-induced end point, and the risks associated with average skeletal doses of the four transuranium radionuclides, relative to radium, were determined. The relative biological effectiveness (RBE) was calculated for each emitter by dividing its risk coefficient (bone sarcomas per 10(6) mouse-rad) by the risk coefficient for 226Ra. Combined data for males and females in both black and albino mice gave the following values +/- SD for the RBE relative to 226Ra = 1.0: 239Pu = 15.3 +/- 3.9, 241Am = 4.9 +/- 1.4, 249Cf = 5.0 +/- 1.4, and 252Cf = 2.6 +/- 0.8. About 70% of the tumors occurred in the axial skeleton, and the risk coefficient for females averaged about four times higher than for males when all five nuclides were included. The RBE of fission fragment irradiation from 252Cf for cancer induction, relative to alpha irradiation, for the combined data in all of the animals given 252Cf and 249Cf, was 0.02 +/- 0.28, in agreement with the calculated theoretical value of 0.03, based on the ratio of summed track lengths in tissue.

Decorporation of Pu and Am by tetrameric catechoylamide (CAM) ligands has been investigated in beagles and mice. Eight dogs were injected intravenously (iv) with 237 + 239Pu(IV) + 241Am(III) citrate, and 30 min later, pairs of dogs were injected iv with 30 mumole/kg of 3,4,3-LICAM(C) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-5-sulfobenzoyl)tetr aazatetradecane, tetrasodium salt], 3,4,3-LICAM(S) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-4-carboxybenzoyl)te traazatetradecane, tetrasodium salt], CaNa3-DTPA, or each of the latter two ligands. Blood was sampled, and excreta were collected for 7 days, at which time the dogs were sacrificed and nuclide retention in liver and nonliver tissue was measured. Groups of five mice were each given 238Pu(IV) or 241Am(III) citrate iv; 3 min later 30 mumole/kg of a CAM ligand was injected intraperitoneally, mice were killed at 24 hr, and separated excreta and tissues were analyzed. In the dogs, average retention at 7 days of the injected Pu and Am, respectively, was as follows: 12 and 70% after treatment with a CAM ligand alone; 30 and 20% after DTPA; 12 and 20% after LICAM(S) plus DTPA; 90 and 89% without a ligand. In the mice, mean retention of the injected Pu and Am, respectively, was as follows: 14 and 66% after treatment with LICAM(C); 21 and 54% after LICAM(S); 91 and 87% without a ligand. In both species, about 99% of net Pu excretion (excretion with ligand - excretion without ligand) promoted in 24 hr by DTPA or LICAM(S) was in the urine, whereas about 10% of net Pu excretion promoted by the less hydrophilic LICAM(C) was in feces. Delayed excretion of both Am and Pu was significant in all ligand-treated dogs. Comparison of the nuclide content of tissues of ligand-treated mice with those of mice killed 3 min after nuclide injection indicated that the CAM ligands chelated circulating Pu and Am and prevented further deposition. In addition, the CAM ligands removed much of the presumably loosely bound Pu present in liver and skeleton at the time of ligand injection. LICAM(C) was more effective in removing Pu from liver and LICAM(S) was more effective in the skeleton. Moderate to severe uremia and histological evidence of cell killing in the distal tubules of the kidney were observed in the four dogs injected once with 30 mumole/kg of LICAM(S).(ABSTRACT TRUNCATED AT 400 WORDS)

A method has been developed whereby the liver content of photon-emitting transuranium elements can be determined in living beagles by a combination of total-body and partial-body counting. Calibration of the system was accomplished through the photon counting of intact dogs and also of the parts of the same animals following autopsy. A determination of the calibration factors for 252Cf, 247Cf, 243Cm, 237Pu, and 241Am has been made. The special case of 252Cf was treated in which a significant fraction of the high energy fission gamma-ray spectrum penetrates the Pb shield employed in partial-body counting, and methods were developed which allow for this effect in the calculation of liver content. Some uniformity of response in the system was evident for all of the emitters which were considered. It is proposed that similar techniques could be applied in the determination of selected organ radioactivity in other species including man.

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.

Decorporation of intravenously injected monomeric 241Am and 237+239Pu by the administration of 30 mumole Zn-diethylenetriaminepentaacetic acid (DTPA)/kg each day beginning 2 weeks after radionuclide injection was compared in beagles entered into the experiment when 3 months (juveniles). 1.9 years (young adults), or 10 years (mature adults) old and studied for about 5 months. DTPA therapy was most effective in the juvenile dogs and least effective in the mature adults. Retention of 241Am in the liver decreased from a pretreatment value for adults of about 50% of the injected activity to about 10% in the mature adults and less than 1% in the young adults at 140 days of treatment, while the liver retention of juveniles decreased from pretreatment values of about 16% to undetectable levels by 28 days of treatment. Plutonium retention in the liver decreased from adult pretreatment levels of about 30% of the injected activity (corrected for radioactive decay) to near 10% in the mature adults and 6% in the young adults at 140 days of treatment, while juvenile liver retention decreased from pretreatment values near 15% to undetectable levels by 56 days of treatment. Nonliver Am retention (mainly skeleton) decreased in mature adults from pretreatment values of about 45% of the injected activity to near 25%, in young adults from 35 to 20%, and in juveniles from roughly 70 to 9% by 140 days of DTPA administration. Nonliver Pu retention decreased from pretreatment values of about 50% of the injected activity (corrected for radioactive decay) for mature and young adults to about 30% by 140 days and from 75 to 16% in juveniles over the time period.

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.