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Childhood severe obesity is a serious, urgent and complex global health problem with long-term co-morbidities. Obstructive sleep-disordered breathing is more common in obese children and adolescents. Increased body mass index is associated with an increase in apnea-hypopnea index. Obstructive sleep apnea leads to a decrease in rapid eye movement sleep, and obese children have been noted to have a decrease in rapid eye movement sleep, leading to weight gain. Short sleep duration and poor sleep quality are associated with childhood obesity and cardiometabolic risks. Public health strategies for obesity prevention should focus more on sleep. Targeting childhood obesity is important in the prevention and management of obstructive sleep-disordered breathing., (© 2020 European Sleep Research Society.)

Asthma is a complex condition that affects 14% of the world's children and the approach to management includes both pharmacologic as well as non-pharmacologic strategies including attention to complex socioeconomic status phenomena. After an historical consideration of asthma, allergic and immunologic aspects of asthma in children and adolescents are presented. Concepts of socioeconomic aspects of asthma are considered along with environmental features and complications of asthma disparities. Also reviewed are links of asthma with mental health disorders, sleep disturbances and other comorbidities. A stepwise approach to asthma management is discussed that includes pharmacologic and non-pharmacologic strategies in the pediatric population. The role of immunotherapy and use of various immunomodulators are considered as well., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

A biokinetic model of the systemic distribution of americium in the beagle dog is presented. The model is based on a previous biokinetic model of plutonium. The data sets used for the development of the model were the measurements of excreted activity (urine and feces) and organ burdens (skeleton, liver, and other soft tissues) for different levels of initial injected activity. In developing the model, the compartmental structure of the skeleton of the plutonium model was adopted, and only the numerical values of parameters were adapted. The model well describes the fractions of americium in the skeleton, liver, and soft tissues and the total fraction excreted in urine and feces. The tuning of the liver clearance parameter provides a realistic description of the change in the partitioning between liver and skeleton for different injection levels. The most significant features of the biokinetics and dosimetry of americium and plutonium in beagles are compared. The total fractions of the clearance to the skeleton and the liver are roughly equal to the value for plutonium, but the partitioning of americium between these organs is reversed with respect to the partitioning of plutonium. 241Am doses to liver and skeleton are similar to 239Pu doses, owing to some counteracting factors. For the highest injection level, the liver mass is dependent on the time post injection. For the skeletal tissues, the dose to the cortical endosteum by far exceeds the dose to the trabecular endosteum and the red marrow. The model provides the basis for statistical survival analyses and risk estimates.

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 241Am and 239Pu 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 241Am was measured before and during the treatment period and organ contents of 241Am and 239Pu were measured at the end of the study. Significant reductions in 241Am occurred within the first week, with Zn-DTPA being the most effective. By 3 weeks, the most lipophilic chelator, C22TT was as effective as Zn-DTPA. After 30 d, reductions in organ content of 239Pu and 241Am directly correlated with increasing lipophilicity of the TT chelators. Oral C22TT was as effective as injected Zn-DTPA in liver and bone, the major organs of actinide deposition. The removal of 239Pu from the liver and reduction of redeposition of 239Pu in newly formed bone by C22TT 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.

Background: A possible genetic link for malignant mammary tumor (MMT) was investigated., Materials and Methods: Records of an internally-irradiated beagle colony followed from the early 1950's until about 1995 were searched and analyzed by standard statistical procedures., Results: Only a single ancestor yielded a "p" value (Fisher's Exact Test) for an overrepresentation among descendants with MMT at < 0.025 (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., Conclusion: 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 severity of effect as a function of skeletal radiation dose for induced skeletal malignancy was investigated among a relatively large group of beagle dogs singly injected as young adults with soluble radionuclide. Bone-seeking radionuclides considered were 239Pu, 226Ra, 228Ra, 224Ra, 228Th, and 90Sr. Variables included skeletal radiation dose, tumor growth rate, maximum tumor volume, sex of the animals, growth period of the tumor, degree of calcification of the tumor, skeletal location of the tumor, year of death, and occurrence of metastases. Except for a significant relationship between tumor volume and metastatic process and for growth rate and tumor volume, no significant dependence of any two of these factors could be established. It is concluded from available data on skeletal malignancies among beagles exposed to bone-seeking radionuclides that the severity of the disease is not dependent upon skeletal radiation dose.

No significant differences in lifespan could be established between control dogs and dogs given 241Am, 228Th, 90Sr, 228Ra, 226Ra or monomeric 239Pu at low dosage levels that induced less than 10% skeletal malignancies (low dose animals) in the Utah beagle colony when all dogs surviving at least 1 y were included in the analysis and dogs given individual radionuclides were considered separately or together. Censoring or exclusion of dogs from these groups that were diagnosed with skeletal malignancies or that died in a gran mal epileptic seizure made no important difference to these results. Therefore, an enhanced lifespan of low dose dogs as compared with controls could not be established. It is concluded that low doses from internal (mainly skeletal) deposits of these radionuclides probably do not benefit the survival of individuals so exposed.

The survival of 132 young adult control beagles and 117 beagles receiving graded injections of 226Ra ranging from 0.27 kBq kg-1 to 384.2 kBq kg-1 body mass was analyzed. The hazards of natural deaths, all deaths in injection groups, and deaths by bone tumors were assumed to follow a Weibull distribution with a common shape factor of 6.3. Only the scale factors of the Weibull distributions depend on the injection level. There were no significant sex differences. The relative risk with respect to controls for all causes of death increases up to 6,925 for 384.2 kBq kg-1. The dependence of the scale factors for all deaths and death by bone tumors on injected activity was fitted to an empirical regression model, which also contains a term representing radiation-caused deaths other than bone tumors. The risk of bone tumors increases nearly as the square of the injected activity, whereas the risk of the other radiation caused deaths increases approximately in proportion to the injected activity. By means of the regression model, it is possible to predict median survival times for all deaths, bone tumor and non-bone tumor deaths for an arbitrary intake level. Also, simple expressions for the fraction of animals with bone tumors and other radiation-caused deaths can be derived. The empirical model of bone tumor induction, which was based on results from a single injection design, can be generalized to an arbitrary systemic intake schema. This is achieved by using the average dose and dose rate to the skeleton as indices of detriment. Applying the generalized model, it was confirmed that no significant differences in survival can be expected for two groups of beagles receiving multiple injections, if compared to the corresponding single injection groups of about the same total activity. The general model also predicts that even extensive protraction of the intake would increase the survival times only to a very limited extent.

Neither Fisher's Exact Test nor linear regression analysis (dose-response relationship) using average skeletal dose from 239Pu as a surrogate for marrow dose could establish a statistically significant association between malignant hematopoietic disease (MHD including leukemia and aleukemia) and exposure to 239Pu among dogs in the Utah beagle colony. In addition, when dog-years at risk was the parameter used to estimate the rate of expected malignant hematopoietic tumors in dogs exposed to 239Pu, the estimate was within the range of the 95% confidence limits of the control dogs for six cases (and also within the 95% confidence limits for five cases when the single case of lymphoma was omitted). It was concluded that if there was an effect of 239Pu exposure on the occurrence of MHD in this beagle experiment, it was not very meaningful. These data could not establish a significant susceptibility to neoplasia of either myeloid or lymphoid tissue of 239Pu exposure.

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.

Data in the archives of the beagle project at the University of Utah were used to determine whether there might have been an association between the occurrence of soft tissue cancer and bone tumor (skeletal malignancy) among the dogs injected with bone-seeking radionuclides. In addition to comparing the numbers of animals with and without bone tumors and with and without soft tissue cancers, data on bone sarcomas and soft tissue sarcomas were compared. Longevity (postinjection survival) of the dogs was investigated. It appeared that survival (time between radionuclide injection and death) was important in the eventual expression of malignancies. There could not be established a possible susceptibility to skeletal malignancy associated with the occurrence of soft tissue cancer (or soft tissue sarcoma). We concluded that, although the literature reports an increased susceptibility for subsequent malignancies for individuals with naturally-occurring or radiation-induced cancer, the data derived from this study do not confirm the concept that the appearance of soft tissue cancer is strongly associated with an increased risk of developing a radionuclide-induced skeletal malignancy.

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.

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.

The intraocular radiotoxicity of intravenously injected 226Ra and 228Ra was studied in beagle dogs. Approximately 0.071% of injected radium was retained in each eye of beagles following intravenous administration. The retention was principally in the tapetum and the intraocular pigmented structures where significant pigmentary lesions were produced. These included melanotic plaques on the iris, melanosis of the ciliary body, varying degrees of tapetal degeneration, and intraocular melanomas. The tumors occurred principally in the ciliary body and to a much lesser extent in the iris. They appeared to arise from the pigment epithelium layer of the ciliary body. Thus, unlike melanomas arising in other sites, they are apparently not of neural crest origin. In addition to bone cancer, they represent another radium-induced neoplasm in beagles. Radium-induced intraocular melanomas have not been reported in people.

Investigation of a possible increase in sensitivity to occurrence of radionuclide-induced skeletal malignancy with increasing body size was analyzed among 358 beagles injected as young adults with either 226Ra or monomeric 239Pu and maintained for their lifespans. Corresponding analyses were performed for about 240 other beagles injected as young adults with 90Sr, 228Ra, or 228Th. Body masses at the time of injection ranged between about 5.6 and 16 kg. Logistic regression analysis using body mass and cumulative skeletal radiation dose as the independent variables indicated that there could not be established a dependency of tumor occurrence upon body mass, although skeletal dose was found to be significantly correlated with occurrence of bone cancer. Regression analysis indicated that for any dosage group there could not be established a correlation between body mass and skeletal dose. Each dosage group having similar injected kBq kg(-1) for each nuclide was divided into 2 subgroups of equal size, one containing the less massive dogs and the other containing the more massive dogs. These subgroups within a roughly uniform value of skeletal dose-rate were compared by Fisher's Exact Test, and the less massive subgroups were combined within each nuclide for an additional, separate analysis against the combined more massive subgroups using the same method. In only one instance (the dosage group given 3607 kBq 90Sr kg(-1)) was there indicated a substantially greater tumor occurrence among dogs in the more massive subgroup (p = 0.061). However, for the group given 0.382 kBq 239Pu kg(-1) there was indicated a significant difference between subgroups, but the effect was exactly opposite to that found for the highest level 90Sr dogs in that the less massive subgroup had a higher relative tumor occurrence than the most massive (p = 0.042). For all groups with a p-value < 0.10, a possible correlation was investigated between survival and body mass at injection (since bone tumor occurrence might be a function of longevity), but a significant relationship could not be determined. No significant differences could be established between the combined more massive and the combined less massive subgroups for any radionuclide. We conclude that, for the conditions in our experiment, relative size within a species does not contribute importantly to the sensitivity (lifetime occurrence) for induction of skeletal malignancy.

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.

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.

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.

A comparison was made of the response to induction of skeletal malignancy from exposure of beagles to monomeric 239Pu or to 226Ra as juveniles (3 mo of age), young adults (1.5 y of age), or mature adults (5 y of age). This indicated that of these age groups, animals injected as young adults are most sensitive per Gy of average skeletal dose evaluated at 1 y before death. Dogs exposed either as juveniles or as mature adults appeared to be less sensitive. Relative radiosensitivities (RRS) of juvenile and mature beagles ranged between about 0.3 and 0.7 that of dogs injected as young adults. Mean values of RRS for both radionuclides were about 0.5, but RRS values derived from dogs given monomeric 239Pu appeared to be most reliable and were 0.27+/-0.09 for dogs injected as juveniles and 0.41+/-0.13 for animals exposed as mature adults.

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

Statistical analysis of bone tumor growth rates as a function of age at initiation of radiation-induced skeletal malignancies in our animal colony indicated that the p value for an association between these parameters was <0.05, suggesting a correlation in beagle dogs. The youngest animals appeared to exhibit the most slowly growing tumors, and the trend was toward more rapidly growing tumors with increasing age. Less effective immune systems in older animals were invoked as a possible explanation of this relationship.

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.

A comparison of the risk coefficients for 239Pu- or 226Ra-induced bone cancer in two canine breeds, one with a relatively low (beagle) and the other with a very high (St. Bernard) natural incidence, indicated only slightly higher risk in the giant breed. The differences in risk for skeletal malignancy in 239Pu and 226Ra dogs were nonsignificant (p > 0.05). Likewise, the values of the 239Pu:226Ra "toxicity ratios" for these respective breeds, using bone cancer as the endpoint, were not significantly different at the 0.05 level. The anatomical distribution of the radiation-induced bone tumors tended to be a function of both the bone mass and the skeletal distribution of the radionuclide, not the site of predilection for naturally occurring bone neoplasia. Although the etiology of the higher natural incidence of bone cancer in the St. Bernard was not determined, several possible factors, including a higher osteoblastic activity level in the St. Bernards, are presented. These data suggest that making extrapolations of radiation-induced bone cancer risk from animals to humans is valid.

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.

Investigations of radionuclide metabolism and effects in various mammalian species revealed important similarities between animals and humans and between some animal species. These include skeletal deposition of radium and radiostrontium in bone volume; deposition on bone surfaces of plutonium and other actinides; liver deposition of actinides; induction of skeletal or liver malignancies by these radionuclides; induction of tooth and jaw abnormalities; mammary cancer induction by radium in humans and in the beagle; depression of circulating cells in blood; and induction of bone fractures. There are also inter-species differences that may not have been noted if multiple species (including humans) had not been studied. Some of these are more rapid excretion of radium in humans compared with most other mammals; induction by radium of eye melanomas in animals but not humans; rapid loss of deposited plutonium from liver in many species of mice and rats but not in humans and dog; substantial sex-related differences in skeletal plutonium retention and bone sarcoma induction in mice but not in humans or dog; and induction of head sinus carcinomas by 226Ra in humans but not the beagle. Leukemia and other related neoplasms were not induced in radionuclide-injected lifespan dogs in excess of the occurrence in control animals. Much of our current understanding of skeletal biology and radionuclide behavior in mammals was derived from this and related projects. The primary goal of the Utah experiment of estimating toxicities of bone-seeking radionuclides relative to radium has been accomplished. For 226Ra = 1.0, comparative toxicities (ratios) of a single injection for bone tumor induction in beagles were about 16 +/- 5 for monomeric 239Pu (32 +/- 10 for chronic exposure), 6 +/- 0.8 for 241Am, 8.5 +/- 2.3 for 228Th, 6 +/- 3 for 249Cf, 4 +/- 2 for 252Cf, 6 +/- 2 for 224Ra (16 +/- 5 for 50 weekly injections), 2 +/- 0.5 for 228Ra, and between 0.01 +/- 0.01 and 1.0 +/- 0.5 for 90Sr, depending on the dose-rate, with the lowest dose-rates approaching a ratio of zero. Corresponding ratios in mice for 226Ra = 1.0 were 16 +/- 4 for monomeric 239Pu, 5.4 +/- 2.0 for 224Ra (16 for 50 weekly injections), 4.9 +/- 1.4 for 241Am, 5.0 +/- 1.4 for 249Cf, 2.6 +/- 0.8 for 252Cf, 4.4 +/- 1.8 for 243,244Cm and about 1.0 for 90Sr at high doses, decreasing to near zero for low doses.

A life-span study was conducted in 128 beagle dogs to determine the biological effects of intravenously injected 224Ra chloride. The 224Ra chloride was prepared by the same method used for intravenous injections in humans who were treated for ankylosing spondylitis and tuberculosis. Thus the results obtained from dogs can be compared directly to the population of treated humans, both for the elucidation of the effect of exposure rate and for comparison with other radionuclides for which data for humans are unavailable. Using equal numbers of males and females, the dogs were injected with one of four levels of 224Ra resulting in initial body burdens of approximately 13, 40, 120 or 350 kBq of 224Ra kg-1 body mass. A control group of dogs was injected with diluent only. All dogs were divided further into three groups for which the amount of injected 224Ra (half-life of 3.62 days) or diluent was given in a single injection or divided equally into 10 or 50 weekly injections. As a result of these three injection schedules, the accumulation of dose from the injected 224Ra was distributed over approximately 1, 3 or 12 months. Each injection schedule included four different injection levels resulting in average absorbed alpha-particle doses to bone of 0.1, 0.3, 1 and 3 Gy, respectively. The primary early effect observed was a hematological dyscrasia in the dogs receiving either of the two highest injection levels. The effect was most severe in the dogs receiving a single injection of 224Ra and resulted in the death of three dogs injected at the highest level. The late-occurring biological effects were tumors. Bone tumors were the most common followed by tumors in the nasal mucosa. The occurrence of bone tumors was highest in the dogs given the highest dose in 50 injections. The age-specific incidence rate for mammary tumors was increased in all three injection groups. The results of this study revealed two important exposure-rate effects. Hematological dyscrasia was amplified by delivery of relatively high doses at a high exposure rate. In contrast, bone tumors were amplified by delivery of relatively high doses at a lower exposure rate (i.e. dose delivered over 1 year rather than 1-3 months). There was a dose-response relationship for the induction of nasal mucosal tumors and mammary tumors. These findings in dogs are similar to those in humans injected with 224Ra, except for the nasal tumors. The calculated risk of developing a bone tumor was about 40 times higher in dogs than reported for humans.

This study presents the results of analyses performed to generate hypotheses concerning the general patterns of risk factors for occupational sprains and strains, using Ontario workers' compensation data housed in the Workplace Health and Safety Agency (WHSA) data base. Historically, the largest percentage of lost-time injuries in Ontario, Canada, have been sprains and strains. In 1990, there were 171,047 compensated lost-time injuries with a known nature of injury, of which 50.43% were sprains and strains. From cross-tabulations, a number of statistics such as odds ratios (ORs), 95% confidence intervals, P values, attributable risks and number of injuries attributable, were calculated. Results indicate that occupational sprains and strains are related to the time of the day and, in particular, time into the workshift. They occur more frequently than expected (based on the occurrence of non-sprain and non-strain injuries) in the morning hours and in the first 4 hours of the workshift. They are not found to be related to the starting or ending time or the length of the workshift. They occur more frequently than expected during the early part of a week, especially on Mondays, and the early part of a year (January to May). With respect to age, workers 30 to 59 years old have an increased risk of sprains and strains, whereas workers less than 30 years of age, or 60 or more years of age, have a decreased risk. Workers who are not single, and female workers, have a higher risk of sprains and strains than expected. With respect to occupations, nurses and truckers have a higher-than-expected risk. A number of work environments and activities, such as overexertion, bodily reaction from involuntary motions, running and stretching, and slippery surfaces, are associated with a high risk of occurrence of sprains and strains. These results suggest that significant reduction in the number of occupational sprains and strains could be achieved by targeting prevention programs to reduce excess risks encountered in the first 4 hours of the workshift, on Mondays, and during the first 5 months of the year, and by workers 30 to 59 years of age, female workers, and nurses and truck drivers. It is estimated that, with proper interventions to avoid sprains and strains, a large percentage of sprain and strain injuries could be avoided each year: ie 82.49% of injuries due to bodily reaction from involuntary motions, 89.43% of overexertions in lifting objects, 84.64% of running, stretching, and related injuries, and 76.64% of injuries resulting from loss of balance on slippery surfaces. This study uses an internal comparison, ie comparing the risk of sprains and strains to the risk of all other injuries for various risk categories of interest. As a result, an increased OR may mean an increased risk of sprains and strains, or it may mean a decreased risk of all other injuries for a particular risk category. There are also limitations in the use of workers' compensation data base for epidemiologic studies. Therefore, findings in this study are only suggestive for further investigations and should await confirmations before prevention programs are designed.

An incident in which a young women became pregnant soon after being treated with 444 MBq 131 I for Graves disease prompted us to search local records for the occurrence of thyroid abnormalities among people exposed in utero to fallout radioiodine. The data base from the Utah Fallout Study (Kerber et al. 1993) indicated that there had been 480 cohort subjects for whom dose to thyroid from fallout radioiodine had been calculated and who could have received any thyroid dose before birth (2473 subjects had been re-examined in 1985-86 of the 4818 examined in 1965-70). Of these 480 subjects in this category, 403 of them could be located in the 1980's and were examined with abnormalities. Although nodules, thyroiditis, hypothyroidism and goiter were seen among the 375 persons with in utero thyroid doses from fallout radioiodine below 0.42 Gy, no thyroid abnormalities of any occurred in the 4 persons with in utero thyroid doses of 0.5 to 2.6 Gy. In addition, no neoplasia was found in any of the 403 subjects examined about 2 decades after in utero fallout exposure. These limited data do not indicate that the fetal thyroid is more sensitive than the postnatal thyroid by more than about a factor of about 4 when thyroid dose is considered and by not much more than unity when the comparison is based on dose equivalent (x ray vs. radioiodine).

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.

Individual records of soft tissue tumor occurrence (lifetime incidence) among 236 beagles injected with 239Pu 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 239Pu. A significant trend was identified in the proportion of animals having malignant liver tumors with increasing radiation dose from 239Pu. 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 239Pu 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 239Pu incorporation. We conclude that the only soft-tissue neoplasia induced by the intake of 239Pu directly into blood is probably a liver tumor.

Comparison of 120 young adult female beagles given 0.026 to 106 kBq 239Pu kg-1 by intravenous injection and 63 comparable female control beagles showed that there were no significant differences in the risk of mammary tumor appearance between the two groups. This was the case for benign tumors only, for malignant tumors only, and for both malignant and benign tumors considered together. For malignant tumors the observed number was 73 as compared with 69 expected; for benign tumors, there were 131 observed and 126 expected; for all tumors (separate analysis, not just the addition of malignant plus benign), there were 199 observed and 199 expected. Chi-square analysis indicated that the p values for all these comparisons were > 0.05. There were 45 controls (71.4%) with any tumor vs. 67 dogs (55.8%) given Pu (95% C. I. = 46.9% to 86.2%). No significant differences could be established (Kaplan-Meier analysis) between these two groups for survival age at diagnosis of the first mammary tumor, 11.75 +/- 0.30 y for dogs given Pu vs. 11.90 +/- 0.36 y for controls. We reported previously that differences in mammary cancer occurrence had been identified between this same group of control dogs and 57 female beagles given 226Ra as young adults. The present study appears to support the earlier conclusion that something other than alpha irradiation of the skeleton (both 226Ra and 239Pu deposit in bone) seems to affect the appearance of mammary cancers, since internally deposited 226Ra does appear to induce these malignancies, possibly from initial deposition in mammary tissue of the parent radionuclide or the subsequent concentration in sensitive tissue of its radioactive progeny, 22Rn or isotopes of polonium, lead, and bismuth, which are absent in the case of 239Pu.

The occurrence of soft-tissue tumors in beagles given 90Sr (88 dogs), 228Ra (76 dogs), or 228Th (81 dogs) as young adults and followed throughout their lifespans was compared with that of 133 control beagles given no radioactivity. For animals injected with 228Ra, tumors of the eye were more prominent (p < 0.05) than in the controls, and soft-tissue tumors of cavities in the head (excluding the brain, mouth, and eye) were more prominent in dogs given 90Sr than in the controls (p < 0.05). There was some indication that eye tumors in animals given about 0.56 kBq 228Th kg-1 were associated with their radionuclide exposure. For tumors at a few other locations, the relative occurrence was greater (p < 0.05) in the controls. These included malignant tumors of the testis and malignant plus benign tumors of the mammae and vagina in 228Th dogs; both malignant and malignant plus benign tumors of the mouth and testis, and malignant plus benign tumors of the mammae and vagina in 228Ra dogs; and malignant plus benign tumors of the mammae in 90Sr dogs (p > 0.05 by Odds Ratio Chi Square analysis but p < 0.05 by Fisher's Exact Test). Differences in relative occurrence between radioactive dogs and controls of all other tumor types that appeared in any of the animals (notably lymphosarcoma, lymph node tumors, leukemia, mast cell tumors, liver tumors, etc.) were not statistically significant (p > 0.05). Intercurrent mortality, mainly from bone cancer, was higher in the radioactive dogs than in the controls. Mean survival was reduced in the dogs given 90Sr, 228Ra, or 228Th (13.17 +/- 2.64 y in controls, 10.95 +/- 4.06 y in 90Sr dogs, 9.07 +/- 3.61 y in 228Ra dogs, and 9.20 +/- 4.15 y in 228Th dogs). Attenuated lifespans could account, at least in part, for the relative paucity of soft-tissue tumors not induced by radiation among the groups of dogs given radioactivity and occurring near the end of life for control animals.

The risk coefficients for liver tumors as derived from 60 beagles with body burdens of 249Cf or 252Cf were used to determine the relative biological effectiveness of fission fragments relative to alpha particles. For liver malignancies the relative biological effectiveness was calculated to be about 2 +/- 3. The estimate based on the combined benign and malignant liver tumors was about 7, with a proportionately larger standard deviation of about +/- 14. Although the confidence intervals were wide, it is possible that the relative biological effectiveness of fission fragments relative to alpha particles, using liver neoplasia as the endpoint, is greater than 1.0 as compared to a value only slightly above zero when bone cancer was the lesion of interest.

This paper discusses the dosimetry methodology used to estimate bone marrow dose and the results of dosimetry calculations for 6,507 subjects in an epidemiologic case-control study of leukemia among Utah residents. The estimated doses were used to determine if a higher incidence of leukemia among residents of Utah could have been attributed to exposure to radioactive fallout from above-ground nuclear weapons tests conducted at the Nevada Test Site. The objective of the dosimetry methodology was to estimate absorbed dose to active marrow specific to each case and each control subject. Data on the residence of each subject were available from records of the Church of Jesus Christ of Latter-day Saints. Deposition of fallout was determined from databases developed using historical measurements and exposure for each subject from each test was estimated using those data. Exposure was converted to dose by applying an age-dependent dose conversion factor and a factor for shielding. The median dose for all case and control subjects was 3.2 mGy. The maximum estimated mean dose for any case or control was 29 +/- 5.6 mGy (a resident of Washington County, UT). Uncertainties were estimated for each estimated dose. The results of the dosimetry calculations were applied in an epidemiological analysis.

Above ground testing of nuclear weapons at the Nevada Test Site (NTS) during the 1950s created radioactive fallout that was dispersed into the atmosphere and deposited over a large geographical area of the U.S. One area believed to have received a considerable amount of exposure to radioiodines (131I and 133I) in the fallout was southwest Utah and southeast Nevada. This paper describes the estimates of doses to the thyroid for a cohort of 3,545 subjects who were children during the atmospheric testing period. This group of children was examined for thyroid disease during 1965-1970 and again in 1985-1986. The cohort was made up of children who lived in three counties in 1965: Washington County, Utah; Lincoln County, Nevada; and Graham County, Arizona (originally thought to be an unexposed group). Pathway analysis was used in the dosimetry, considering exposures through the ingestion of milk and vegetables, inhalation of iodine during the passage of the fallout cloud, and external exposure. Specific data were obtained on diet (including sources and levels of milk and vegetables consumed, residence history, and lifestyle) by interviewing the parents or nearest living relative of subjects. The final dosimetry file for each member of the cohort contained specific doses to the thyroid glands and uncertainties (reported as geometric standard deviations, GSD) related to each dose estimate. The mean absorbed dose to the thyroid for subjects living in Washington County, Utah, was 170 mGy; for Lincoln County, Nevada, 50 mGy; and for those living in Graham County, Arizona, 13 mGy. The maximum dose to any subject was 4,610 mGy. There were 10 subjects who had doses greater than 1 Gy. The majority of uncertainty values calculated in this study were GSD values between 2.0 and 4.0. The results of the dosimetry were combined with the results of clinical examinations of the cohort to determine if a causal relationship exists between dose to thyroid from NTS generated radioactive iodines and the incidence of thyroid disease.

The occurrence of soft tissue tumors has been studied in 117 beagles assigned to 8 dosage groups of between 2 and 26 animals each and injected with 0.07 to 104 kBq 241Am kg-1 as the citrate. In addition, 133 control beagles given no radioactivity were used as a comparison group. All 250 dogs were maintained under identical conditions and were observed for their entire lifespans. An important competing risk for the appearance of soft tissue tumors appeared to be the occurrence of skeletal malignancy, and at the highest injected activity (104 kBq kg-1), kidney and liver failure brought about the death of both of the two dogs in this group. Thyroid and liver were the only soft tissues that exhibited greater concentrations of 241Am than the skeleton. Liver tumors were associated with 241Am exposure (p < 0.001), but the thyroid tumor rate was not increased significantly in the irradiated animals (p > 0.10) as compared with the occurrence in controls. There was a greater relative occurrence of all vaginal tumors in control animals than in dogs given 241Am, a situation also found for all tumors of the pancreas, skin, testis, and mammary glands and for malignant ovarian tumors. All of these differences were statistically significant. The survival of animals given 0.07 to 0.59 kBq 241Am kg-1 could not be established (p > 0.10) as significantly different from controls, but the survival of all groups given 1.8 to 104 kBq kg-1 was decreased (p < 0.05). There was no indication in our studies of a positive association between relative exposure to 241Am and the occurrence of mammary tumors, mast cell sarcomas originating outside the liver, lymphosarcoma or tumors of marrow, including leukemia.

The toxicity ratio (relative effectiveness per gray of average skeletal dose) has been estimated for bone cancer induction in beagles injected as young adults for a number of bone-seeking internal emitters. These experiments yielded calculated toxicity ratios (+/- SD) relative to 226Ra = 1.0 of 239Pu = 16 +/- 5 (single exposure to monomeric Pu) and 32 +/- 10 (continuous exposure from an extraskeletal deposit in the body), 224Ra = 16 +/- 5 (chronic exposure) and approximately 6 +/- 2 (single exposure), 228Th = 8.5 +/- 2.3, 241Am = 6 +/- 0.8, 228Ra = 2.0 +/- 0.5, 249Cf = 6 +/- 3, 252Cf = 4 +/- 2, 90Sr = 1.0 +/- 0.5 (for high doses) and 0.05 +/- 0.03 (for low doses) and 0.01 +/- 0.01 (for extremely low doses). Because no skeletal malignancies were observed among beagles given only 253Es, the toxicity ratio is undefined.