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PubMed1999

Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate.

Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.

Administration, Oral↗
PubMedDate not supplied

Semiautomated preparation of 3,5,6-trichloro-2-pyridinol in human urine using a Zymate XP laboratory robot with quantitative determination by gas chromatography-negative-ion chemical ionization mass spectrometry.

A rapid and sensitive semiautomated method was developed for quantitation of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCP) in human urine. A Zymark Zymate XP laboratory robotics system was used to mix urine samples, transfer aliquots, add the stable-isotope-labeled TCP internal standard (13C2- or 13C2,15N-), and liberate conjugates of TCP from urine via acid hydrolysis. Samples were manually extracted into toluene, derivatized, and analyzed by gas chromatography-negative-ion chemical ionization mass spectrometry. Determination of the metabolic TCP was performed by selected ion monitoring of the dichloropyridinol fragment ions: m/z 161 for TCP and m/z 165 for 13C2-TCP or m/z 168 for 13C2,15N-TCP. Interday precision and accuracy were demonstrated over 3 years of analyses using the 13C2-TCP internal standard, with an average recovery from fortified urine samples of 93+/-12% (N = 54, concentration range 1-140 ng/mL). The method was found to be linear over the range of 0.5 to 200 ng/mL, and the limit of detection for TCP in urine was estimated to be 0.2 ng/mL with a limit of quantitation of 1 ng/mL. The effect of solids distribution on the concentration of TCP in the thawed urine samples was examined, and the results indicated that homogeneous distribution is critical for quantitation. The precision and accuracy of the automated method with respect to the transfer of homgeneous urine aliquots and delivery of internal standard yielded equivalent or improved results over the manual techniques. Overall, this method is more simple than existing methodologies, and it yields results with improved precision, accuracy, and sensitivity over previously developed methods.

Automation↗
PubMed1983

Regulation of 2,4,5-trichlorophenoxyacetic acid and chlorophenol metabolism in Pseudomonas cepacia AC1100.

The expression of the degradative genes encoding 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 2,4,5-trichlorophenol (2,4,5-TCP), and pentachlorophenol (PCP) dechlorination in a 2,4,5-T-degrading strain of Pseudomonas cepacia was examined during growth on alternate carbon sources. The dechlorination mechanisms for all three compounds were expressed in 2,4,5-T- and 2,4,5-TCP-grown cells but were not expressed in cells grown on succinate, glucose, or lactate. The addition of 2,4,5-TCP or PCP to cells grown on succinate or lactate resulted in the expression of the 2,4,5-TCP dechlorination mechanism in resting cells after 1-h lag. This expression was prevented by the presence of chloramphenicol in the resting cell suspension. Succinate-plus-PCP-grown resting cells preincubated with 2,4,5-TCP fully induced the trichlorophenol dechlorination system and partially induced the PCP dechlorination system. Preincubation of succinate-plus-PCP-grown resting cells with PCP induced neither the 2,4,5-TCP nor the PCP dechlorinating system. Succinate-grown resting cells converted 2,4,5-T to 2,4,5-TCP even in the presence of chloramphenicol. Thus, the data indicate that the enzyme(s) which converts 2,4,5-T to 2,4,5-TCP is constitutively expressed, whereas those that convert 2,4,5-TCP to central intermediates are induced by 2,4,5-TCP but not by 2,4,5-T or PCP and are repressed in the presence of an alternate carbon source.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1991

Immunogenicity of Vibrio cholerae O1 toxin-coregulated pili in experimental and clinical cholera.

A functional tcpA gene, encoding the major subunit of toxin-coregulated pili (TCP), is necessary for Vibrio cholerae O1 Ogawa strain 395 to colonize the human intestine and confer protective immunity to virulent challenge. The immunogenicity of TCP and other antigens in experimental and naturally acquired cholera was determined. Seroconversion to cholera toxin (CT), whole cell preparations, and to Ogawa lipopolysaccharide but not to purified native TCP or to a TcpA mimiotope was found in volunteers. Local intestinal secretory immunoglobulin A from volunteers showed conversions to cholera toxin and lipopolysaccharide but not to TCP. Cholera patients in Indonesia showed a seroconversion rate to TCP of 3 of 6 and a seroconversion to a TcpA mimiotope of 1 of 6. Volunteer and patient sera showed similar vibriocidal seroconversions when assayed against either TCP-positive and TCP-negative V. cholerae O1 strains, suggesting that TCP do not contribute demonstrably to the vibriocidal antigen. We conclude that although seroconversion to TCP can occur in naturally acquired cholera, solid long-term protection can be engendered in the absence of a detectable anti-TCP immune response.

Amino Acid Sequence↗
PubMedDate not supplied

Biomaterial resorption rate and healing site morphology of inorganic bovine bone and beta-tricalcium phosphate in the canine: a 24-month longitudinal histologic study and morphometric analysis.

PURPOSE: An inorganic xenograft (inorganic bovine bone [IBB]) and a porous alloplast (beta-tricalcium phosphate [beta-TCP]) material were compared at different healing periods in experimental bone defects in dogs. MATERIALS AND METHODS: Six round defects, 5 x 4 mm, were made on the lateral bony mandibular angle in 8 dogs at different times. Two defects were randomly filled with IBB, 2 with beta-TCP, and 2 were left to blood clot. A bi-layer collagen membrane covered 1 defect of each type. Four specimens per treatment group were obtained for each treatment group at 3, 6, 12, and 24 months postoperatively. Morphometric analysis of decalcified (Donath technique) histologic slides was conducted using the measured areas of regenerated bone, grafted particles, and remaining concavity. RESULTS: In IBB sites, complete bone healing was evident at 12 and 24 months, but grafted particles dominated the sites. In beta-TCP sites, only particle remnants remained at 12 months. At 24 months, particles had completely resorbed in both membrane-protected (MP) and uncovered (UC) defects. Data were combined for final analysis since there were no statistically significant differences within each graft material group (MP or UC). Mean bone area fraction increased from 3 to 24 months at all sites. In bone area fraction a statistically significant difference was found between 3 and 6 months in the IBB and beta-TCP groups. IBB sites also showed such significance between 6 and 12 months. A statistically significant difference was found between MP ungrafted sites (42.9%) vs IBB (24.7%) and vs the control (24.8%) at 3 months. At 6 months, beta-TCP bone area fraction (68.8%) was significantly greater than IBB (47.9%) and control (37.5%) sites. At 12 months, beta-TCP bone area fraction (79.0%) was significantly greater than the control (42.5%). At 24 months, beta-TCP bone area fraction (86.5%) was significantly greater than IBB (55.6%) sites. Mean particle area fraction of beta-TCP sites decreased gradually until complete resorption at 24 months. IBB sites showed a significant decrease only between 3 (38.7%) and 6 (29.4%) months. DISCUSSION AND CONCLUSION: Complete bone healing was established in all grafted defects. IBB and beta-TCP are both excellent biocompatible materials. However, at 24 months beta-TCP particles were completely resorbed, whereas IBB particles still occupied a remarkable area fraction without significant resorption beyond 6 months. (More than 50 references.)

Alveolar Bone Loss↗
PubMed1993

Reaction of lysyl oxidase with trans-2-phenylcyclopropylamine.

trans-2-Phenylcyclopropylamine hydrochloride (tranylcypromine; TCP) was found to be both an inhibitor and a substrate of lysyl oxidase, the enzyme which oxidizes peptidyl lysine in elastin and collagen to initiate cross-linking in these proteins. The reaction of TCP with this enzyme was further characterized in view of the potential interference that chronic administration of this antidepressant compound may exert on the development and repair of connective tissues. In contrast to the irreversible and/or competitive inhibitors of lysyl oxidase previously described, TCP noncompetitively and reversibly inhibited the oxidation of both alkylamine and elastin substrates with Ki values of 386 and 375 microM, respectively. The noncompetitive mode of interaction affected the accessibility of the active site to productive amine substrates since the reductive trapping of n-hexylamine to lysyl oxidase was largely prevented by the presence of TCP. It was of additional interest that lysyl oxidase catalyzed a limited degree of conversion of TCP to cinnamaldehyde accompanied by the production of hydrogen peroxide. The lack of significant incorporation of protein-bound tritium accompanying reduction of the enzyme-TCP complex with [3H]NaBH4 argued against the formation of a Schiff base between the enzyme and the cinnamaldehyde product as the basis of the inhibitory effect. Spectral evidence was also obtained for an additional interaction between TCP and lysyl oxidase that was independent of the inhibitory effect of TCP. Cyclopropylamine, lacking the benzene moiety of TCP, inhibited lysyl oxidase irreversibly and competitively, and was not a substrate, pointing toward a defining role for the benzene moiety in the interaction of TCP with lysyl oxidase.

Animals↗
PubMed1993

Polyethylene glycol-modified chimeric toxin composed of transforming growth factor alpha and Pseudomonas exotoxin.

Modification of proteins with monomethoxy-polyethylene glycol (mPEG) has been shown to prolong circulation time and to reduce immunogenicity. To make a mPEG-modified recombinant toxin that retained cytotoxic activity but had a longer residence time in circulation, we have constructed an altered form of TGF alpha-PE40, a recombinant toxin composed of human transforming growth factor alpha (TGF alpha) fused to a fragment of Pseudomonas exotoxin (PE38) devoid of its cell-binding domain. In the newly designed protein, termed TGF alpha R29-L2-CH2-PE38QQ delta (TCP), there are no lysine residues in the TGF alpha and PE38 portions. Human IgG4 constant region CH2 and a tetradecapeptide linker; L2, are inserted between TGF alpha and PE38. Together, L2 and CH2 contain 13 lysine residues as potential modification sites for mPEG. mPEG conjugates of TCP (PEG-TCP) were generated and the products were resolved by ion exchange chromatography. Two PEG-TCP species termed B4 and B6 retained 15 and 4% of cytotoxicity, respectively, and 26% of their receptor binding activity compared with the unmodified TCP. Both B4 and B6 had prolonged circulation times in the blood and reduced toxicity in animals. The mean residence times of B4 and B6 were 37 and 68 min, respectively, compared to 7 min for TCP. When administered i.v. to tumor bearing mice, both B4 and B6 produced marked antitumor effects whereas the unmodified TCP had none. Also, the immunogenicity of PEG-TCP was 5-10 times less than that of TCP. We suggest that the prolonged circulating time and reduced toxicity of PEG-TCP compensate for a diminished cytotoxic activity and enlarge significantly the therapeutic window of this chimeric toxin.

ADP Ribose Transferases↗
PubMed2007

Biological activity of tri-calciumphosphate/hydroxyl-apatite granules mixed with impacted morsellized bone graft. A study in rabbits.

Reconstruction of bone defects with impacted morsellized cancellous bone grafts (MCB) is a popular method. Because of a shortage of human bone, mixing with biomaterials may be attractive. Ceramics may be used as bone graft extenders. In this study, various volume mixtures of biphasic tri-calciumphosphate/hydroxyl-apatite (TCP-HA) granules (1.5-2 mm) with MCB were examined in a non-loaded defect model in rabbits. Direct post-operatively, many 10-150 microm TCP-HA particles were present due to impaction. Irrespective to the group, after 8 weeks, virtually all MCB was resorbed and most TCP-HA granules were osseous-integrated with newly formed bone. The cross-sectional areas of TCP-HA after 8 weeks was generally smaller compared with direct post-operatively and the number of small 10-150 microm TCP-HA particles seemed reduced. Macrophages and giant cells were sparse after 8 weeks. In conclusion, the osteoconductivity of various mixtures of MCB and TCP-HA granules is not dependent on the ratio of TCP-HA over MCB. The reduced number of the 10-150microm TCP-HA particles after 8 weeks, may suggest that a cellular mediated resorption process of TCP-HA granules took place. Based on these favorable biological findings subsequent in-vivo experiments are warranted in load-bearing conditions to investigate whether these findings hold for joint reconstruction purposes.

Animals↗
PubMed1983

Regional surface changes during the development of the telencephalic choroid plexus in the chick. A scanning-electron microscopic study.

The surface morphology of the developing chick telencephalic choroid plexus (TCP) was examined by scanning electron and light microscopy. A blunt evagination develops rostro-cranially to the foramen of Monro on the medial telencephalic septum. The pseudostratified TCP epithelium differs in its surface morphology from that of the surrounding ependyma. Subsequently the TCP becomes elongated and branches. On the 9th embryonic day (ED) the pseudostratified epithelium progressively becomes high columnar epithelium in a distal to proximal direction along the branches of the TCP. The apical poles of the high columnar epithelial cells protrude into the ventricular lumen. Later, additional branches sprout at the base of the TCP, which then resembles a tree with a bush growing at its roots. Before the time of hatching, the high columnar epithelium changes to low columnar epithelium again in a distal to proximal direction. The surface of the TCP becomes flatter, in the process of which the number of cilia per unit surface area is reduced. On the developing TCP the epiplexus cells vary in shape, depending upon their functional state. It is proposed that not only the morphological but also the functional differentiation of the TCP proceeds in a distal to proximal direction along the branches of the choroid plexus. The surface differentiation of the TCP has a more regular character than that of the diencephalic CP (DCP), described previously, which seems to be influenced in its development by other anatomical structures.

Animals↗
PubMed1999

Body residues and responses of the midge chironomus riparius to sediment-associated 2,4,5-trichlorophenol in subchronic and chronic exposures

Subchronic and chronic toxicity of sediment-associated 2,4, 5-trichlorophenol to the midge Chironomus riparius was determined by conducting a 10-day growth and a 50-day emergence tests with spiked lake sediment (nominal initial TCP concentrations were 25, 51, 101, 203, 304 and 405 &mgr;mol kg-1 dry weight in the growth test and 25, 76, 152 and 304 &mgr;mol kg-1 dry weight the emergence test). In addition, we measured the residue of chlorophenol in larval tissue and made an attempt to relate it with the observed adverse biological responses. The larvae were exposed individually to avoid density-dependent effects of mortality on food ration and growth of the surviving larvae. In the growth test, mortality was low at sediment concentrations </=193 &mgr;mol TCP kg-1, but it increased sharply at the higher concentrations being 37 and 94% at 334 and 441 &mgr;mol kg-1 DW, respectively. The effect of sediment TCP concentration on larval mortality was highly significant (10-day LC50 337 &mgr;mol TCP kg-1 dry sediment) in the growth test. In the emergence test, however, mortality was low (3-13%) at all concentrations. TCP did not affect larval growth at the concentrations used. The concentration of TCP in the whole larvae after the 10-day exposure was proportional to sediment concentration, being at highest 160 &mgr;mol kg-1 fresh weight. When the average body residues of TCP were below 80 &mgr;mol kg-1, mortality was low, but it increased when the body residue approached 100 &mgr;mol kg-1. After the 10-day exposure, the body residue, at which 50% of the larvae survived (CBR50) was 113 &mgr;mol g-1. TCP exposure accelerated larval development and the midges exposed to 171 and 324 &mgr;mol TCP kg-1 emerged earlier than those in the other concentrations or in the control sediment. In natural environments, sediment-associated chlorophenolics are probably not a major environmental problem to benthic fauna because concentrations similar to that which we observed to cause adverse effects to C. riparius (>60 mg kg-1 dry sediment) are rare.http://link.springer-ny. com/link/service/journals/00244/bibs/37n1p42.html

Journal Article↗
PubMed1999

Degradation of 2,4,5-trichlorophenol and 2,3,5,6-tetrachlorophenol by combining pulse electric discharge with bioremediation.

Degradation of 2,4,5-trichlorophenol (2,4,5-TCP) and 2,3,5,6-tetrachlorophenol (TeCP) was studied using a two-stage approach that utilized efficient pulse electric discharge (PED) followed by biological degradation with a consortium from acclimated return activated sludge. The chlorinated phenols were treated in the PED reactor as an aerosol at a voltage of 55-60 kV, a frequency of 385 Hz, a current of 50-60, and with a 200-ns pulse. As determined by gas chromatography and mass spectrometry (GC/MS), the first stage converted 500 ppm 2,4,5-TCP to 163 ppm 2,4,5-TCP and dimethyldecene, dichloronaphthalenol, octyl acetate, and silyl esters. The total carbon content of 2,4,5-TCP after PED treatment was determined to be 228 +/- 35 ppm. The remaining 2,4,5-TCP and the products formed were then mineralized by the acclimated activated sludge in shake flasks; the initial rate of degradation of 2,4,5-TCP was calculated to be 5 nmol min-1 mg protein-1 at 163 ppm initial concentration (three orders of magnitude higher than the only rate found in the literature). By combining the two techniques, a synergistic effect (2.3-fold increase in the concentration of 2,4,5-TCP degraded and 3.3-fold increase in total carbon degraded) was observed, in that bacteria without any treatment degraded a maximum of 70 ppm, 2,4,5-TCP but after PED treatment 163 ppm 2,4,5-TCP was degraded. TeCP was also mineralized by the acclimated activated sludge after treatment with PED. This two-stage approach was also evaluated using a continuous 1-l fluidized-bed reactor.

Chlorophenols↗
PubMed2006

Biodegradation kinetics of 2,4,6-trichlorophenol by an acclimated mixed microbial culture under aerobic conditions.

The objective of this study was to achieve a better quantitative understanding of the kinetics of 2,4,6-trichlorophenol (TCP) biodegradation by an acclimated mixed microbial culture. An aerobic mixed microbial culture, obtained from the aeration basin of the wastewater treatment plant, was acclimated in shake flasks utilizing various combinations of 2,4,6-TCP (25-100 mg l(-1)), phenol (300 mg l(-1)) and glycerol (2.5 mg l(-1)) as substrates. Complete primary TCP degradation and a corresponding stoichiometric release of chloride ion were observed by HPLC and IEC analytical techniques, respectively. The acclimated cultures were then used as an inoculum for bench scale experiments in a 4 l stirred-tank reactor (STR) with 2,4,6-TCP as the sole carbon/energy (C/E) source. The phenol acclimated mixed microbial culture consisted of primarily Gram positive and negative rods and was capable of degrading 2,4,6-TCP completely. None of the predicted intermediate compounds were detected by gas chromatography in the cell cytoplasm or supernatant. Based on the disappearance of 2,4,6-TCP, degradation was well modelled by zero-order kinetics which was also consistent with the observed oxygen consumption. Biodegradation rates were compared for four operating conditions including two different initial 2,4,6-TCP concentrations and two different initial biomass concentrations. While the specific rate constant was not dependent on the initial 2,4,6-TCP concentration, it did depend on the initial biomass concentration (X (init)). A lower biomass concentration gave a much higher zero-order specific degradation rate. This behaviour was attributed to a lower average biomass age or cell retention time (theta(x)) for these cultures. The implications of this investigation are important for determining and predicting the potential risks associated with TCP, its degradation in the natural environment or the engineering implications for ex situ treatment of contaminated ground water or soil.

Acclimatization↗
PubMed2006

Effect of lead on the sorption of 2,4,6-trichlorophenol on soil and peat.

The effect of lead on the sorption of 2,4,6-trichlorophenol (2,4,6-TCP) on soil and peat was investigated using a batch equilibration method. Lead markedly diminished the sorption of 2,4,6-TCP, and 2,4,6-TCP had little effect on lead sorption. Peat was a more effective adsorbent for 2,4,6-TCP than soil. The desorption hysteresis of 2,4,6-TCP verified the presence of high-energy sorption sites. Mechanisms of lead suppression effect on the 2,4,6-TCP sorption included the following: Firstly, lead accelerated the aggregation of colloids, the aggregates covered the surface in part and shrunk the pore sizes of the adsorbents, hence decreased the sorption of 2,4,6-TCP. Secondly, X-ray absorption and Fourier transform infrared spectroscopy study suggested that lead competed with 2,4,6-TCP for carboxylic, phenolic and Si-OH groups of organic matter and clay minerals. Such competition was partly responsible for the overall suppression effect of lead on the sorption of 2,4,6-TCP.

Adsorption↗
PubMed2006

Performance of a hybrid-loop bioreactor system in biological treatment of 2,4,6-tri-chlorophenol containing synthetic wastewater: effects of hydraulic residence time.

A hybrid-loop bioreactor system consisting of a packed column biofilm and an aerated tank bioreactor with effluent recycle was used for biological treatment of 2,4,6-tri-chlorophenol (TCP) containing synthetic wastewater. Effects of hydraulic residence time (HRT) on COD, TCP and toxicity removal performance of the reactor were investigated for the HRT values between 5 and 30 h, while the feed COD (2700+/-100 mgl(-1)), TCP (300+/-10 mgl(-1)) and the solids retention time (sludge age, SRT, 20 d) were constant. Percent TCP, COD and toxicity removals increased with increasing HRT resulting in more than 90% COD, TCP and toxicity removals at HRT values above 25 h. Biomass concentrations in the packed column and in the aeration tank increased with increasing HRT resulting in low reactor TCP concentrations and therefore high TCP, COD and toxicity removals at high HRT values. Volumetric and specific rates of TCP and COD removals decreased with increasing HRT due to increased biomass and decreased flow rates at high HRT levels. Volumetric and specific removal rates of COD and TCP were maximum at an HRT of 5 h.

Bioreactors↗
PubMed2000

Structural insights of glass-reinforced hydroxyapatite composites by Rietveld refinement.

Phase transformations and interstitial and/or substitution of trace elements during the liquid-phase sintering process of P2O5-CaO-MgO glass-reinforced hydroxyapatite (GR-HA) composites were examined by X-ray diffraction and Rietveld analyses. Using the Rietveld method for structure refinement, changes in the lattice parameters of the two main phases of the composites, hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP), as well as changes in several bond lengths and in the occupancy of the hydroxyl oxygen site in the HA phase structure were assessed. The glasses gave rise to formation of between approximately 45 and 50% of beta-TCP, with evidence for the Mg2+ enhancing the formation of beta-TCP. Between 1,300 and 1,350 degrees C, the beta-TCP inverts to alpha-TCP, without further decomposition of the residual HA. The glasses showed evidence for stabilisation of the hydroxyl group located in the hydroxyl channels. This is supported by measurements of the hydroxyl channel radius (Rc), the Ca2-OH bond length and the hydroxyl oxygen occupancy (Oocc). Results showed that the Mg2+ containing glasses induced the beta-TCP phase formation in the structure of GR-HA composites and retarded the beta-TCP into alpha-TCP transformation at higher temperatures. The chemical composition of the P2O5 glasses also induces modifications in the lattice parameters of the crystallographic phases present in the microstructure of the composites. This suggests some substitution of Mg2 + -for-Ca2+ in the beta-TCP structure during the liquid-phase sintering process.

Biocompatible Materials↗
PubMed1999

Improved bone anchorage of hydroxypatite coated implants compared with tricalcium-phosphate coated implants in trabecular bone in dogs.

Tricalcium phosphate (TCP) and hydroxyapatite (HA) ceramic coatings are bioactive coatings that have been shown to stimulate bone apposition onto ceramic-coated implants. TCP and HA ceramics have well-documented differences in physical properties, but both types of ceramics are used for stimulation of bone ongrowth to cementless endo-prosthetic components clinically. However, little is known about the difference in osteoconductive properties between these coatings when inserted into trabecular bone in a controlled experimental situation. Unloaded cylindrical gritblasted titanium (Ti-6A1-4V) implants (6 x 10 mm) coated with either hydroxyapatite (HA) or tricalcium phosphate (TCP) ceramic were inserted into the proximal humerus of 20 skeletally mature dogs. The implants were initially surrounded by a 2 mm gap. Each animal received one HA-coated implant and one TCP-coated implant. All dogs were sacrificed 6 weeks after surgery. Results were evaluated by histomorphometry and mechanical push-out test. Push-out tests demonstrated that HA-coated implants were 10-fold stronger fixated in comparison to TCP-coated implant. Bone ongrowth was significantly higher for HA-coated implants compared to TCP-coated implants. Bone volume in the gap showed a tendency to less bone volume around HA-coated implants compared to TCP-coated implants but this difference was insignificant. As expected almost all of the TCP coating were resorbed after 6 weeks and almost none of the HA coating. HA-coated implants with a grit-blasted surface provide a favorable early mechanical implant anchorage most likely due to superior ceramic stability compared to TCP-coated implants.

Alloys↗
PubMed2003

Inverse and forward optimization of one- and two-dimensional intensity-modulated radiation therapy-based treatment of concave-shaped planning target volumes: the case of prostate cancer.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) was suggested as a suitable technique to protect the rectal wall, while maintaining a satisfactory planning target volume (PTV) irradiation in the case of high-dose radiotherapy of prostate cancer. However, up to now, few investigations tried to estimate the expected benefit with respect to conventional three-dimensional (3D) conformal radiotherapy (CRT). PURPOSE: Estimating the expected clinical gain coming from both 1D and 2D IMRT against 3DCRT, in the case of prostate cancer by mean of radiobiological models. In order to enhance the impact of IMRT, the case of concave-shaped PTV including prostate and seminal vesicles (P+SV) was considered. MATERIALS AND METHODS: Five patients with concave-shaped PTV including P+SV were selected. Two different sets of constraints were applied during planning: in the first one a quite large inhomogeneity of the dose distribution within the PTV was accepted (set (a)); in the other set (set (b)) a greater homogeneity was required. Tumor control probability (TCP) and normal tissue control probability (NTCP) indices were calculated through the Webb-Nahum and the Lyman-Kutcher models, respectively. Considering a dose interval from 64.8 to 100.8 Gy, the value giving a 5% NTCP for the rectum was found (D(NTCP(rectum)=5%)) using two different methods, and the corresponding TCP(NTCP(rectum)=5%) and NTCP(NTCP(rectum)=5%) for the other critical structures were derived. With the first method, the inverse optimization of the plans was performed just at a fixed 75.6 Gy ICRU dose; with the second method (applied to 2/5 patients) inverse treatment plannings were re-optimized at many dose levels (from 64.8 to 108 Gy with 3.6 Gy intervals). In this case, three different values of alpha/beta (10, 3, 1.5)were used for TCP calculation. The 3DCRT plan consisted of a 3-fields technique; in the IMRT plans, five equi-spaced beams were applied. The Helios Inverse Planning software from Varian was used for both the 2D IMRT and the 1D IMRT inverse optimization, the last one being performed fixing only one available pair of leaves for modulation. A previously proposed forward 1D IMRT 'class solution' technique was also considered, keeping the same irradiation geometry of the inversely optimized IMRT techniques. RESULTS: With the first method, the average gains in TCP(NTCP(rectum)=5%) of the 2D IMRT technique, with respect 3DCRT, were 10.3 and 7.8%, depending on the choice of the DVHs constraints during the inverse optimization procedure (set (a) and set (b), respectively). The average gain (DeltaTCP(NTCP(rectum)=5%)) coming from the inverse 1D IMRT optimization was 5.0%, when fixing the set (b) DVHs constraints. Concerning the forward 1D IMRT optimization, the average gain in TCP(NTCP(rectum)=5%) was 4.5%. The gain was found to be correlated with the degree of overlapping between rectum and PTV. When comparing 2D IMRT and 1D IMRT, in the case of the more realistic set (b) constraints, DeltaTCP(NTCP(rectum)=5%) was always less than 3%, excepting one patient with a very large overlap region. Basing our choice on this result, the second method was applied to this patient and one of the remaining. Through the inverse re-optimization of the treatment plans at each dose level, the gain in TCP(NTCP(rectum)=5%) of the inverse 2D technique was significantly higher than the ones obtained by applying the first method (concerning the two patients: +6.1% and +2.4%), while no significant benefit was found for inverse 1D. The impact of changing the alpha/beta ratio was less evident in the patient with the lower gain in TCP(NTCP(rectum)=5%). CONCLUSIONS: The expected benefit due to IMRT with respect to 3DCRT seems to be relevant when the overlap between PTV and rectum is high. Moreover, the difference between the inverse 2D and the simpler inverse or forward 1D IMRT techniques resulted in being relatively modest, with the exception of one patient, having a very large overlap between rectum and PTV. Optimizing the inverse planning at each dose level to find TCP(NTCP(rectum)=5%)e level to find TCP(NTCP(rectum)=5%) can improve the performances of inverse 2D IMRT, against a significant increase of the time for planning. These results suggest the importance of selecting the patients that could have significant benefit from the application of IMRT.

Dose-Response Relationship, Radiation↗
PubMed1999

The modelled benefits of individualizing radiotherapy patients' dose using cellular radiosensitivity assays with inherent variability.

OBJECTIVE: To model the increases in local tumour control that may be achieved, without increasing normal tissue complications, by prescribing a patient's dose based on cellular radiosensitivity measured using an assay possessing inherent variability. METHOD: Patient populations with varying radiosensitivity were simulated, based on measured distributions among cancer patients of the surviving fraction of their fibroblasts given a dose of 2 Gy in vitro (SF2). The dose-response curve for complications in the population was assessed using a formula relating SF2 to normal tissue complication probability (NTCP), by summing the data for the individuals. This curve was similar to clinically-derived dose-response curves. The effect of individualizing the patients' doses was explored, based on individual radiosensitivities measured by SF2, so that every patient had the same low (5%) value of NTCP. RESULTS: It was found that a significant gain (up to around 30%) in tumour control probability (TCP) was predicted for the population when the doses were individualized using a predictive assay result strongly correlated with NTCP. A greater gain in TCP was predicted when each of the individuals were assumed to have a higher sensitivity and the distribution of radiosensitivity in the population was widened to compensate. The gain in TCP was less (around 20%) when considering less-sensitive patients and a narrower distribution of radiosensitivities. The effect of assay variability and other factors that could affect the predictive power of the assay was simulated. Assay variability and an imperfect correlation between in vitro cell survival and tissue complications, rapidly increased the NTCP for the population when treated with individualized doses. However the individualized doses could be reduced so that NTCP declined to an acceptable level, but in this case the TCP for the population also declined. For example, when the assay variability was half the true variability in SF2, the gain in TCP was reduced to around 6%. Also, the predicted gains in population TCP were higher if tumour and normal tissue radiosensitivity were assumed to be correlated. In this case, and in the absence of assay variability, increases in population TCP of about 50% and 30% were predicted, depending on the assumed relative sensitivities of the individual patients compared with that of the population average. For practical application, the division of the patient population simply into three groups of high, average and low radiosensitivity was also examined. The three groups were treated with different doses and the NTCP for the population was kept below 5%. Although the gain in population TCP was less than that predicted with the full individualization, considerable gains of up to 20% were still predicted. This method of dividing the population was more resilient to assay variability and other factors that may affect complications in patients. The modelling suggests that small improvements in TCP (5-10%) may still be achievable even if the correlation between SF2 and late complications is lower at around - 0.4 to - 0.6, as reported in some clinical series. CONCLUSION: Modelling based on measured distributions of fibroblast radiosensitivity shows that improvements in tumour control rates may be achievable through the individualization of radiotherapy dose prescriptions of cancer patients, when assay variability is less than about 50% of the true variability in radiosensitivity, and with greater benefits if tumour and normal tissue radiosensitivity are correlated. Tripartite stratification of the population proved to be less sensitive to assay uncertainty, and can provide most of the benefits of the full individualization.

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