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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.

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 (<3 Gy for 239Pu, <20 Gy for 226Ra) than bone volume-seeking radium for the induction of skeletal malignancy by about a factor of 16 for a single intravenous injection of monomeric 239Pu. In addition, ancillary studies have shown that when plutonium transfers continuously onto bone surfaces from a depot of particulate 239Pu in phagocytic cells, its relative toxicity per Gy average skeletal dose is enhanced by about a factor of 2. Juvenile animals or dogs injected as mature adults were only about half as sensitive for equal mean skeletal doses as dogs injected as young adults. Male and female dogs were about equally sensitive to radiation of the skeleton by either radionuclide. Findings about radiation-induced fractures are summarized as well as data on the induction of soft-tissue malignancies by 239Pu or 226Ra. Natural survival was not affected at the lower dosage levels of either 226Ra or 239Pu as compared with control dogs given no radioactivity, but the survival of animals at higher levels was reduced. No additional life-shortening effects beyond those attributable to occurrence of radiation-induced malignancies or other radiation-induced effects were suggested by analysis of data for low dosage levels.

Regression analyses of longevity as a function of skeletal radiation dose among groups of beagles injected with 226Ra, 228Ra, 228Th, 241Am, 90Sr or monomeric 239Pu suggested that at low doses and dose-rates (those at which induced effects are low), age at death seems to be independent of dose when animals dying with specific radiation effects were excluded, although longevity does appear to be a function of dose when animals dying with established radiation effects and at all doses were included. We conclude tentatively that, for mammals receiving skeletal dose from bone-seeking radionuclides at low doses and low dose-rates, longevity may not be dependent upon skeletal radiation dose in the absence of radiation-induced malignancies or other radiation effects.

Because skeletal fractures were an important finding among persons contaminated with 226Ra, experience with fractures among dogs in our colony was summarized to determine the projected significance for persons contaminated with bone-seeking radionuclides. Comparison by Fisher's Exact Test of lifetime fracture occurrence in the skeletons of beagles injected as young adults suggested that for animals given 226Ra, 228Ra, 228Th, or 239Pu citrate, there was probably an excess over controls in fractures of the ribs, leg bones, spinous processes, and pelvis (os coxae) plus the mandible for dogs given 226Ra and the scapulae for dogs given 228Ra or 228Th. Regression analysis indicated that significantly elevated fracture occurrence was especially notable at the higher radiation doses, at about 50 Gy average skeletal dose for 239Pu, 140 Gy for 226Ra, about 40 Gy for 228Ra, and more than 15 Gy for 228Th. The average number of fractures per dog was significantly elevated over that noted in controls for the highest radiation doses of 239Pu and 226Ra and for the higher doses of 228Ra and 228Th. For those dogs given 90Sr citrate, there was virtually no important difference from control beagles not given radionuclides, even at group mean cumulative skeletal radiation doses up to 101 Gy. Because of a large proportion of dogs with fractures that died with bone malignancy (even at dosage levels lower than those exhibiting an excess average number of fractures per dog), we conclude that fracture would not be an important endpoint at lower levels of plutonium contamination in humans such as would be expected to occur from occupational or environmental exposure.

An analysis of bone tumor occurrences among male and female beagles given monomeric 239Pu or 226Ra was not able to establish a difference in sensitivity to induction of bone malignancy by radium or plutonium exposure. This is in contrast to the situation reported for mice. Female mice are substantially more sensitive to 239Pu irradiation than males, but this difference is obliterated by gonadectomy, females becoming less sensitive and males becoming more sensitive. Although there may be some nonuniformity between human males and females for radiation-induced bone sarcoma occurrence, analysis of data sets containing both men and women exposed to 224Ra, 226Ra, 228Ra, or 226+228Ra appears not to reveal substantial differences in sensitivity by gender, a situation similar to that reported herein for beagles.

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.

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(-1) 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.

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 232U, 233U, 238U, or a combination of 232 (+) 233U. 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 232U, 233U, or 238U.

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.

Retention of administered 226Ra was substantially greater in beagles injected as 3-month-old juveniles than as 1.4-year-old young adults, but the measured 222Rn/226Ra ratio in bone was significantly less in juveniles for about the first 600 days after injection. An equation that describes the total-body biological retention R in beagles injected with 226Ra at 3 months of age at any time t (in days) after injection during the first 6.6 years is R = 0.331e-0.206t + 0.245e-0.00374t + 0.424e-0.000114t. The rate constant of the final term in the equation for juveniles is similar to that for young adults, suggesting that this component reflects the net turnover rate in the slowly remodeling component of adult bone. Compared to young adult beagles, animals injected as juveniles had a greater fraction of their retained 226Ra in parts of the skeleton containing much cortical bone, such as paws, and a smaller fraction in those parts containing much trabecular bone.

Retention of 226Ra was substantially lower in mature beagles injected at 5 years of age compared to corresponding values for young adult beagles injected at 17 months of age. As with young adults, the percentage retention in mature dogs given about 10 microCi/kg exceeded that in mature dogs given 4 microCi/kg or less. Percentage retention, R, at t days after the injection of 10 microCi/kg in mature beagles could be represented by the equation, R = 64.1e-0.233t + 13.0e-0.0048lt + 22.9e-0.000329t, and for mature beagles given 4 microCi/kg or less, R = 38.8e-0.40t + 30.6e-0.0424t + 11.9e-0.00567t + 18.7e-0.000352t. Measured 222Rn/226Ra ratios in bone were similar in mature and young adults. Roughly 66% of the injected radium was excreted by mature dogs during the first 3 weeks, about two-thirds of the total excretion appearing in the feces. Distribution of 226Ra within the skeleton was similar in mature and young adult beagles.

The age at exposure significantly affects the retention and distribution of 226Ra and 239Pu, both of which deposit in the skeleton although in somewhat different patterns. Beagles aged 2 days (neonates), 90 days (juveniles), 18 months (young adults), or 5 yrs (mature) received a single subacute injection of one of these nuclides and were sacrificed serially during a 2-yr interval. Nuclide concentrations in plasma, the skeleton, individual bones and bone sections were determined and retention equations were calculated. The microanatomical skeletal nuclide distribution was studied after fission track or conventional autoradiography. Elimination of 239Pu and its translocation from bone surfaces to the bone volume caused by bone growth and turnover processes were measured. Average radiation doses and dose rates as a function of age at exposure were determined. Initial uptake and retention, skeletal nuclide concentration, proliferative activity of local cell populations and residence time of the nuclide on skeletal surfaces were affected significantly by age at exposure. The effect of these parameters on tumor induction is discussed. This study has provided early retention and distribution data which together with data from a chronic toxicity study will be used to estimate the risk of Pu exposure relative to that of Ra to humans of all ages.