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Dose responses for adaption to low doses of (60)Co gamma rays and (3)H beta particles in normal human fibroblasts.

The dose response for adaption to radiation at low doses was compared in normal human fibroblasts (AG1522) exposed to either (60)Co gamma rays or (3)H beta particles. Cells were grown in culture to confluence and exposed at either 37 degrees C or 0 degrees C to (3)H beta-particle or (60)Co gamma-ray adapting doses ranging from 0.1 mGy to 500 mGy. These cells, and unexposed control cells, were allowed to adapt during a fixed 3-h, 37 degrees C incubation prior to a 4-Gy challenge dose of (60)Co gamma rays. Adaption was assessed by measuring micronucleus frequency in cytokinesis-blocked, binucleate cells. No adaption was detected in cells exposed to (60)Co gamma radiation at 37 degrees C after a dose of 0.1 mGy given at a low dose rate or to 500 mGy given at a high dose rate. However, low-dose-rate exposure (1-3 mGy/min) to any dose between 1 and 500 mGy from either radiation, delivered at either temperature, caused cells to adapt and reduced the micronucleus frequency that resulted from the subsequent 4-Gy exposure. Within this dose range, the magnitude of the reduction was the same, regardless of the dose or radiation type. These results demonstrate that doses as low as (on average) about one track per cell (1 mGy) produce the same maximum adaptive response as do doses that deposit many tracks per cell, and that the two radiations were not different in this regard. Exposure at a temperature where metabolic processes, including DNA repair, were inactive (0 degrees C) did not alter the result, indicating that the adaptive response is not sensitive to changes in the accumulation of DNA damage within this range. The results also show that the RBE for low doses of tritium beta-particle radiation is 1, using adaption as the end point.

Acclimatization↗

Pure beta-particle-emitting stents inhibit neointima formation in rabbits.

BACKGROUND: Considerable experimental evidence exists that neointimal hyperplasia after angioplasty is inhibited by gamma-irradiation of the treated arteries. A beta-particle radiation is absorbed in tissue within a shorter distance away from the source than gamma-radiation and may be more suitable for localized vessel irradiation. This study outlines a method to implant a beta-particle-emitting radioisotope (32P; half-life, 14.3 days) into metallic stents. The effects of these stents on the inhibition of neointimal hyperplasia was compared with conventional stents in a rabbit model. METHODS AND RESULTS: 32P was produced by irradiation of red amorphous phophorus (31P) with neutrons and was implanted into Palmaz-Schatz stents (7.5 mm in length) after being kept apart from 31P in a mass separator. The radioisotope was tightly fixed to the stents, and the ion implantation process did not alter the surface texture. Stent activity levels of 4 and 13 microCi were chosen for the study. Four and 12 weeks after placement of conventional stents and 32P-implanted stents in rabbit iliac arteries, vascular injury and neointima formation were studied by histomorphometry. Immunostaining for smooth muscle cell (SMC) alpha-actin was performed to determine SMC cellularity in the neointima. SMCs were quantified by computer-assisted counting of alpha-actin immunoreactive cells. Endothelialization of the stents was evaluated by immunostaining for endothelial cell von Willebrand factor. No difference in vessel wall injury was found after placement of conventional and 32P-implanted stents. Neointima formation was potently inhibited by 32P-implanted stents only at an activity level of 13 microCi after 4 and 12 weeks. Neointimal SMC cellularity was reduced in 32P-implanted stents compared with conventional stents. Radioactive stents were endothelialized after 4 weeks, but endothelialization was less dense than in conventional stents. CONCLUSIONS: Neointima formation in rabbits is markedly suppressed by a beta-particle-emitting stent incorporating the radioisotope 32P. In this model, a dose-response relation with this type of radioactive stent was observed, indicating that a threshold radiation dose must be delivered to inhibit neointima formation after stent placement over the long term.

Angioplasty, Balloon↗

Time- and dose-related changes in the thickness of skin in the pig after irradiation with single doses of thulium-170 beta particles.

Time-related changes in skin thickness have been evaluated in the pig using a noninvasive ultrasound technique after exposure to a range of single doses of 0.97 MeV beta particles from (170)Tm plaques. The reduction in relative skin thickness developed in two phases; the separation into two phases was statistically justified only after 120 Gy (P = 0.04). The first phase was between 12 weeks and 24 weeks after irradiation. No further changes were seen until 48-60 weeks after irradiation, when a second phase of skin thinning was observed. No further changes in relative skin thickness were seen in the follow-up period of 104 weeks. The timing of these phases of relative skin thinning was totally independent of the radiation dose; however, the severity of each phase of radiation-induced skin thinning was related to the dose. The pattern of changes was similar to that reported previously after irradiation with 2.27 MeV beta particles from (90)Sr/(90)Y, but the degree of dermal thinning was less for a similar skin surface dose. From a comparison of the depth-dose distribution of the beta particles from the two radionuclides, it was concluded that the target cell population responsible for both the first and second phase of skin thinning in pig skin after irradiation may be located at approximately 800 microm depth. This corresponds to an area in the reticular dermis in pig skin and may be the appropriate site at which to measure the average dose to the dermal tissue.

Animals↗

Calculation of radiation-induced DNA damage from photons and tritium beta-particles. Part II: Tritium RBE and damage complexity.

Yields of DNA single- and double-strand breaks (SSB and DSB) in nucleosomal DNA were calculated for 137Cs, 70 keV photons and tritium beta-particles by Monte Carlo means. Monte Carlo-generated electron tracks for liquid water were used to model energy deposition. Chemical evolution of a track and interactions between species and DNA following water radiolysis were modelled in an encounter-controlled manner. The calculated relative biological effectiveness (RBE) for DSB production for tritium against 137Cs was 1.2 for the total DSB yield. Tritium beta-particles were slightly more efficient compared to 137Cs in producing complex DSB, defined as DSB accompanied by additional strand breaks. The RBE for complex DSB formation was 1.3. Most complex DSB exhibited associated base damage; the extent of the base damage was similar for all the radiation types considered. Correlated DSB conforming to nucleosome periodicity were observed. However, their frequency was low, of the order of 2% of total DSB. For all the DNA damage endpoints considered and their response to variation of the scavenging environment or DNA conformation no difference was observed between 70 keV photons and tritium beta-particles.

Beta Particles↗

Dose and dose rate effects of beta-particle emitting radioactive stents in a porcine model of restenosis.

BACKGROUND: Radioactive stents have been proposed as a means to prevent in-stent restenosis by inhibiting intimal proliferation with continuous low-dose irradiation. OBJECTIVES: The purpose of this study is to determine the effects of cumulative dose and dose-rate delivery on neointimal formation using 32P and 90Y beta-particle emitting radioactive stents in a porcine coronary model of restenosis. METHODS AND MATERIALS: We compared the late histologic results of 0.25 to 32.0 microCi 90Y (half-life 64 hours) (n = 64 stents) and 0.1 to 57.6 microCi 32P (half-life 14.3 days) (n = 55 stents) Beta-particle emitting radioactive stents with non-radioactive (n = 40) stents in a porcine coronary model of restenosis. A computer-based dosimetry modeling program was used to determine the 28 day cumulative dose and dose-rate delivery for the beta-particle emitting radioactive stents at a distance of 0.1 mm from the stent surface. RESULTS: Continuous low dose-rate (1 to 5 cGy/hr) radiation delivery for > 2 weeks via a 0.1 to 0.5 microCi 32P radioactive stent effectively reduced in-stent neointimal hyperplasia at 90 days. Cumulative doses of > 55 Gy induced severe adventitial fibrosis, microvascular damage and promoted the formation of a matrix-rich neointima. Delayed vascular repair was evident at focal regions within the body of radioactive stents that delivered cumulative doses of > or = 140 Gy at 28 days and cumulative doses of 1,100 Gy at 90 days. CONCLUSIONS: These data may be useful in predicting safe and effective dose and dose rate delivery for beta-particle emitting radioactive stents.

Animals↗

Measurement of the rate of wear of dental composite resins by a 90Sr beta particle transmission gauge.

The wear rate of restorative dental composite resins is an important parameter in the assessment of their in vivo performance. The two more widely used methods of quantifying wear are measuring the dimensional change and measuring the change in the mass of the specimen. The former method is complicated by uneven wear of specimens and presents difficulties with samples of irregular shape, and the latter method involves measurements of changes in mass as small as tens of micrograms with specimens of sizes similar to those encountered clinically. A 90Sr beta particle transmission gauge has been designed and constructed to enable the wear rate of small specimens of dental composite resins to be measured. The 90Sr beta particle transmission gauge enables indirect measurements of changes in mass to be made and overcomes some of the difficulties inherent in the direct measurement of mass and length. Applications of the 90Sr beta particle transmission gauge to the measurement of wear rates are given for restorative dental resins having a range of inorganic filler contents and types. The results show that the 90Sr beta particle transmission gauge is capable of measuring the rate of wear to a degree of precision similar to that of micrometer-derived measurements.

Composite Resins↗

The scaling method applied to beta particle line sources with a finite diameter.

The well-known scaling method for planar and punctiform beta particle sources is extended to the case of a cylindrical source with a length larger than the beta particle range times two and with an infinitesimal or finite diameter. The equation for a spherical source with a finite diameter is also given. As a means of illustration, previously measured and simulated radial depth-dose distributions of a 40-mm-long prototype 188W/188Re intravascular beta source in polymethylmethacrylate are scaled to H2O and compared with simulations in the latter medium. The results suggest that the scaling method is accurate to within about 3%, provided that the finite diameter of the source is taken into account.

Beta Particles↗

Thermoluminescent response of ZrO2 + PTFE prepared in Mexico to 90Sr/90Y beta particles.

Results of studying the thermoluminescent response of undoped ZrO2 + PTFE pellets irradiated with 90Sr/90Y beta particles are presented. Previously, TL characteristics of ZrO2 films doped with rare earths were studied. Phosphor powder was obtained by evaporating a solution of zirconium nitrate in ethanol. In order to stabilise the traps in ZrO2 this phosphor was submitted to different thermal treatments. Optimal thermal treatment consisted in heating at 1100 degrees C for 24 h. With this powder. pressing at room temperature a mixture (2:1) of ZrO2 and polytetrafluoroethylene (PTFE), pellets of 5 mm diameter and 0.8 mm thickness were made. The glow curve of ZrO2 + PTFE pellets exhibited two peaks at 200 and 250 degrees C: its TL response as a function of beta particles dose was linear in the range from 2 to 60 Gy. Repeatability over 10 cycles was 1.8%. Fading at room temperature was 3.8% per month.

Beta Particles↗

Differential interactions of beta particles with liquid enantiomers and internal timing of chiral molecules.

The Cerenkov and liquid scintillation technique was applied to detect differential interactions between beta particles and chiral molecules. The highly helical beta emitting 32P and the barely helical beta emitting 3H were dissolved in the liquid enantiomers of 2-phenylbutyric acid. The interactions of the beta particles with the enantiomers were compared. Differential interactions were observed in case of 32P. The stopping power of R enantiomers was greater than that of the S enantiomer. The apparent decay of 32P was faster in the S enantiomer than in the R enantiomer. It is not clear whether this is due to some mistake in measurement or reflects the postulated difference of internal timing of the two enantiomers. Since, in spite of all efforts, contamination could not totally be excluded and data are significant only to one sigma, results must be considered preliminary. The method, however, seems to be more sensitive than all previously used methods. The differential effect was always in the same direction in at least 5 replicas.

Beta Particles↗

Radionuclides linked to a CD74 antibody as therapeutic agents for B-cell lymphoma: comparison of Auger electron emitters with beta-particle emitters.

UNLABELLED: We demonstrated previously that human B-cell lymphomas were effectively and specifically killed in vitro by an antibody to CD74 (LL1) linked to (111)In or other Auger electron emitters. This study was intended to more accurately compare the potency and specificity of 3Auger electron emitters, (111)In, 67Ga, and 125I, and to evaluate beta-particle emitters, 131I and 90Y. The unique property of LL1 is its high level of intracellular uptake. METHODS: Raji B-lymphoma cells were incubated with serial dilutions of the radiolabeled Abs for 2 d and then monitored for cell growth by 2 assays: a cell counting assay and a clonogenic assay. The uptake of radioactivity per cell was monitored at various time points, and the radiation dose was calculated using published S values for radioactivity located in the cytoplasm. Both specific and nonspecific toxicity were evaluated. RESULTS: The beta-particle emitters had considerably higher levels of nonspecific toxicity than the Auger electron emitters, but both 131I and 90Y, and particularly 131I, still had high levels of specificity. Both of these results were consistent with dosimetry calculations. Relative to the delivered disintegrations per cell, 131I and 67Ga were the most potent of the radionuclides tested, with 125I and (111)In being significantly weaker and 90Y being intermediate. The high potency of 67Ga, together with its low nonspecific toxicity, caused this radionuclide to have the highest specificity index. CONCLUSION: When delivered by Ab LL1, both Auger electron and beta-particle emitters can produce specific and effective toxicity. The choice of the optimal radionuclide for therapy may depend on the ease and efficiency of labeling, the specific activity obtained, the nature of the tumor being targeted, and other factors, but the high specificity indices of the Auger electron emitters may be an advantage.

Antibodies↗

The induction of chromosome aberrations in human lymphocytes by in vitro irradiation with beta particles from tritiated water.

The yields of unstable chromosome aberrations induced in human lymphocytes by beta particles from tritiated water ( HTO ) have been measured. HTO was mixed with heparinized blood in various amounts so that doses of 0.25 to 7.0 Gy were delivered in 20 min and 1.5 and 2.5 hr. After culturing for 48 hr, the dicentric yield was measured as a function of dose to the blood and compared with data previously reported for X rays. Using a linear-quadratic dose-effect relation to fit the experimental data, a significant linear contribution was found. The main difference between the coefficients for beta and X radiation is in the alpha values, indicating that HTO beta rays are more efficient, particularly at lower doses, in producing two lesions with a single ionizing track. In accord with the theory of dual radiation, the RBE of HTO beta particles relative to X rays is 2.6 at 0.25 Gy and decreases with increasing dose. When the number of cells without aberrations is plotted against radiation dose, a curve is obtained which is similar in shape to those from human cell survival experiments.

Chromosome Aberrations↗

Effects of endovascular radiation from a beta-particle-emitting stent in a porcine coronary restenosis model. A dose-response study.

BACKGROUND: Neointimal formation causes restenosis after intracoronary stent placement. Endovascular radiation delivered via a stent has been shown to reduce neointimal formation after placement in porcine and rabbit iliac arteries. The objective of this study was to evaluate the dose-related effects of a beta-particle-emitting radioactive stent in a porcine coronary restenosis model. METHODS AND RESULTS: Thirty-seven swine underwent placement of 35 nonradioactive and 39 beta-particle-emitting stents with activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 microCi of 32P. Treatment effect was assessed by histological analysis 28 days after stent placement. Neointimal and medial smooth muscle cell density were inversely related to increasing stent activity. The neointima of the high-activity (3.0- to 23.0-microCi) stents consisted of fibrin, erythrocytes, occasional inflammatory cells, and smooth muscle cells with partial endothelialization of the luminal surface. In the 1.0-microCi stents, the neointima was expanded and consisted of smooth muscle cells and a proteoglycan-rich matrix. The neointima of the low-activity (0.15- and 0.5-microCi) stents was composed of smooth muscle cells and matrix with complete endothelialization of the luminal surface. At low and high stent activities, there was a reduction in neointimal area (low, 1.63 +/- 0.67 mm2 and high, 1.73 +/- 0.97 mm2 versus control, 2.40 +/- 0.87 mm2) and percent area stenosis (low, 26 +/- 7% and high, 26 +/- 12%) compared with control stents (37 +/- 12%, P < or = .01). The 1.0-microCi stents, however, had greater neointimal formation (4.67 +/- 1.50 mm2) and more luminal narrowing (64 +/- 16%) than the control stents (P < .0001). CONCLUSIONS: The differential response to the doses of continuous beta-particle irradiation used in this experimental model suggests a complex biological interaction of endovascular radiation and vascular repair after stent placement. Further study is required to determine the clinical potential for this therapy to prevent stent restenosis.

Animals↗

Induction of chromosome aberrations by 90Sr beta-particles in cultured human lymphocytes.

Human blood was irradiated with beta-particles from an external source of 90Sr. The source was a rolled piece of silver foil, active dimensions: 100 X 12.5 mm, incorporating 3.7 X 10(8) Bq (10 mCi) of 90Sr/90Y. After culturing for 48 h, the dicentric yield in the lymphocytes at the first metaphase was measured as a function of the dose in the blood. The aberration yield fitted the linear-quadratic function well, which is consistent with the single-track and two-track model for aberration formation at low LET radiation. The curve for 90Sr beta-rays was compared with a curve for 60Co gamma-rays. The main difference between the coefficients was in the alpha values. With respect to 60Co gamma-rays, the RBE calculated from the dose-effect relationships for dicentric production was 2.8 at the dose of 0.14 Gy; it decreased with increasing doses. The distribution of dicentrics was consistent with the Poisson distribution but showed a tendency to over-dispersion in the region of higher doses. A reason for these discrepancies is discussed.

Beta Particles↗

Mean skeletal dose factors for beta-particle emitters in human bone. Part II: surface-seeking radionuclides.

Mean skeletal dose factors for surface-seeking beta-emitting radionuclides have been derived on the basis of the beta-particle dose factors calculated for human bones by Spiers et al. (1978b), or from empirical formulae representing these calculations given by Beddoe and Spiers (1979). The dose factors are derived for the same tissues as in Part I (Spiers et al., 1978a), namely, (1), sDM/Dskel, the mean dose to haemopoietic marrow in trabecular bone, and (2), sDs/Dskel, the mean dose to endosteal tissues lying in a zone 0-10 microns from trabecular surfaces. The dose factors are given as fractions of Dskel, the "dose to bone", calculated from the energy released by the retained radionuclide divided by the total mass of mineral bone. As in Part I, the dose factors are given for three ages, 1.7, 9 and 44 years and extrapolation to lower ages is made on the basis of calculations for a lumbar vertebra of an infant aged 3.5 weeks. The factors are given for six radionuclides covering a range of mean beta-particle energies from 0.0255 MeV (171Tm) to 0.93 MeV (90Y). The dosimetry is also considered for some radionuclides that first deposit on bone surfaces before being translocated to the bone volume. In the case of 45Ca, for example, it is shown that the dose calculation that includes both the surface and the volume depositions gives integrated doses to ten days and 100 days that are respectively 4.5 and 1.9 times the corresponding values calculated conventionally on a volume deposition only. Endosteal dose factors are similarly considered, and other radionuclides included as surface-plus-volume depositions are 47Ca, 89Sr and 90Sr + 90Y.

Adult↗

Cholesterol efflux, lecithin-cholesterol acyltransferase activity, and pre-beta particle formation by serum from human apolipoprotein A-I and apolipoprotein A-I/apolipoprotein A-II transgenic mice consistent with the latter being less effective for reverse cholesterol transport.

Studies assessing fatty streak formation in mice have revealed that human apolipoprotein A-I (apoAI) transgenic mice (TgAI) have 15-fold less atherosclerosis susceptibility than combined human apolipoprotein A-I/human apolipoprotein A-II (apoAI:AII) transgenics (TgAI:AII) and 40-fold less than nontransgenic control mice. In order to examine the biochemical mechanisms underlying those in vivo observations, we have compared in vitro properties of serum from the different groups of animals for participation in cholesterol efflux, LCAT activation, and pre-beta particle formation. Analysis of cholesterol efflux from both Fu5AH hepatoma and Ob1771 adipose cells revealed serum from the TgAI to be the most efficient in promoting efflux. The two-dimensional electrophoresis of mouse serum shows that control mice have exclusively apoAI in alpha particles. TgAI and TgAI:AII mice have 30 and 38% of total apoAI in particles with pre-beta electrophoretic mobility, respectively. The distribution of cell-derived cholesterol between these apoAI-containing lipoprotein subspecies after 1 and 60 min of incubation with Fu5AH hepatoma cells was examined. This revealed after a 1 min incubation 66 +/- 8 and 83 +/- 9% of the counts in particles with pre-beta mobility for TgAI and TgAI:AII mice, respectively; while after 60 min of incubation, only 6 +/- 2% of counts remained in pre-beta particles from the TgAI and 30 +/- 3% for the TgAI:AII. This suggests faster movement of cholesterol from pre-beta to alpha particles in plasma from the TgAI. Consistent with this is the observation that LCAT activity with both exogenous and endogenous substrate increased in the TgAI versus the TgAI:AII mice. The previously observed decrease in fatty streak formation in the TgAI versus the TgAI:AII and control mice is consistent with the in vitro studies presented here and suggests that HDL containing human apoAI is a more effective participant in the postulated early steps in reverse cholesterol transport than HDL containing both human apoAI and human apoAII, and/or murine HDL.

Animals↗

Assessment of 90Sr concentration in dental tissue using thin-layer beta-particle detectors and verification with numerical calculations.

Electron paramagnetic resonance (EPR) measurements of tooth enamel can be used as an individual biological dosimeter for external dose assessment. However, the presence of 90Sr in the tooth tissues makes the task of interpreting EPR tooth dosimetry more complicated. The determination of the dose contribution of incorporated 90Sr in calcified tissue to the total dose measured by EPR is one of the main aspects of correct interpretation of EPR tooth dosimetry. In this work, experimental and numerical calculations were performed to convert the measured beta-particle dose rate to 90Sr concentration in calcified tissue. The cumulative beta-particle dose was measured by exposing artificially contaminated dentin and enamel to thin-layer alpha-Al2O3:C detectors in two different exposure geometries. Numerical calculations were performed for experimental exposure conditions using calculations of electron transport and secondary photons [Monte Carlo n-Particle Transport code version 4C2 (MCNP)]. Numerical calculations were performed to optimize the sample size and exposure geometry. The applicability of two different exposure conditions to be used in routine analysis was tested. Comparison of the computational and experimental results demonstrated very good agreement.

Beta Particles↗