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A compartmental model of the distribution of radium in humans and young adult beagle dogs (approximately 500-550 d) is presented. The model consists of one soft tissue compartment and seven skeletal compartments for humans, and five skeletal compartments for beagles. The number of transfer parameters to be estimated was reduced by using remodeling rates of bone and imposing several constraints deduced from known features of bone physiology, radium metabolism, and autoradiographic analyses. The model predictions are in good agreement with measured retentions in plasma, whole body, skeleton, and soft tissues of both species. Moreover, for beagles even the retention in individual bones can be predicted quite well if the relevant morphometric parameters are known. While some of the estimated transfer parameters are similar in both species, others differ by an order of magnitude or more. Wherever possible, a comparison of model parameters with those of previous models is given. The new model not only is instrumental for calculating local doses in the skeleton but also can be used for characterizing the microdistribution of radium in this organ.

Osteosarcomas occur from exposures to bone-seeking, alpha-particle-emitting isotopes, particularly plutonium. The skeletal distribution of putative 239Pu-induced osteosarcomas reported in Mayak Metallurgical and Radiochemical Plutonium Plant workers is compared with those observed in canine studies, and these are compared with distributions of naturally occurring osteosarcomas in both species. In the Mayak workers, 29% and 71% of the osteosarcomas were in the peripheral and central skeleton, respectively, with the spine having the most tumors (36%). An almost identical distribution of plutonium-induced osteosarcomas was reported for dogs injected with 239Pu as young adults. This distribution of osteosarcomas is quite different from the distributions of naturally occurring osteosarcomas for both species. In the Cooperative Osteosarcoma Study Group in humans (1,736 osteosarcomas from all ages), over 91% of the tumors occurred in the peripheral skeleton. In the Mayo Clinic group of older individuals (40 years old), over 60% of the osteosarcomas appeared in the peripheral skeleton. The distribution of naturally occurring osteosarcomas in the canine is similar to that in the adult human. The similarities of the distributions of plutonium-associated osteosarcomas in the Mayak workers with those found in experimental studies suggest that many of the reported osteosarcomas may have been associated with plutonium exposures. These results also support the experimental paradigm that plutonium osteosarcomas have a preference for well vascularized cancellous bone sites. These sites have a greater initial deposition of plutonium, but also greater turnover due to elevated bone remodeling rates.

A long term biological study has been completed that was designed to assess the predicted effects in humans of internally deposited 239Pu by comparison with 226Ra in beagles. Herein we summarize for the first time results of several previous reports about the effects of these two radionuclides in our beagles in an attempt to elucidate what has been learned since the beginning of the study in the early 1950's. Perhaps the most important finding was that bone surface-seeking plutonium is more toxic at equal mean skeletal radiation doses (

A three-stage model for the induction of bone tumors in beagles from single injections of ^2^3^9Pu is presented. The model involves branching with one or two initiation steps controlled by radiation. It was applied to six groups of animals with graded injection levels between 0.38 and 33.6 kBq/kg bodymass, assuming an endosteal dose rate constant in time and proportional to the injected activity. The density of osteosarcoma survival times is Weibull with shape factor three and the scale factor being a function of the injected activity. The fraction of animals with bone tumors can be predicted using the survivor function of the controls, but some systematic deviations occur between calculations and observed fractions in an intermediate dosage range. It is shown that for low levels of ^2^3^9Pu the fraction of animals with tumors is proportional to the injected amount of plutonium.

A biokinetic model of the systemic distribution and dosimetry of 239Pu in the beagle dog is presented. To achieve maximum consistency with experimental data, known histomorphometric parameters and results of autoradiographic studies were adopted directly. The remaining parameters were determined from retention and excretion measurements by optimization procedures. The beagle model attempts to parallel the human model as much as possible, but only one liver compartment and one compartment representing other soft tissues were needed to describe the data adequately. The salient features and differences of the biokinetic behavior of 239Pu beagles and humans are compared. Generally the organ retention of the beagle in relation to the lifetime is longer than in humans. This is particularly pronounced in the skeleton. Trabecular deposits of plutonium are gradually shifted to cortical sites. For the dosimetric model some additional features disregarded in the human model were employed. These relate to bone volume labels, a gradation of concentrations in marrow, the energy-dependence of absorbed fractions, and the self-absorption in marrow. The model predicts that the contribution of surface deposits to the endosteal dose still exceeds the contributions from bone volume and marrow labels. The average endosteal dose is about eight times and the marrow dose about two times larger than the average skeletal dose. The model provides the basis for the analysis of survival and relative risks.

X-ray structural analyses reveal that the title complex contains the Fe(Salen) moieties bridged by single acetate groups in an anti–anti configuration to form linear polymer chains, which is found for the first time in the Fe(Schiff bases)L type of complexes. The shorter axial distance of Fe–O (2.077 (2) A) than that of Mn–O (2.201 (5) A) to the bridging carboxylate in the analogous complex of Mn(Salen)(AcO) is explained by Jahn–Teller distortions.

The microdistribution Of 239Pu was analyzed in the humerus, lumbar vertebra, and proximal ulna of young adult beagles using neutron induced autoradiography. The animals were sacrificed serially in groups of three at 4, 8, 16, 32, and 64 wk after a single injection of 3.5 kBq kg-' body weight. The kinetic behavior of surface concentrations was modeled using a simple concept of deposition and clearance in skeletal regions. Bones with high turnover showed a larger initial uptake and a faster clearance than bones with low turnover rates. Using a regression procedure, the surface deposition and clearance of plutonium was calculated as a function of the turnover rate. With time after injection the initial nonuniformity of trabecular surface labels tends to become more uniform. The trabecular: cortical affinity ratio is about 10. Trabecular activity is gradually translocated to cortical sites. The affinity ratio of forming to resting surfaces is about three. In some bones a continuous increase of marrow stars was observed, whereas in other bones no clear-cut tendency could be seen. The highest level of marrow labeling occurred in the lumbar vertebra and the humerus shaft.

The kinetics of Fe(III) complexation by lipophilic 3-hydroxy-2-methyl-l(γ-stearoamidopropyl)-4-pyridinone (HMSP) were studied when [Fe(III)] > [HMSP] in MeOH/H2O mixed solvent and [Fe(III)] < [HMSP] in MeOH, respectively. When Fe(III) was in excess, the observed rate constants depend on [Fe(III)]2 tot and on the reciprocal of [H+] and decrease with increasing pressure. ΔV ‡ values are around +8.0 cm3 mol–1. A mechanism consisting of the complexations of the hydrolyzed monomer Fe(H2O)5OH2+ and dimer species Fe2(H2O)7 (μ-OH)2OH3+ by HMSP is proposed. This mechanism is supported by the solvent effect and the work of other researchers. When HMSP is in excess, Fe(HMSP)3 is formed and three kinetic steps on different time-scales are observed. An "intermolecular chelate ring-closure" mechanism is proposed, differing from the "intramolecular chelate ring-closure" complexation reported for the formation of ferrioxamine B.

Several geological formations of the Utah-Colorado mining region mined for uranium ore during and after World War II had been mined earlier for vanadium. Therefore, most miners and millers from that region were exposed to those metals’ ores or tailings at one time or another. Preliminary investigation to determine uranium and vanadium retained in the lungs of a former uranium miner and miller from this region, who died of lung cancer (mesothelioma), showed a high nonuniform distribution of vanadium. This observation led to the hypothesis that the vanadium content in the lungs could be associated with inhaled particles. Further examination of spectra of characteristic X-rays obtained by scanning particle-induced X-ray emission (microPIXE) of an autopsy sample of this lung indicated that vanadium was indeed present in localized sites within the 20-μm spatial resolution of the proton beam. This work points out that the microPIXE-RBS (Rutherford backscattering) test for vanadium can be used for site localization of inhaled particles retained in the lungs. Further studies are in progress to: (i) locate uranium-bearing particles in lung tissues of former uranium miners and millers; and (ii) evaluate the local doses of alpha radiation received from these particles.

Uranium isotopes were given via single intravenous injection into 22 young adult beagle dogs of both sexes to determine the metabolism of this element. Animals were given either {sup 232}U, {sup 233}U, {sup 238}U, or a combination of {sup 232+233}U. Calculations to assign a value of skeletal dose for each dog were performed using published radioactive properties of each uranium isotope and the metabolic data (including measured retention and skeletal distribution) derived from this study during a period of up to 2 y after injection. We believe that the procedures illustrated in this communication can serve as a useful pattern for estimating skeletal radiation doses to humans contaminated with {sup 232}U, {sup 233}U, or {sup 238}U. 13 refs., 2 tabs.

Individual records of soft tissue tumor occurrence (lifetime incidence) among 236 beagles injected with 239 Pu citrate as young adults and 131 comparable control beagles given no radioactivity enabled us to analyze the possible effects on soft tissue tumor induction resulting from internal exposure to 239 Pu. A significant trend was identified in the proportion of animals having malignant liver tumors with increasing radiation dose from 239 Pu. There was also a significant difference in the relative numbers of both malignant liver tumors (3.2 expected, 22 observed) and benign liver tumors (18.1 expected, 66 observed). Malignant tumors of the mouth, pancreas, and skin were more frequent among controls than among the dogs given 239 Pu as were all tumors (malignant plus benign) of the mouth, pancreas, testis, and vagina. For all other tumor sites or types,there was no significant difference for both malignant and all (malignant plus benign) tumors. Mammary tumor occurrence appeared not to be associated with 239 Pu incorporation. We conclude that the only soft-tissue neoplasia induced by the intake of 239 Pu directly into blood is probably a liver tumor. Health Phys. 69(4):530-537; 1995

Hydrophilic 2- hydroxy-3-methyl-4-pyridinone derivatives were acylated with either long chain acid chlorides or with 1,3,5-benzenetricarbonyl trichloride. The products are either partially lipophilic, bidentatate or hexadentate chelators that form strong 3:1 and 1:1 complexes, respectively, with Fe (III).

The distribution of skeletal malignancies among our beagles injected with {sup 239}Pu as young adults roughly seems to follow the distribution of skeletal mass and skeletal {sup 239}Pu. These findings are similar to those we reported previously for a group of dogs given {sup 226}Ra. Although there were differences in tumor distribution between the animals given {sup 239}Ra and those given {sup 239}Pu, most of them were not statistically significant; however, the radium dogs seemed to show a greater sensitivity to bone tumor origin in the tibia, while there may have been a tendency among the plutonium dogs toward increased relative sensitivity in the scapula, lumbar vertebrae, sacrum, and ribs. In contrast, the most common site for the formation of naturally-occurring bone malignancy in the dog is the distal radius. Perhaps there were too few tumors and too few dogs to establish statistical significance. A correlation between tumor location and at least two anatomical-physiological factors in the skeleton indicated that these two factors (site-specific bone turnover rate and percent of red marrow at the site, which is correlated with vascularity) may influence the appearance of malignancies both individually and in combination. Except for the femur, there appeared to be nomore » difference between the relative distribution of skeletal malignancies of low-level (30 Bq-2 Bq kg{sup -1} injected) and high-level (3-122 kBq kg{sup -1}) dogs. Distribution of bone tumors between the axial and appendicular skeleton was 50% vs. 50% for {sup 239}Pu (42 and 42), but it was 39% axial vs. 61% appendicular (22 and 35, respectively) for dogs given {sup 226}Ra. This difference was not significant (p > 0.2). 15 refs., 4 tabs.« less

A total of 409 primary soft-tissue tumors (189 malignant) occurred among 87 of 120 young adult beagles (72.5%) injected with 226Ra in eight dose levels ranging from 0.2-440 kBq kg-1 body mass, while a total of 565 primary soft-tissue tumors (208 of them malignant) were seen among 117 of 133 control beagles not given radioactivity (88%). Because the p-value for the difference in these two percentages was0.05, further comparisons were not made of all tumor locations or types taken together but only of the individual tumor locations or types. There was a clear excess of malignant tumors and all tumors (benign plus malignant) in the eye among dogs injected with radium (p0.05, p0.01, respectively), but the occurrence of all the other types of soft-tissue tumors was not greater in irradiated vs. control dogs (p0.05). This was also true for hematopoietic tumor types (including just one leukemia in a control and none in irradiated dogs) in which there was no difference between controls and dogs given radium. The following total tumors (benign plus malignant) occurred in control dogs but not in radium dogs: brain = 3, peritoneum = 1, and pituitary = 4. Malignant tumors other than leukemia appearing in control animals and not among radium dogs were brain = 2, lymph nodes = 1, adrenal = 3, uterus = 1, and pancreas = 5. Tumors that occurred in dogs given radium and not in controls were 3 mast cell sarcomas and 2 tumors of the thymus (1 malignant). Age at first tumor diagnosis for corresponding tumor types did not seem to differ (p0.10 or p0.05) between radium dogs and controls except for the eye (p0.05), with radium dogs being somewhat younger than controls at first diagnosis, at death, or at loss from the colony. Cox regression indicated differences between radium dogs and controls in risk of dying with specific tumors. The following tumors had p values of0.05 and risk ratios of2.2:eye, mouth (mostly melanomas), and thyroid for malignant tumors and for malignant and benign tumors together. When all sarcomas were considered as a group, there was no difference between controls and radium dogs but there was a difference for all carcinomas taken together, even when mammary tumors and eye tumors were excluded and when eye tumors alone were excluded.

Analysis of eye tumors and other eye lesions among beagles given either 90Sr or 226Ra, and among control animals, indicated that intraocular tumors in excess of the rate for our control animals were not associated with radiation from incorporated 90Sr + 90Y. It is unequivocal that eye melanomas were produced by injected 226Ra. Intraocular neoplasia, hyperplasia, hyperpigmentation, and melanosis in the eye all occurred in our control beagles given no radioactivity; however, tumor experience as currently reported for different beagle colonies may not be directly comparable because of differing rates of discovery, nonuniform nomenclature, and varying criteria for classification of lesions with their discordant interpretation by different pathologists.

One of the features of 241 Am 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

Acetylated polyethylenepolyamines CH3CONHCH2(CH2-NH-CH2)CH2NH2 (n=1,2;) were synthesized using α-D-pentaacetyl-glucose as an acetylating agent.

Hydrophilic 2- hydroxy-3-methyl-4-pyridinone derivatives were acylated with either long chain acid chlorides or with 1,3,5-benzenetricarbonyl trichloride. The products are either partially lipophilic, bidentatate or hexadentate chelators that form strong 3:1 and 1:1 complexes, respectively, with Fe (III).

Several ribonucleosides, named 2-alkyl-3-hydroxy-1-(β-D-ribofuranosyl or pyranosyl)-4-pyridinones, were synthesized in good yield. The method provides a useful means to obtain α-ketohydroxypyridin derivatives with different sugar moieties that, if used as drugs, might enhance their absorption from the intestine and certain other desirable pharmacological properties.

Replacing alkyl groups by sugar moieties at N-1 position of 3-hydroxyl-2-methyl-4-pyridinone did not affect the geometry of the iron chelating sites but increased the hydrophilic nature. The formation of a polymer cluster through the intermolecular hydrogen bonds was also revealed by X-ray crystal structure analysis for the first time in all known 3-hydroxy-4-pyridinone crystal structures. Iron removal from ferritin by the title compounds was more efficient than with DFO.

Acetylated polyethylenepolyamines CH3CONHCH2(CH2-NH-CH2)CH2NH2 (n=1,2;) were synthesized using α-D-pentaacetyl-glucose as an acetylating agent.

A limited long-term experiment has been completed in which the chronic toxicity resulting from a single intravenous injection of 31.4 kBq of a poly-disperse 239Pu colloid sol per kg of body weight was tested in Beagle dogs. The Pu deposited mostly in the phagocytic cells of liver, spleen and to a lesser degree in lung and bone marrow. Slow solubilization of the Pu particles by endogenous ligands caused translocation of the nuclide and redeposition mostly as monomeric Pu in the skeleton and in liver hepatocytes. Thus, the deposit behaved as expected from a pulmonary or wound contamination in humans with a moderately soluble depot of Pu such as Class W hot particles. Therefore, this type of deposit provided the basis for a practical model to study the ensuing radiation effects under various experimental conditions. The dogs were divided into three groups of four animals each, and the following conditions were applied: (a) no further treatment was given, allowing free translocation of the Pu to its secondary deposition sites; (b) interception of the Pu translocation by weekly injections of 30 mumol of Ca-DTPA/kg of body weight (Ca-chelate of diethylene-triaminepentaacetic acid); and (c) interception of translocation by daily injections of 30 mumol/kg body weight of Zn-DTPA. For each of the groups (b) and (c), three dogs were used in a lifetime study, and one was sacrificed for nuclide distribution studies. Free translocation and subsequent deposition in the skeleton resulted in the death of each of the non-chelated dogs from osteosarcoma between 1267 and 1594 days after injection. Weekly treatment with Ca-DTPA reduced the total Pu burden significantly, but these dogs also died with osteosarcoma between 1462 and 1783 days. Daily injections with Zn-DTPA reduced the total Pu burden more efficiently than Ca-DTPA and prevented continuous deposition of solubilized Pu on bone surfaces. The mean post-injection survival of these dogs was 3520 days or about 2.1 times that of the animals receiving Ca-DTPA, while the latent period for bone tumour induction was about 2.6 times longer. This treatment reduced the severity of liver lesions and eliminated the occurrence of persistent leukopenia, but it did not prevent the formation of bone cancer.

Analysis of the ancestry of the 1,262 lifespan beagles (LSB) entered into lifespan studies at the Radiobiology Division, University of Utah, beginning in 1952 and ending in 1980, indicated that about 97% of ancestor citations in the various pedigrees were of only 10 breeding animals (breeders) among breeders within the beagle colony. In turn, just 18 AKC-registered "champion" beagles from outside of this colony (founders) accounted for about 98% of all ancestor citations among founders for the LSB. We conclude from this study that the animals used in the lifespan radionuclide experiments can be considered to be somewhat genetically interrelated.

Chelators are used to promote excretion of actinides and some other metals, but few are orally effective. The relative efficacies of orally administered triethylenetetraminepentaacetic acids (TT) with varying lipophilic properties on the removal of 241 Am and 239 Pu and comparison with parenteral Zn-DTPA was determined. The actinides were administered to adult rats 2 weeks prior to initiation of 30 d of chelation treatment. The TT compounds were given orally while Zn-DTPA was given twice weekly by injection. Total body content of "'Am was measured before and during the treatment period and organ contents of 'Am and 239 Pu were measured at the end of the study. Significant reductions in 241 Am occurred within the first week, with Zn-DTPA being the most effective. By 3 weeks, the most lipophilic chelator, C 22 TT was as effective as Zn-DTPA. After 30 d, reductions in organ content of 239 Pu and 241 Am directly correlated with increasing lipophilicity of the TT chelators. Oral C 22 TT was as effective as injected Zn-DTPA in liver and bone, the major organs of actinide deposition. The removal of 239 Pu from the liver and reduction of redeposition of 239 Pu in newly formed bone by C 22 TT was confirmed by neutron-induced autoradiographs. The amphipathic TT chelators may be useful as orally administered alternatives to current parenteral DTPA for the removal of actinide elements from the body, particularly for longer-term therapeutic applications.

A possible genetic link for malignant mammary tumor (MMT) was investigated.Records of an internally-irradiated beagle colony followed from the early 1950's until about 1995 were searched and analyzed by standard statistical procedures.Only a single ancestor yielded a "p" value (Fisher's Exact Test) for an overrepresentation among descendants with MMT at0.025 (one-sided test), and the number of comparisons for the 169 ancestors where the relative fraction of animals with MMT was greater than that for non MMT dogs (61) suggests that this could have occurred by chance alone. Results of other statistical tests were not remarkable.No genetic link for MMT in this colony could be established with the available data. These findings may or may not be relevant to humans.

The method of synthesizing acyclonucleoside iron chelators is both convenient and cost effective compared to that of synthesizing ribonucleoside iron chelators. The X-ray crystal structural analysis shows that the 2-hydroxyethoxymethyl group does not affect the geometry of the iron chelating sites. Therefore, the iron binding and removal properties of the acyclonucleoside iron chelators should remain similar to the ribonucleoside iron chelators, which is confirmed by the titration and competition reaction of the acyclonucleoside chelators with iron and ferritin, respectively. The acyclonucleoside iron chelators are more lipophilic with measured n-octanol and Tris buffer distribution coefficients than ribonucleoside iron chelators.

In this paper, carbon nanotubes/nanofibers for microwave amplifiers and parallel e-beam lithography have been discussed. Field emission properties of CN arrays will be presented.

—A new, orally administered, partially lipophilic polyaminocarboxylic acid chelator was tested for its ability to remove incorporated 239Pu deposits in rats. Animals were injected with 239Pu-citrate and 14 d later were treated for an additional 10 d with docosyl-triethylenetetraminepentaacet

The purpose of this paper is to demonstrate the derivation and use of exact formulas, and their algorithms, for calculating the probabilities alpha of Type I errors, and beta of Type II errors, for low blank total counts (Poisson-distributed). The calculations are carried out to examine the alpha and beta probabilities at low blank levels of the decision level (DL) and minimum detectable amount (MDA) formulations as adopted in the Health Physics Society Standard, "Performance Criteria for Radiobioassay." These formulations are consistent with those published by L.A. Currie, which have received wide acceptance in defining lower limits of detection (LLD). Although Currie's formulation was derived assuming a normal distribution in net counts, the behavior of the distribution of net counts at low count levels, which is a distribution of the difference between two Poisson variates, is such that the MDA formulation in the standard could be considered acceptable for the purpose of providing one simple formulation of MDA. The derivations in this note can also be useful in other problems involving differences in Poisson variates, such as those in certain population studies.

Replacing alkyl groups by sugar moieties at N-1 position of 3-hydroxyl-2-methyl-4-pyridinone did not affect the geometry of the iron chelating sites but increased the hydrophilic nature. The formation of a polymer cluster through the intermolecular hydrogen bonds was also revealed by X-ray crystal structure analysis for the first time in all known 3-hydroxy-4-pyridinone crystal structures. Iron removal from ferritin by the title compounds was more efficient than with DFO.

Statistical analyses have indicated that there was a significant difference between dogs injected with bone volume-seeking 226Ra as compared to those given bone surface-seeking 239Pu with respect to location within the skeleton of 334 radiation-induced primary bone malignancies. Corresponding differences also were evident when dogs given bone volume-seeking 90Sr or bone surface-seeking 241Am, 228Th, (249,252)Cf, or 224Ra (which decays mostly on bone surfaces because of its short, 3.6 d half time) were included along with the 226Ra or 239Pu, respectively (562 total tumors). Further analysis suggested that higher values of percent red marrow (M) and bone turnover rate (R) are correlated with increased probability of tumor appearance at a particular location within the skeleton for the surface seekers. Proportionately higher values of M and R are associated with skeletal sites containing mostly trabecular bone as compared to those with mostly compact (cortical) bone. Coefficients of determination (r2) for the relationship between percent of total tumors vs the combination of percent red marrow and turnover rate (= MR) was about 0.7 for the surface seekers but only about 0.1 for the volume seekers. This indicates that the neoplastic effects of surface seekers, but not volume seekers, are associated with the presence of trabecular bone at the various sites of radionuclide deposition within the skeleton.

A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with 226Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given 226Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose, but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon--polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. Results of this study are potentially useful in understanding risks of radium-induced breast cancers in humans.

A recently developed, orally administered, partially lipophilic polyaminocarboxylic acid-based chelator, docosyl-triethylenetetraminepentaacetic acid (C22TT), was tested for its ability to promote decorporation of 239Pu and 241Am. The effects of dose and duration of treatment were determined in rats injected with 239Pu or 239Pu/241Am 2 weeks before the initiation of C22TT treatment and compared with untreated controls. In the dose-effects study, significant reductions in total body Am content were seen within 3 days after the initiation of C22TT treatment. After 30 days of treatment, there were dose-related reductions in the Pu and Am content of soft tissues and bones. All doses of C22TT resulted in substantial reductions in Pu and Am content of the liver. In the time-response study, there were rapid reductions in total body Am content in the C22TT-treated animals. The greatest reductions occurred within the first 30 days of treatment. Significant decreases in Pu content of soft and hard tissue were observed in the treated animals at 30, 60 or 90 days compared with untreated controls. The greatest reductions in organ Pu content occurred within the first 30 days of treatment, particularly in the liver, but it continued throughout the experiment. Neutron-induced autoradiography showed that C22TT greatly reduced the incorporation of Pu into new bone and substantially reduced the Pu content of the bone marrow. There was no evidence of overt toxicity in either experiment. This study demonstrates that orally administered C22TT is effective in reducing soft and hard tissue content of internally deposited Pu and Am.

A new, orally administered, partially lipophilic polyaminocarboxylic acid chelator was tested for its ability to remove incorporated 239Pu deposits in rats. Animals were injected with 239Pu-citrate and 14 d later were treated for an additional 10 d with docosyl-triethylenetetraminepentaacetic acid (C22TT) added to the diet. There were significant reductions in the 239Pu content of selected organs in the chelated animals compared with controls. These results suggest that this class of chelators should be studied further for their ability to remove plutonium deposits from the body when given orally.

Several new powerful chelating agents, suitable for the removal of a variety of certain heavy-metal ions from the body by oral application, have been synthesized and tested. Structurally, these compounds are partially lipophilic polyamino carboxylic acids (PACA). They were synthesized in nonaqueous media from triethylenetetramine (TT) by monoalkylation of a primary amino group, followed by exhaustive carboxymethylation of the remaining amino groups using ethyl bromoacetate and subsequent alkaline hydrolysis of the ester. Compounds were characterized using IR, 1H NMR, 13C NMR, and mass spectrometry. Synthesis and testing of two of these compounds, C12- and C22-triethylenetetraminepentaacetic acid (CnTT), is described in detail. Gel permeation chromatography of a mixture of the PACA and actinide elements have shown these substances to be strong chelating agents similar to EDTA or DTPA. They were capable of removing plutonium from contaminated liver cytosol in vitro. In contrast to their nonlipophilic counterparts EDTA and DTPA, the model substances exhibited appreciable absorption from the intestine and, therefore, can be administered orally. With increasing length of the alkyl chain, the chelons can be directed primarily to the liver, one of the target organs for actinide contamination. In vivo, absorption from the ligated duodenum and jejunum of rats after 2 h was 27% of the amount introduced. Compared to untreated controls, daily feeding of 200 mumol of the chelons (C12TT or C22TT)/kg of body weight to rats for 10 days reduced the whole body Am by 29% and 44%, respectively. Am was eliminated most efficiently from the liver, with a reduction of 71% and 89% (p less than 0.001). However, the skeletal retention also was reduced by 17% and 32% from the femora (p less than 0.001) and 20% and 37% from the carcass for the C12TT and C22TT compounds, respectively. No weight loss or other obvious signs of blood, kidney, liver, or intestinal toxicity were observed after the 10-day treatment. These new chelators are promising as agents for oral chelation therapy to remove actinides and possibly other elements from body stores.

The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 +/- 0.04 kBq 239Pu/kg, 23 dogs injected with 2.31 +/- 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 +/- 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 +/- 0.030 kBq 228Th/kg, and 12 dogs injected with 21.13 +/- 1.74 kBq 90Sr/kg was evaluated statistically. The amounts of these radionuclides are related directly to the estimated maximum permissible body burdens for humans suggested in ICRP II (1959). They constitute a level of exposure that initially was assumed to cause no deleterious effects in dogs. This study had two objectives: (1) identification of homogeneous control groups against which to evaluate the survival of the irradiated groups and (2) comparison of the survival characteristics and estimation of mortality or hazard rate ratios for control dogs vs dogs injected with the baseline dosages given above. It was shown, by goodness-of-fit plots, that the Cox proportional hazards model was an appropriate method of analysis. Therefore, covariates that possibly could influence survival were tested for significance. Only the effects of grand mal seizure, which is caused in epileptic dogs by an external stimulus and can be fatal if untreated, were significant (P less than 0.0001). Consequently, in the final model, death from grand mal seizure was considered as accidental. After censoring the dogs dying from grand mal seizure, it was established that the data for the control groups from previous and contemporary experiments could be pooled. The change in hazard rates relative to controls resulting from exposure to the baseline radionuclide level was modest, 1.6 times for 239Pu (P = 0.033), 1.0(4) for 226Ra (P = 0.86), 1.9 for 228Ra (P = 0.035), 2.5 for 228Th (P less than 0.001), and 0.52 for 90Sr (P = 0.041). Bone tumor induction was clearly elevated in dogs injected with 239Pu and 228Th. When the effect of these bone tumors on survival was removed by censoring, the dogs injected with 239Pu were indistinguishable from the controls. In contrast, the effects of bone tumor on group survival of the 228Ra and 228Th dogs were not significant. Thus, no additional life-shortening effects beyond those attributable to bone tumor were suggested by these data for 239Pu, but other, as yet unspecified, confounders are suggested for 228Ra and 228Th.

The influence of age at injection of 226Ra or 239Pu on skeletal deposition and local distribution, the pattern of bone tumor formation, and postinjection survival was assessed in parallel short-term studies of mechanisms and lifetime toxicity. Beagles received a single intravenous injection of 226Ra or 239Pu at 3 months (juveniles), 17-19 months (young adults) or 60 months (mature). Data from short-term studies of mechanisms and dosimetry and from one dosage level (41 kBq 226Ra/kg or 11 kBq 239Pu/kg body mass) of each of the toxicity experiments were compared. Skeletal growth and turnover produced differential initial deposition and distribution patterns typical for each age group. At 1 week after injection, skeletal retention of 226Ra or 239Pu was 68 and 68%, respectively, in the juveniles, 32 and 46% in the young adults, and 31 and 43% in the mature dogs. Comparing individual bones in the juveniles, gradients in the concentration of 239Pu were small since all bones were actively growing, but substantial gradients, corresponding to centers of ossification, were present within individual bones. In other age groups, local concentration gradients were less pronounced, but much larger differences were present among the various bones. In the toxicity study all animals injected with either 41 kBq 226Ra/kg or 11 kBq 239Pu/kg have died. The cumulative average skeletal doses to the presumed time of start of tumor growth (1 year before death) were 25 and 4 Gy, respectively, for the juveniles, 22 and 5 Gy for the young adults, and 15 and 4 Gy for the mature dogs. The highest bone tumor incidence was seen in the young adult groups. Differences were observed in location of bone tumors between dogs in the same age group given radium or plutonium and among age groups injected with either radionuclide, some of which could be explained by differences in local dose distributions. Median postinjection survival assessed by the Kaplan-Meier nonparametric method ranged from 2513 and 2592 days for the juveniles to 2099 and 1617 for the young adults to 2086 and 1421 in the mature groups. Cox regression analysis indicated no significant differences in postinjection survivals (uncorrected for the different preinjection periods) of groups injected with radium, but there was a statistically significant difference among the groups injected with plutonium. It was demonstrated that differences in the effects of 239Pu in the three groups were due primarily to the age- and time-dependent local distribution of the radionuclide.

An unusually high incidence of kidney disease (tubular degeneration and necrosis with fibrous replacement) was observed among 24 beagles injected at about 5 years of age with 116 or 329 kBq 226Ra kg-1 but not among an additional 10 beagles given about 39 kBq 226Ra kg-1. This 226Ra solution also contained 210Pb, 210Bi, and 210Po. To determine whether the kidney disease was related to the radiation from 226Ra and its short-lived progeny or to the alpha radiation from 210Po, 2 beagles about 7 years of age were injected with 451 kBq 226Ra kg-1 of 210Po citrate. Measurements of polonium retention in the kidneys of 4 additional beagles given 210Bi citrate enabled us to model the retention of these emitters in the dog kidney and to estimate the kidney dose from the alpha radiation of 210Po following injection of either 226Ra + 210Bi + 210Po or 210Po only. Autoradiography revealed that almost equal concentrations of 210Po were in the tubular epithelium and/or its basement membrane and in the glomeruli, but very little of the 210Bi deposited in kidney tissue was present in the glomeruli. Radiation damage to the kidneys similar to that observed previously in beagles given 226Ra solutions that also contained 210Bi and 210Po was seen among the beagles given 210Po but not in the dogs given purified 226Ra. The analysis of these data indicated that the relatively high incidence of kidney disease among the mature beagles injected with 226Ra and its accompanying 210Bi and 210Po resulted from alpha irradiation of the kidneys by the substantial amount of 210Po that was in the injection solution.

A new plasma source configuration, coaxial source, has been developed at the Lawrence Berkeley National Laboratory suitable for ion and electron beam lithography applications. The axial ion energy spread and electron temperature of the multicusp ion source have been reduced considerably from 2 and 0.3 eV to a record low of 0.6 eV by employing a coaxial source arrangement. Results of ion projection lithographic exposure at the Fraunhofer Institute demonstrate that feature size less than 65 nm can be achieved by using a filter-equipped multicusp ion source. Langmuir probe measurements also show that very low energy spread electron beams can be obtained with the multicusp plasma generator.

Interest in thick photoresist applications is steadily growing. Besides the bump fabrication and wire interconnect technology, the process of patterning thick layer photoresists by UV lithography is specially qualified for applications in micro electro mechanical systems. Specialized equipment and new photoresists have been developed or are under development to cope with the new challenges in the field of preparing extremely thick photoresist layers, to plan the process of patterning these thick resists, and to deal with the difficulties of the following galvanoplating step. A technology called three‐dimensional (3D) UV‐microforming was developed, consisting of a resist preparation process for very thick photoresists (positive or negative tone), UV lithographic steps, resist development, moulding procedures by galvanodeposition, and finally stripping and cleaning for finishing the structures. A minimum width of 3 μm for the resist bars was found to be necessary to withstand the fabrication process of line...

A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with {sup 226}Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given {sup 226}Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P < 0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose,more » but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon {yields} polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. 27 refs., 5 figs., 4 tabs.« less

The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 ? 0.04 kBq 239pu/kg, 23 dogs injected with 2.31 ? 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 ? 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 ? 0.030 kBq 228Th/kg, and 12 dogs injected with 21.13 ? 1.74 kBq 9oSr/kg was evaluated statistically. The amounts of these radionuclides are related directly to the estimated maximum permissible body burdens for humans suggested in ICRP II (1959). They constitute a level of exposure that initially was assumed to cause no deleterious effects in dogs. This study had two objectives: (1) identification of homogeneous control groups against which to evaluate the survival of the irradiated groups and (2) comparison of the survival characteristics and estimation of mortality or hazard rate ratios for control dogs vs dogs injected with the baseline dosages given above. It was shown, by goodness-of-fit plots, that the Cox proportional hazards model was an appropriate method of analysis. Therefore, covariates that possibly could influence survival were tested for significance. Only the effects of grand mal seizure, which is caused in epileptic dogs by an external stimulus and can be fatal if untreated, were significant (P < 0.0001). Consequently, in the final model, death from grand mal seizure was considered as accidental. After censoring the dogs dying from grand mal seizure, it was established that the data for the control groups from previous and contemporary experiments could be pooled. The change in hazard rates relative to controls resulting from exposure to the baseline radionuclide level was modest, 1.6 times for 239Pu (P = 0.033), 1.0(4) for 226Ra (P = 0.86), 1.9 for 228Ra (P = 0.035), 2.5 for 228Th (P < 0.001), and 0.52 for 9oSr (P = 0.041). Bone tumor induction was clearly elevated in dogs injected with 239Pu and 228Th. When the effect of these bone tumors on survival was removed by censoring, the dogs injected with 239Pu were indistinguishable from the controls. In contrast, the effects of bone tumor on group survival of the 228Ra and 228Th dogs were not significant. Thus, no additional life-shortening effects beyond those attributable to bone tumor were suggested by these data for 239pu, but other, as yet unspecified, confounders are suggested for 228Ra and 228Th. ? 1991 Academic Press, Inc.

The influence of age at injection of226 Ra or239 Pu on skeletal deposition and local distribution, the pattern of bone tumor formation, and postinjection survival was assessed in parallel short-term studies of mechanisms and lifetime toxicity. Beagles received a single intravenous injection of226 Ra or239 Pu at 3 months (juveniles), 17-19 months (young adults) or 60 months (mature). Data from short-term studies of mechanisms and dosimetry and from one dosage level (41 kBq ${}^{226}{\rm Ra}/{\rm kg}$ or 11 kBq ${}^{239}{\rm Pu}/{\rm kg}$ body mass) of each of the toxicity experiments were compared. Skeletal growth and turnover produced differential initial deposition and distribution patterns typical for each age group. At 1 week after injection, skeletal retention of226 Ra or239 Pu was 68 and 68%, respectively, in the juveniles, 32 and 46% in the young adults, and 31 and 43% in the mature dogs. Comparing individual bones in the juveniles, gradients in the concentration of239 Pu were small since all bones ...

An unusually high incidence of kidney disease (tubular degeneration and necrosis with fibrous replacement) was observed among 24 beagles injected at about 5 years of age with 116 or 329 kBq 226Ra kg-1 but not among an additional 10 beagles given about 39 kBq 226Ra kg-1. This 226Ra solution also contained 210Pb, 210Bi, and 210Po. To determine whether the kidney disease was related to the radiation from 226Ra and its short-lived progeny or to the alpha radiation from 210Po, 2 beagles about 7 years of age were injected with 451 kBq 226Ra kg-1 of 210Po citrate. Measurements of polonium retention in the kidneys of 4 additional beagles given 210Bi citrate enabled us to model the retention of these emitters in the dog kidney and to estimate the kidney dose from the alpha radiation of 210Po following injection of either 226Ra + 210Bi + 210Po or 210Po only. Autoradiography revealed that almost equal concentrations of 210Po were in the tubular epithelium and/or its basement membrane and in the glomeruli, but very little of the 210Bi deposited in kidney tissue was present in the glomeruli. Radiation damage to the kidneys similar to that observed previously in beagles given 226Ra solutions that also contained 210Bi and 210Po was seen among the beagles given 210Po but not in the dogs given purified 226Ra. The analysis of these data indicated that the relatively high incidence of kidney disease among the mature beagles injected with 226Ra and its accompanying 210Bi and 210Po resulted from alpha irradiation of the kidneys by the substantial amount of 210Po that was in the injection solution.