Effective thresholds for induction of skeletal malignancies by radionuclides.

Our analysis of data from the beagle project completed at the University of Utah has provided some comparisons that appear to be useful in testing the model proposed by Raabe of effective thresholds for induction of skeletal malignancy by bone-seeking radionuclides in beagles. Raabe's model predicted that cumulative skeletal doses of less than about 0.9 to 1.4 Gy from alpha emitters or 28 to 70 Gy from beta emitters deposited in the skeleton require a long enough time for bone cancer expression that the dog's natural lifespan would be exceeded before the tumor appeared. Results from the Utah beagle project seem to confirm these projections for 226Ra, 228Ra and, perhaps, for 90Sr. The lowest doses at which malignant bone tumors were observed in animals injected with these radium isotopes were about 0.9 Gy (226Ra) and 3 Gy (228Ra). For the beta emitter, 90Sr, the lowest doses at which bone tumors were seen were about 18, 50, and 70 Gy with an expectation for naturally occurring tumor of about one. Twenty-six of the two hundred and thirty-three Utah beagles given monomeric 239Pu that developed skeletal malignancies had doses between 0.02 and 0.51 Gy (80 of these dogs had skeletal doses of less than 0.9 Gy). Three dogs of 54 given 241Am with doses lower than 0.9 Gy had bone tumors at 0.23, 0.56, and 0.88 Gy with the expectation of about one naturally occurring case. For 25 animals injected with 228Th at skeletal doses below 0.9 Gy, one bone tumor dog had a dose of about 0.4 Gy, and the expectation of a dog with natural tumor among the group was only about 0.38. Five beagles of 74 given 224Ra with resulting doses of less than 0.9 Gy died with skeletal malignancy at 0.32 Gy or less with an expectation for non 224Ra induced tumor of about one. It appears that Raabe's proposal might be confirmed for some but not all of the radionuclides used in the Utah studies. Models presented in earlier papers by Raabe provide results that are somewhat different from his recent abstract and compare more favorably with those cited herein for Utah dogs. Re-examination of our data for these analyses has suggested a novel concept for calculation of carcinogenic dose to endosteal bone surfaces.

Some problems in the skeletal dosimetry of bone-seeking radionuclides.

There are fundamental problems with the calculation of radiation doses to the skeleton from internal emitters deposited in bone. Some of these include dose inhomogeneities, identity of cells at risk and their dynamics, changing deposition patterns of bone-seeking radionuclides with time after exposure, seemingly unique responses of the skeleton to each deposited radionuclide, the role of radioactive progeny produced by deposited emitters and their individual dynamics and effects, different responses of mammals of different ages at exposure to identical dosages, different responses to different chemical forms of a given radionuclide, and different responses to an identical dose from a given radionuclide at different dose-rates. This situation makes it necessary to choose some common dose parameter that will allow the overall effects of different radionuclides to be compared directly so that projected effects of each of them in humans can be estimated. For radiation protection purposes, it appears premature to abandon the concept of average skeletal dose (which appears to be a practical compromise for use) until an undelusive, non-artificial and uncontrived method of calculating absorbed dose to the appropriate cells in bone is developed that fulfills the requirement of equal cancer response for equal skeletal dose for all circumstances.

Bone surface concentrations and dose rates 11 years after massive accidental exposure to 241Am.

Alpha-particle spectrograms of bone samples from USTUR Case 246 were analyzed to determine the depth in tissue from which the 241Am alpha-particles were emitted. In four samples of bone, the lack of energy straggling in the alpha spectra indicated that essentially all the 241Am was deposited directly on the exposed bone surface, and none had been translocated to within bone volume. These findings agree well with the results of autoradiographic examination of bone samples from the same case, but are in marked contrast to findings on another case (USTUR Case 102) who had been exposed to a much smaller amount of 241Am at a younger age and survived approximately twice as long after the exposure. It is problematical whether the lack of 241Am redistribution, and therefore the implied absence of bone remodeling, in Case 246 was due to his advanced age at exposure or to a deterministic effect of alpha-irradiation on bone metabolism, but the observation of radiation effects on bone metabolism in former radium workers supports the latter.

Alteration of the c-fms gene in a blood sample from a Thorotrast individual.

We analyzed six different tissue DNA samples from a leukemic individual who received an injection of Thorotrast for alterations in proto-oncogene or tumor-suppressor gene structure. Our examination of the DNA indicated an alteration of the c-fms gene in the blood sample from this individual. This locus showed a deletion in which the 3' end of the deleted region maps between exons 11 and 12. In this particular case, the type of leukemia is unknown but myeloid leukemia is a neoplasm associated with individuals injected with Thorotrast. It is possible that the alteration in the c-fms gene of this individual is a consequence of the radiation exposure. No apparent alterations in the c-mos gene were observed in any of the tissues from the individual. This is in contrast to previous studies that described alterations in methylation patterns associated with the c-mos locus in radium-exposed individuals. A number of the individuals exposed to radium also had alterations of the retinoblastoma gene while no such alterations were observed in any tissue DNA samples from this Thorotrast case. It is possible that our inability to detect alterations of the c-mos and retinoblastoma gene may be attributable to the nature of alpha-emitting radionuclides or their distribution, or to the limited set of tissues available for analysis.

Radon exposure system for mammalian cells in culture: design, operation, and dosimetry.

A novel system for Rn gas exposure of mammalian cells in culture has been designed, constructed, and used to directly assess both the magnitude and the nature of chronic, low-dose Rn/Rn daughter toxicity of exposed vital lung cells isolated from normal pulmonary tissue, propagated and exposed in vitro. Direct correlations between atmospheric Rn concentrations, alpha-particle fluences, and macro- and microdoses of absorbed radiation doses by lung cells provide for a heretofore unavailable assessment of critical doses to vital cells.

Effects of human growth hormone in men over 60 years old.

BACKGROUND: The declining activity of the growth hormone--insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging. METHODS: To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites. RESULTS: In group 1, the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in average lumbar vertebral bone density (P less than 0.05 in each instance). Skin thickness increased 7.1 percent (P = 0.07). There was no significant change in the bone density of the radius or proximal femur. In group 2 there was no significant change in lean body mass, the mass of adipose tissue, skin thickness, or bone density during treatment. CONCLUSIONS: Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age.

Interspecies scaling of risk for radiation-induced bone cancer.

The induction of bone cancer in mice, dogs and humans, due to protracted alpha-irradiation from skeletal burdens of radium, was found to be represented by a single dose-rate/time/response function, when time was normalized with respect to species natural life-span. In the absence of other causes of death, the median time to death from bone cancer after 226Ra intake is given by tm* = 790-d*-0.29, based on the dog data, with -d* the time-weighted average absorbed dose rate in cGy/mLSF to skeleton and where time is measured as milli-life-span-fraction. On the basis of life-span scaling of the time dimension, data on cancer induction from studies with laboratory animals can be scaled to estimate human risks in a three-step process involving a three-dimensional analysis. The overall cancer risk distribution is shown to be a mountain-like surface rising from a Euclidean plane formed by the dose rate and survival time co-ordinates. At lower dose rates the time required for cancer induction may exceed the natural life-span yielding a quasi-threshold for cancer risk. For intakes of 226Ra in young adults this quasi-threshold is predicted to occur at a cumulative life-time alpha-radiation dose to the skeleton of about 1 Gy.

Alteration of the c-mos locus in "normal" tissues from humans exposed to radium.

The structure of a number of human protooncogenes of persons with internal systemic exposure to radium was analyzed by restriction enzyme digestion and Southern blotting of their DNA. Two extra c-mos EcoRI restriction fragment length bands of 5.0 and 5.5 kilobases were found in tissue DNA from six of seven such individuals. The extra c-mos bands were detected in DNA from many, but not all, of the tissues of the individuals exposed to radium. Kidney DNA, however, from three of four individuals exposed to radium contained these alterations; kidney DNA from six age-matched controls did not. The 5.0- and 5.5-kilobase bands, which were of a similar intensity, varied in their intensity with respect to that of the normal 2.5-kilobase band of the c-mos gene. The DNAs that have the polymorphic bands also appear to have a more complex c-mos methylation pattern. Our results suggest that the c-mos restriction fragment length alterations found in individuals exposed to radium were induced rather than inherited, are epigenetic in origin, and most likely result from changes in the methylation of bases surrounding the single exon of the c-mos protooncogene.

Skeletal 212Pb retention following 224Ra injection: extrapolation of animal data to adult humans.

Two methods of interspecies extrapolation, one based on a correlation of skeletal 212Pb/224Ra with body weight, the other based on the mechanistic relationship between skeletal 212Pb/224Ra and reciprocal bone surface-to-volume ratio, lead to the conclusion that the retention of 212Pb in the adult human skeleton is approximately complete a few days after injection. The correlation-based method gives most probable values for 212Pb/224Ra of 1.0 and 1.1 at 2 d and 7 d after injection, compared with values of 1.05 and 1.27 expected at these same times if the retention of 212Pb were complete from the time of injection and if no 212Pb were in the injection solution. The range of values corresponding to one geometric standard error on either side of the most probable value is 0.87 to 1.21 at 2 d post-injection. With the method based on the reciprocal bone surface-to-volume ratio, the best estimate of 212Pb/224Ra at 2 d after injection is 0.88, equal to the value observed in young adult beagles. An alternative interpretation of the results of this latter method leads to the conclusion that retention is complete, with 212Pb/224Ra equal to 1.0 for a 212Pb-free injection solution and 1.1 for a solution containing 212Pb in secular equilibrium with 224Ra. This work, which uses 224Ra daughter product retention data from mice, rats and dogs following 224Ra injection, provides a scientific foundation for retention assumptions made in the calculation of mean skeletal dose for adult humans. There now appear to be few uncertainties in these latter dose values, stemming from inaccurate retention assumptions; but substantial uncertainties remain in the mean skeletal dose values for juveniles and in the endosteal tissue doses regardless of age. Risk coefficients such as those in the BEIR III report that give the lifetime probability of bone tumor induction per unit mean skeletal dose may be correct for adult humans but are probably too low for juveniles due to overestimation of juvenile dose. BEIR III risk coefficients that give tumor induction probability per unit endosteal tissue dose may be substantially too small, regardless of age, due to overestimation of endosteal dose.

Comparison of intake and committed dose equivalent permitted by radiation protection systems based on annual dose equivalent and committed dose equivalent for a nuclide of intermediate effective half-life.

Comparison of the 226Ra ingestion permitted by a radiation protection system that limits dose equivalent, with that permitted by the ICRP system and by the ICRP system modified through the use of the Norris retention function in place of the ICRP alkaline earth model, shows that the total ingested activity and the total committed dose equivalent to bone-surface tissues are approximately the same under the three protection systems when exposure occurs at the maximum permissible level for 50 y. Under the dose-equivalent-limitation system, annual ingestion decreases from 451 kBq during the first year to 36 kBq during the fiftieth year. The total ingestion equals 3.45 MBq. Annual committed dose equivalent decreases from 3.6 Sv during the first year to 0.3 Sv during the fiftieth year. The total committed dose equivalent equals 27 Sv. Under the ICRP system and its modified version, the annual limits on intake are constant with time at 70 kBq and 63 kBq, respectively. The total intakes are 3.50 MBq and 3.15 MBq. The annual committed dose equivalent is also constant with time at 0.5 Sv for both versions. The total committed dose equivalent is 25 Sv. These results suggest that a pure dose equivalent limitation system similar to that which has evolved at U.S. defense-related facilities permits lifetime exposures similar to those permitted by a committed dose limitation system for radionuclides of intermediate effective half-life. Lifetime cancer risk for the maximally-exposed individual may be greater under the dose equivalent-limitation system due to the more rapid increase in committed dose equivalent which occurs with time compared to the increase under the ICRP system or its modified version.

Mucosal structure and radon in head carcinoma dosimetry.

(1) The location of the epithelial cells implied by ICRP Publication 26 is incorrect. It leads to dose rates from bone and to dose rate ratios which are much too high. (2) Epithelial thickness has little effect on the ratio of dose rates. (3) The dose rate ratio is strongly dependent on the thickness of the lamina propria and would depend strongly on the thickness of the cytoplasm layer if direct nuclear hits were required for cell transformation. (4) Based on the limited data available for lamina propria and epithelial thicknesses, the airspaces would probably be the dominant source of dose in the mastoid air cells if the ratio of radioactivity levels in bone and airspace were no more than 1 l./g. This would be true whether targets were spread throughout the whole cell or confined to the nucleus alone. (5) The airspaces would probably be the dominant source of dose in the paranasal sinuses if the ratio of radioactivity levels were no more than 1 l./g. and targets were spread throughout the cell. If targets were confined to the nucleus, no conclusion could be drawn due to the lack of information on the thickness of the nucleus-free region of cytoplasm. (6) Four quantities require further study for a better understanding of the importance of radon: (a) the airspace radon concentration, (b) the specific activity of bone adjacent to the mucous membrane, (c) the thickness of the nucleus-free region of cytoplasm, and (d) the thickness of the lamina propria.

Soft tissue dosimetry of radium in humans--I. Alpha-particle doses from the decay of 226Ra and 228Ra in soft tissues.

Estimates are presented of the alpha particle doses accumulated by individual organs and soft tissues of Reference Man in a 50-yr period following single intakes of 226Ra and 228Ra. With no decay of 226 Ra daughter products in soft tissue, the median dose is 67 mrad per muCi 226Ra intake. With no translocation of 228Ra daughter products, the dose per muCi 228Ra intake is 5.77 times the corresponding value for 226Ra. Biological variability introduces substantial uncertainty when applying these estimates to a particular individual.

Quantitative histology of the mucous membrane of the accessory nasal sinus and mastoid cavities.

The mucous membranes of the accessory nasal sinuses and of the mastoid labyrinth were measured in undecalcified, plastic-embedded specimens from nonpathologic postmortem cases. Epithelial thicknesses, lamina propria thicknesses and the ratio of nuclear to total cell area of the epithelia are presented for these organs to provide a quantitative basis for dosimetric calculations of alpha-emitting radionuclides. These data will be of value for studies in populations at risk for head carcinomas from the intake of radium and related nuclides.

Effect of arm orientation on bone mineral mass and bone width measured using the Cameron-Sorenson technique.

Bone mineral content and bone width were measured as the distal and midshaft locations in the right radius and ulna with the arm in different orientations. The values of mineral content, width, and the ratio of bone mineral content divided by width, determined at each bone site were compared to establish the effect of orientation. Seven orientations were studied, two of which involved rotations of the forearm and five of which involved rotations of the upper arm about the axis of the forearm. Rotation of the forearm was found to affect the values of one or more of the measured quantities at all of the sites. Orientation of the upper arm was found to affect the values of all quantities at the midshaft radius, but not to affect the values of any of the quantities at the other sites.