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Biomedical subjects

W S Jee

Publications and source records attributed to W S Jee.

At least 37 records · Page 2Linked to original sources
PubMed1999

Droloxifene does not blunt bone anabolic effects of prostaglandin E2, but maintains prostaglandin E2-restored bone in aged, ovariectomized rats.

Droloxifene (DRO) is a selective estrogen receptor modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2 (PGE2)-restored bone after discontinuation of PGE2 in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2 plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2 (3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2 plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2 or PGE2 plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (-15%, -19%, and -19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2 alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2 alone or PGE2 plus DRO. Upon cessation of PGE2 treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (-12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2 plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2 alone or both PGE2 and DRO. However, treatment with DRO following 2 months of PGE2 plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2 in PGE2 alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibited bone turnover and prevented bone loss induced by withdrawal of PGE2. Trabecular bone mass was maintained in the PGE2 plus DRO followed by vehicle group and further increased in the PGE2 plus DRO followed by DRO groups. We found that: (a) DRO is efficacious in maintaining PGE2-restored bone after discontinuation of PGE2; (b) DRO did not blunt the anabolic effects of PGE2; (c) bone loss occurred after cessation of treatment in the PGE2-alone group, whereas it was maintained after cessation of treatment in PGE2 plus DRO group; and (d) an additional anabolic effect was found in ovx rats treated with PGE2 plus DRO followed by DRO.

Absorptiometry, Photon↗
PubMed1999

Interferon-alpha, unlike interferon-gamma, does not cause bone loss in the rat.

Interferons (IFN) are a group of related glycoproteins. IFN-gamma, in vitro, has been shown to inhibit resorption; however, an in vivo experiment showed that it had the opposite effect, resulting in bone loss that was comparable to that caused by cyclosporine A. IFN-alpha has numerous clinical applications but is used most extensively in the treatment of chronic hepatitis B and chronic hepatitis C. Research into the effects of IFN-alpha on bone mineral metabolism has been very sparse, and the majority of studies reflect in vitro models. Like IFN-gamma, there exists discordance between in vitro and in vivo studies on IFN-alpha. Both in vivo and in vitro studies demonstrate that IFN-alpha decreases bone resorption, whereas osteoblasts may or may not be affected in vivo. This study was designed to provide information on the in vivo effects of IFN-alpha in the rat model, because we feel that, given its widespread clinical use, this is an extremely important issue. Rats were given low dose IFN-alpha (1.6 x 10(6) IU/m2), intermediate dose IFN-alpha (5.35 x 10(6) IU/m2), and high dose IFN-alpha (30 x 10(6) IU/m2) three times per week for 28 days. Serum osteocalcin (bone gla protein, or BGP) and parathyroid hormone (PTH) were measured serially and, after double labeling, the bones were examined histomorphometrically. IFN-alpha did not alter any of the histomorphometric parameters measured and did not affect PTH. However, it produced a disparate BGP response. Low dose IFN-alpha resulted in a statistically significant increase in serum BGP on days 14 and 28, whereas intermediate and high doses of IFN-alpha did not. Overall, these results provide no evidence of a deleterious effect of IFN-alpha on bone metabolism and confirm the limited clinical study.

Animals↗
PubMed1999

Anabolic effect of prostaglandin E2 on cortical bone of aged male rats comes mainly from modeling-dependent bone gain.

In this study, prostaglandin E2 (3 mg/kg per day) was administered to 20-month-old male Wistar rats for 10 and 30 days. Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections. Thirty days of prostaglandin E2 (PGE2) administration increased bone formation rate/total bone surface from undetectable levels to 0.6 microm/day at the periosteal surface and from 0.5 to 2.1 microm/day at the endocortical surface. Endocortical osteoid surface area increased from 2% to 67% at day 10 and decreased to 6% at day 30; woven and lamellar bone formation started at day 0, but was most obvious at day 30, resulting in a 12% increase of total bone mass. The red to yellow marrow ratio was 0.2 in pretreatment controls, and increased to 1.6 by day 10 and 2.4 by day 30 with PGE2 administration. Intracortical cavity number and area increased after 10 days of PGE2 treatment, but with forming osteon number and area far exceeding those of resorption cavities at day 30. Endocortical modeling surface/endocortical surface was only 1.5%, and remodeling was 11.1% in pretreatment controls. PGE2 treatment increased modeling to 24.5% in the 10 day group and 93.7% in the 30 day group, whereas remodeling remained unchanged at 10 days, and decreased to 6.2% at 30 days. Osteoprogenitor cells and osteoblasts could not be detected in pretreatment controls, but increased by day 10, and returned almost to control levels by 30 days. Our data indicate that PGE2 induced periosteal and endocortical bone formation mainly by modeling-dependent bone gain, accompanied by increases in intracortical remodeling and red bone marrow, and a transient increase in the osteoprogenitor cells adjacent to the endocortical surface. These findings suggest that 20-month-old male Wistar rats were very responsive to the anabolic action of PGE2 in the tibial shaft, a site consisting mainly of cortical bone and yellow marrow.

Aging↗
PubMed1999

Relative radiosensitivity of bone tumor induction among beagles as a function of age at injection of 239Pu or 226Ra.

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.

Age Factors↗
PubMed1999

Parathyroid hormone and mechanical usage have a synergistic effect in rat tibial diaphyseal cortical bone.

Previous reports showed that bone mass and architecture only partially recovered by remobilization (RM) after immobilization (IM)-induced osteopenia, and that parathyroid hormone (PTH) had an anabolic effect on the skeleton. The aim of this study was to determine whether low doses of PTH could restore IM-induced cortical bone loss and whether a combination of PTH plus loading (RM) treatment would be more effective than the PTH in unloaded (IM) limbs. One hundred and sixty 6-month-old rats were divided into aging and IM groups. The right hindlimb of the rat was immobilized by elastic bandage for 18 weeks, and then groups of rats were either kept IM or RM and treated with 30 microgram or 80 microgram of hPTH(1-38)/kg/day for 2, 10, and 20 weeks. Fluorescent-labeled, undecalcified cross-sections of right tibial shafts were studied. We found that RM for 20 weeks after 18 weeks of IM only partially recovered IM-induced muscle weight loss and PTH had no effect on muscle weight in either IM or RM limbs; that RM for 20 weeks after 18 weeks of IM partially restored some minimal cortical width by stimulating periosteal and endocortical bone formation and decreasing endocortical resorption; that PTH treatment of IM limbs completely restored IM-induced cortical bone loss and added extra bone by stimulating bone formation indices on all bone surfaces and depressing bone resorption on endocortical surface; that PTH treatment of RM limbs produced similar anabolic effects as in IM limbs with 30 microgram/kg/day dose but the 80 microgram/kg/day dose-treated limbs had a higher periosteal bone formation rate, which created a larger cross-sectional area, more cortical bone area, and a thicker cortex than the same dose treated IM limbs; and that PTH 80 microgram/kg/day treatment produced more anabolic effect than the 30 microgram/kg/day in both IM and RM limbs. We concluded that reloading the hindlimb by RM after long-term IM could not recover the cortical bone mass. PTH at employed doses was able to completely restore IM-induced cortical bone loss, and this effect was independent of mechanical stimulation. However, when PTH was combined with mechanical loading (RM), a synergistic anabolic effect on periosteal bone formation occurred which increased the cross sectional area that can increase bone strength.

Aging↗
PubMed1999

Animal models of immobilization osteopenia.

There are numerous animal and human models to study the effects upon the skeleton of eliminating mechanical usage by immobilization (IM). Care must be taken in employing the various models. They all have the same pattern of bone loss, but they respond slightly differently in the location and the amount of bone loss, depending upon the degree of unloading. Experimental immobilization studies involving local disuse-induced bone loss models can lose up a baseline level of 60% of their trabecular bone mass. This baseline level suggests a physiological threshold where basal hormonal and cellular activity determined by genetics is reached in the absence of mechanical stimuli. During the transient, immediate, or acute phase of immobilization, remodeling-dependent bone loss occurs in bone adjacent to marrow and from an increase in bone resorption and a decrease in formation. At steady state, or chronic phase, bone mass has plateaued at baseline with cellular activities back to normal levels. Further lowering of immobilization-induced bone loss from immobilization baseline levels can occur with nonmechanical factors like estrogen deficiency. A reasonable working model of immobilization-induced bone loss uses Frost's mechanostat theory and skeletal adaptation to mechanical usage highway to show the IM-induced bone loss, the mechanical usage feedback from the overloaded osteopenic bone and the modification of the IM-induced baseline response with non-mechanical agents. Lastly, an investigator should employ the combination of IM plus OVX model for evaluating agents in the prevention and healing of osteoporosis because it combines the skeletal response of estrogen deficiency in postmenopausal osteoporosis and age-related bone loss due to decreased physical activity.

Adaptation, Physiological↗
PubMed1998

Mycophenolate mofetil: a promising new immunosuppressant that does not cause bone loss in the rat.

BACKGROUND: Posttransplantation bone disease is a well-described phenomenon; among its etiology is immunosuppressant-induced bone disease. Mycophenolate mofetil (MMF) has emerged as a promising new immunosuppressant. Our study was designed to investigate the effect of MMF on in vivo bone mineral metabolism. METHODS: Twenty-four 6-month-old male Sprague-Dawley rats were randomized into two groups to receive either MMF vehicle daily for 28 days or 30 mg/kg MMF daily for 28 days. The serum was assayed for osteocalcin and 1,25-dihydroxy vitamin D3. Subsequent to double-labeling, the right tibiae were removed on day 28 for histomorphometry. RESULTS: MMF suppressed bone gla protein (osteocalcin) levels on days 14 and 28 (P < 0.05). Except for percentage osteoid perimeter, there was no difference in bone histomorphometry between the two groups. CONCLUSION: In this relatively short-term study, MMF did not cause osteopenia in the rat model, but the suppressed bone gla protein merits further study.

Animals↗
PubMed1998

Estrogen and bone-muscle strength and mass relationships.

The largest voluntary loads on bones come from muscles. To adapt bone strength and mass to them, special strain threshold ranges determine where modeling adds and strengthens bone, and where remodeling conserves or removes it, just as different thermostat settings control the heating and cooling systems in a house. If estrogen lowers the remodeling threshold, two things should occur. First, at puberty in girls, bone mass should begin to increase more than in boys with similar muscle strengths, owing to reduced remodeling-dependent bone losses, while gains from longitudinal bone growth and bone modeling continue normally. That increase in bone mass in girls should plateau when their muscle strength stops increasing, since their stronger bones could then reduce bone strains enough to turn modeling off, but could let remodeling keep conserving existing bone. Second, decreased estrogen secretion [or a related factor(s)], as during menopause, should raise the remodeling threshold and make remodeling begin removing that extra bone. That removal should also tend to plateau after the remaining and weaker bone lets bone strains rise to the higher threshold. Postmenopausal bone loss shows the second effects. Previously unremarked relationships in the data of a 1995 Argentine study showed the first effects. This supports the idea that estrogen can affect human bone strength and mass by lowering the remodeling threshold, and loss of estrogen would raise the threshold and help cause postmenopausal bone loss even if other factors help to do it. The Argentine study also suggested ways to study those things and the roles of muscle strength and other factors in controlling bone strength and mass in children and adult humans. Those factors included, in part, hormones, vitamins, calcium, diet, sex, race, age, medications, cytokines, genetic errors, gene expression patterns, and disease.

Absorptiometry, Photon↗
PubMed1998

Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models.

We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 microg/kg x day, unlike 17alpha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (p.o.) with CP-336,156 at 10 or 100 microg/kg x day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 microg/kg x day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.

Adipose Tissue↗
PubMed1997

Aging- and ovariectomy-related skeletal changes in spontaneously hypertensive rats.

BACKGROUND: The skeletal impact of estrogen deficiency on subjects with hypertension has not been studied previously. In this study, we examined the skeletal characteristics of female spontaneously hypertensive rats (SHR) and their normotensive genetic control Wistar-Kyoto rat (WKY). We aimed to reveal: 1) the skeletal characters of female SHR, and 2) the response of SHR to ovariectomy (ovx) when compared to WKY and other strains. METHODS: Undecalcified double-fluorescent labeled cancellous (proximal tibial metaphysis, PTM) and cortical (tibial shaft, TX) bones from 23-weeks-old, and from rats 2 and 8 weeks post-ovx were studied. RESULTS: The SHR showed lower body weight, higher heart rate, and higher blood pressure than the WKY. Female SHR possessed more percent cancellous bone, less net cortical bone, smaller tissue area, and thinner cortex than WKY. Furthermore, SHR exhibited an age-related cancellous (-18%) and cortical (-7%) bone loss associated with a decrease in the longitudinal growth rate and bone balance and a decrease in periosteal bone formation in cortical bone. In contrast, the WKY maintained most of these parameters unchanged at their 23-week-old levels. Ovariectomy induced earlier and greater cancellous bone loss in the SHR than in the WKY, with greater increases in bone turnover rate, eroded surface, activation frequency, and a decrease in the ratio of labeled to eroded perimeter in PTM at 2 weeks postsurgery. However, the two groups exhibited no differences in bone loss at 8 weeks after ovx in PTM and TX. CONCLUSIONS: Spontaneously hypertensive rats were highly sensitive to estrogen deficiency. This might have clinical relevance to those postmenopausal women who suffer from hypertension, in that they may be more susceptible to osteopenia. If so, preventive measures should be initiated sooner than otherwise.

Aging↗
PubMed1997

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment.

To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 microg/kg) or pamidronate (3.7-370 microg/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure.

Animals↗
PubMed1997

Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model.

The purpose of this study was to compare the effects of droloxifene (DRO), tamoxifen (TAM), and 17 alpha-ethynyl estradiol (EE) on bone mineral density, bone histomorphometry, total serum cholesterol, and uterine histology in the ovariectomized (ovx) rat model. Sprague-Dawley female rats at five months of age were sham-operated and treated orally with vehicle (n = 8), or ovx (n = 56) and treated (p.o.) with either vehicle, DRO at 0.1 or 1.0 mg/kg daily, TAM at 0.1 or 1 mg/kg daily, or EE at 3 or 30 micrograms/kg daily for 4 weeks. The uterine wet weight and uterine histologic parameters (cross-sectional tissue area, stromal thickness, and luminal epithelial thickness) were determined. Femoral and lumbar vertebral bone mineral density was determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometry was performed on double-labeled, undecalcified longitudinal sections from proximal tibial metaphyses. Furthermore, the changes in total serum cholesterol and body weight gain were also determined. Compared to sham controls, ovx for four weeks significantly decreased uterine weight (-72%), uterine cross-sectional tissue area (-74%), stromal thickness (-52%), and luminal epithelial thickness (-53%). ovx rats treated with EE at 30 micrograms/kg/day maintained these parameters at the levels of sham controls. Uterine weight and uterine cross-sectional tissue area in 3 micrograms/kg/day of EE treated ovx rats were higher than that of vehicle-treated ovx rats. In ovx rats treated with TAM at both 0.1 and 1 mg/kg/day, these parameters were significantly less than sham controls but significantly higher than ovx controls. DRO at 0.1 mg/kg/day had no effects on all above parameters. Uterine weight and cross-sectional tissue area in 1 mg/kg/day of DRO treated ovx rats was slightly but significantly higher than that in ovx controls. However, DRO at 1 mg/kg/day had no effects on uterine stromal thickness and luminal epithelial thickness compared to ovx controls. The ovx-induced decrease in femoral and lumbar vertebral bone mineral density was prevented by treatment with EE at 30 micrograms/kg/day, TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Similarly, the decrease in bone mass and the increase in bone resorption and bone turnover in proximal tibial metaphyses were prevented by treatment with EE at 30 micrograms/kg/day or TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Total serum cholesterol decreased significantly in ovx rats treated with either EE, DRO, or TAM at all dose levels compared to vehicle treated ovx controls (-32% to -56%). The ovx-induced body weight gain was completely prevented by EE at 30 micrograms/kg/day, and partially prevented by DRO at 1 mg/kg/day. TAM at both 0.1 and 1 mg doses caused a significant decrease in body weight compared to both sham and ovx controls. Our results indicated that DRO prevented ovx-induced bone loss and lowered total serum cholesterol with an ED50 less than 1 mg/kg/day. The bone protective and cholesterol lowering effects of DRO were comparable to those observed with TAM and EE. However, DRO differed from TAM and EE in its lack of significant estrogenic effects on uterine tissue at doses which were bone protective. These data suggest that DRO may be a significant alternative to EE and TAM for prevention and treatment of postmenopausal osteoporosis.

Absorptiometry, Photon↗
PubMed1997

Alendronate prevents cyclosporin A-induced osteopenia in the rat.

Post-transplantation bone disease is an increasingly recognized clinical entity whose etiology is multifactorial. The immunosuppressant agent cyclosporine-A (CsA) has repeatedly been shown experimentally to induce a high-turnover osteopenic state. Alendronate (Alen.) is a new generation bisphosphonate having far greater antiresorptive potency than previous bisphosphonates. It inhibits osteoclast resorption in vitro and in vivo without adversely affecting bone mineralization. This study was designed to investigate whether alendronate could prevent CsA-induced osteopenia in the rat. Forty-eight 8-month-old male Sprague Dawley rats were randomized into four groups to receive the following for 28 days: (1) CsA vehicle (veh.) p.o. daily and alendronate vehicle subcutaneously (s.c.) twice/week, (2) CsA 15 mg/kg p.o. daily and Alen. veh. s.c. twice/week, (3) Alen. 70 micrograms/kg s.c. twice/ week and CsA veh. p.o. daily, and (4) CsA 15 mg/kg p.o. daily and Alen. 70 micrograms/kg s.c. twice/week. Rats were weighed and bled and serum was assayed serially for calcium, PTH, 1,25(OH)2vit.D, and osteocalcin. Tibiae were removed following sacrifice on day 28, after double demeclocycline and calcein labeling, for histomorphometric analysis. Treated groups were compared to the vehicle-treated control. We confirmed previous findings that CsA produces elevated 1,25(OH)2 vitamin D and serum osteocalcin levels. Alendronate treatment by itself decreased osteocalcin by day 28 and resulted in a marginal decrease in serum total calcium on day 14. The histomorphometry findings reconfirmed that the administration of CsA induces a state of high-turnover osteopenia. Alendronate prevented CsA's adverse effects, particularly in maintaining trabecular bone volume, presumably by decreasing bone remodeling. Alendronate would seem to hold therapeutic promise in post-transplantation bone disease.

Administration, Oral↗
PubMed1997

Comparison of internal emitter radiobiology in animals and humans.

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.

Animals↗
PubMed1997

Relationship of natural incidence and radiosensitivity for bone cancer in dogs.

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.

Animals↗