David R. Atherton

The Incorporation of Various Metal Ions into in Vivo- and in Vitro-Produced Melanin

Small amounts of a number of metal ions have been found in melanins obtained from natural sources, and

The Distribution and Retention of Hexavalent 233U in the Beagle

{}^{140}{\rm Ba}

Comparative toxicity of 226Ra, 239Pu, 241Am, 249Cf, and 252Cf in C57BL/Do black and albino mice.

and226 Ra have been found to deposit in tissues containing melanin. In the studies reported here, some aspects of the chemical nature of the incorporation were investigated with radionuclides of high specific activity. The uptake of metal ions by synthetic melanin from a physiological buffer increased with decreasing hydrated ionic radius, decreased with decreasing pH, and decreased in the presence of chelating agents. Replacement of melanin-bound

Increased toxicity of Na3CaDTP when given by protracted administration

{\rm Ra}^{++}

RADIUM (Ra

with H+ demonstrated the reversibility of the reaction. Comparative studies with synthetic melanin and natural melanin plus its protein showed that the role of the protein in the reactions is small. Both the reaction characteristics and the chemical structures of melanin and of weak acid cation exchangers are similar, which suggests that metal ions and melanin interact by ion exchange.

sup 226

The distribution, retention, and excretion of 233U were measured in seven beagles injected intravenously with 2.8 /zCi 233U(VI)/kg (-3 mg/dog) in citrate buffer and sacrificed at times ranging from 1 to 726 days postinjection (PI). The concentration of U in plasma decreased rapidly, and for the first 24 hr PI could be described by a triphasic exponential equation with half-times of 0.92, 46, and 315 min. The uranium in the blood at 5 min PI was present as either a protein (transferrin-albumin) or a carbonate/bicarbonate complex. Up to 60% of the injected U was excreted during the first day, most of it in the urine. Whole-body retention was 17% at 7 days, 10% at 94 days, 7.6% at 1 year, and less than 5% at 2 years PI. Except for the kidney, only a small fraction of the injected U was retained in soft tissues. At 1 day PI, the liver contained 1.1% of the injected U and its subcellular distribution was similar to that seen with Pu(IV). At 1 day PI, 7.7% of the U was found in the skeleton; this amount decreased with a biological half-life of 883 days. Initially, U was deposited nonuniformly on bone surfaces with areas of intense hot spots adjacent to areas with intermediate and low concentrations. At later times redistribution and/or diffusion of U into the bone volume produced a deposition pattern intermediate to that of 239Pu (surface) and 226Ra (volume). The heterogeneity of surface deposits persisted, and isolated segments of the trabecular bone showed intense surface deposits at times greater than 1 year PI. Twenty-two percent of the injected U was found in the kidneys at 1 day PI with high concentrations localized in the proximal tubules. The initially high concentration of U in this organ was correlated with extensive diuresis and a persistent elevation in blood urea nitrogen. Damage to proximal tubules was attributed primarily to chemical toxicity but was aggravated by simultaneous a irradiation. It is postulated that the deposition of U on trabecular endosteal surfaces will induce osteosarcoma(s) following prolonged exposure to 233U or 232U.

) AND RADON (Em

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.

sup 222

Protracted administration greatly enhanced the toxicity of Na,CaDTP in beagles. Injections of 5.8 p moles/kg of Na3CaDTP, given every 5 hr, were fatal as early as 4 days after the onset of treatment. The most serious lesions were induced in the epithelial lining and related structures of the intestinal tract. Protracted administration of equal molar amounts of Na,ZnDTP was found to be much less toxic.

) METABOLISM IN DOGS

The metabolism of radium in beagle dogs after a single intravenous injection was studied. Radon exhalation in dogs was compared with radon exhalation data for other species, and a theoretical method for calculating radon retention and excretion ratios is presented. The metabolism of radium and calcium-46 in dogs was compared, and considerable differences were found in renal clearance rates, plasma levels, and skeletal binding. Radium retention in beagles was found to decrease as age at injection increased. Calculations of average radiation dosage from deposited radium in beagles are compared with dosage measurements made on humans. (C.H.)

Americium-241 studies in beagles.

Forty-eight adult beagles were injected with 0.00179 to 4.49 pCi 241Am/kg body mass. Retained activity in the living animals was evaluated via the 60 keV gamma-ray using a combination of total-body and partial-body counting to determine the proportion in the liver and in non-liver tissue. Soon after injection, about 50% and 40%, respectively, of the administered 241Am was deposited in the liver and non-liver tissue (mainly skeleton). In the animals injected with 0.00179-0.305 pCi/kg the liver and non-liver burdens decreased slowly each with a biological half-time of about 10 yr during the first 850 days. Two dogs injected with about 2.80 ,uCi/kg exhibited a sharp decrease in liver retention beginning about 100 days after injection accompanied by an increase in non-liver 241Am. Both showed extreme degenerative liver changes at death 401 and 448 days after injection. Similar but more slowly progressing effects were observed in the retention of 241Am by two animals injected with about 0.904pCi/kg. Excreta collections from four dogs during the first 3 weeks after injection showed that f of the excretion was urinary and that nearly 2 of the total z41Am excreted during this period appeared in the first day’s collection. Evaluation of the activity of individual bones, organs, and tissues of six animals autopsied 1-448 days after injection showed that although 241Am was distributed in many soft tissues, the liver and skeleton were the principal deposition sites; however, americium concentration in the thyroid gland was higher than in the skeleton and was higher than in any other soft tissue except the liver. Autoradiography showed that 2aArn was deposited close to the location of the functioning thyroid cells. The kidney also had a relatively high concentration of activity, selectively deposited in the glomeruli.