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Amniotic fluid contains heterogeneous cell types and has become an interesting source for obtaining fetal stem cells. These stem cells have a high proliferative capacity and a good differentiation potential and may thus be suitable for regenerative medicine. As there is increasing evidence, that these stem cells are also able to be directed into the neural lineage, in our study we investigated the neuronal and glial differentiation potential of these cells, so that they may also be applied to cure degenerative diseases of the retina. Mesenchymal stem cells were isolated from routine prenatal amniocentesis at 15 to 18 weeks of pregnancy of human amniotic fluid and expanded in the cell culture. Cells were cultivated according to standard procedures for mesenchymal stem cells and were differentiated along the neural lineage using various protocols. Furthermore, it was also tried to direct them into cell types of the retina as well as into endothelial cells. Cells of more than 72 amniotic fluid samples were collected and characterized. While after induction neural-like phenotypes could actually be detected, which was confirmed using neural marker proteins such as GFAP and ßIII tubulina further differentiation into retinal like cells could not reliably be shown. These data suggest that amniotic fluid derived cells are an interesting cell source, which may also give rise to neural-like cells. However, a more specific differentiation into neuronal and glial cells could not unequivocally be shown, so that further investigations have to becarried out.

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Mesenchymal stem cells are regarded as common cellular precursors of the musculoskeletal tissue and are responsible for tissue regeneration in the course of musculoskeletal disorders. In equine veterinary medicine extracorporeal shock wave therapy (ESWT) is used to optimize healing processes of bone, tendon and cartilage. Nevertheless, little is known about the effects of the shock waves on cells and tissues. Thus, the aim of this study was to investigate the influence of focused ESWT on the viability, proliferation, and differentiation capacity of adipose tissue-derived mesenchymal stem cells (ASCs) and to explore its effects on gap junctional communication and the activation of signalling cascades associated with cell proliferation and differentiation. ASCs were treated with different pulses of focused ESWT. Treated cells showed increased proliferation and expression of Cx43, as detected by means of qRT-PCR, histological staining, immunocytochemistry and western blot. At the same time, cells responded to ESWT by significant activation (phosphorylation) of Erk1/2, detected in western blots. No significant effects on the differentiation potential of the ASCs were evident. Taken together, the present results show significant effects of shock waves on stem cells in vitro.

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Amniotic fluid (AF) has become an interesting source of fetal stem cells. However, AF contains heterogeneous and multiple, partially differentiated cell types. After isolation from the amniotic fluid, cells were characterized regarding their morphology and growth dynamics. They were sorted by magnetic associated cell sorting using the surface marker CD 117. In order to show stem cell characteristics such as pluripotency and to evaluate a possible therapeutic application of these cells, AF fluid-derived stem cells were differentiated along the adipogenic, osteogenic, and chondrogenic as well as the neuronal lineage under hypoxic conditions. Our findings reveal that magnetic associated cell sorting (MACS) does not markedly influence growth characteristics as demonstrated by the generation doubling time. There was, however, an effect regarding an altered adipogenic, osteogenic, and chondrogenic differentiation capacity in the selected cell fraction. In contrast, in the unselected cell population neuronal differentiation is enhanced.

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Adipose-derived stromal cells (ADSCs) are multipotent cells which, in the presence of appropriate stimuli, can differentiate into various lineages such as the osteogenic, adipogenic and chondrogenic. In this study, we investigated the effect of transforming growth factor beta 1 (TGF-ß1) in comparison to hydrolyzed fish collagen in terms of the chondrogenic differentiation potential of ADSCs. ADSCs were isolated from subcutaneous fat of horses by liposuction. Chondrogenesis was investigated using a pellet culture system. The differentiation medium was either supplemented with TGF-ß1 (5 ng/ml) or fish collagen (0.5 mg/ml) for a 3 week period. After the 3 weeks in vitro differentiation, RT-PCR and histological staining for proteoglycan synthesis and type II collagen were performed to evaluate the degree of chondrogenic differentiation and the formation of cartilaginous extracellular matrix (ECM). The differentiation of ADSCs induced by TGF-ß1 showed a high expression of glycosaminoglycan (GAG). Histological analysis of cultures stimulated by hydrolyzed fish collagen demonstrated an even higher GAG expression than cultures stimulated under standard conditions by TGF-ß1. The expression of cartilage-specific type II collagen and Sox9 was about the same in both stimulated cultures. In this study, chondrogenesis was as effectively induced by hydrolyzed fish collagen as it was successfully induced by TGF-ß1. These findings demonstrated that hydrolyzed fish collagen alone has the potential to induce and maintain ADSCs-derived chondrogenesis. These results support the application of ADSCs in equine veterinary tissue engineering, especially for cartilage repair.

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PURPOSE: In the mouse, paternal F0 acute irradiation of Type B spermatogonia produces biological effects in offspring, including altered signalling kinase activities and protein levels. It was hypothesized that these effects represented cellular reprogramming that would alter the response of somatic cells in these offspring to an acute ionizing radiation exposure. MATERIALS AND METHODS: Nineteen-day-old third generation (F3) CD1 mice with and without an acute 1.0 Gy paternal F0 radiation history each received an acute dose of 1.0 Gy from attenuated 137C n-rays. Kidney PKC and MAPK activities, and p53 protein levels were evaluated immediately following F3 irradiation. The same endpoints and DNA damage were evaluated in kidney-derived fibroblast primary cell cultures 3 weeks post-irradiation. RESULTS: Kidneys had significantly decreased PKC and MAPK activities and p53 protein levels related to F0 irradiation and increased PKC and MAPK activities following F3 irradiation irrespective of F0 radiation history. Kidney-derived fibroblasts had significant changes or strong trends for all selected endpoints based upon cross-interaction of F0 radiation history with F3 irradiation. Comet assays demonstrated significantly increased DNA damage in fibroblasts related to F0 irradiation and increased DNA damage following F3 irradiation. However, significantly decreased F3 irradiation damage was demonstrated based upon cross-interaction of F0 radiation. CONCLUSIONS: The data suggest that irradiation of paternal F0 Type B spermatogonia resulted in cellular reprogramming causing offspring with this radiation history to have altered responses to acute somatic n-irradiation.

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We evaluated F3 mouse offspring from paternal F0 attenuated 137Cs gamma-irradiation (1.0 Gy) for heritable effects on gene products that can modulate cell proliferation rate and that may be markers for genomic instability. The F3 generation was selected for evaluation as a stringent test for heritability of effects from paternal F0 germline irradiation. Male CD1 mice were bred 6 weeks after irradiation so that the fertilizing sperm were type B spermatogonia at the time of irradiation. The resulting F1 males were bred to CD1 females to produce F2 four-cell embryos. The F2 embryos with a radiation history were paired with 'control' CD1 four-cell embryos that were heterozygous for the neo transgene. These F2 XY-XY chimeras, consisting of cells derived from both an embryo with a paternal F0 radiation history and a control embryo, were transferred to foster mothers, raised to adulthood and bred to produce F3 offspring. F3 offspring were evaluated for hepatic activities of receptor tyrosine kinase, protein kinase C and MAP kinase and for protein levels of nuclear p53 and p21(waf1). All three protein kinase activities were altered and nuclear levels of p53 and p21(waf1) protein were higher in the group of offspring that included F3 offspring with a paternal F0 radiation history than in littermates in the neo-positive control group. To our knowledge, this is the first observation in the descendants of paternal germline irradiation of effects on signal protein kinase activities and downstream nuclear target proteins that can influence cell proliferation rates.

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The transportation of critically ill patients requiring mechanical ventilation is recognized as a high-risk and expensive procedure. Approaches have included using manual bag-type valve resuscitators and expensive portable transport ventilators. This study evaluated the effectiveness of the inexpensive portable RespirTech PRO (RTP) gas-powered automatic resuscitator during intrahospital transport of critically ill mechanically ventilated patients. Twenty medical intensive care patients on stable mechanical ventilator settings had arterial blood gas and vital sign determination before routine transport out of the intensive care unit (ICU). Repeat measurements were made during transport approximately 30 minutes after being placed on the RTP portable pressure-cycled automatic resuscitator using an FiO2 of 100%. During use of the RTP for transport, there were no statistically significant variations observed in mean arterial blood pressure [82 +/- 11 SD (range 65 to 112) mm Hg before transport versus 85 +/- 14 SD (range 59 to 110) mm Hg during transport], heart rate [94 +/- 16 SD (range 74 to 127) beats/min) before versus 96 +/- 17 SD (range 69 to 132) beats/min during], arterial pH [7.41 +/- 0.07 SD (range 7.31 to 7.58) before versus 7.42 +/- 0.05 SD (range 7.37 to 7.52) during], and PaCO2 [43 +/- 10 SD (range 26 to 65) mm Hg before versus 43 +/- 10 SD (range 27 to 61 mm Hg) during]. Because the FiO2 before transport was 63 +/- 26 SD (range 30% to 100%) versus 100% during transport using the RTP, the mean PaO2 was significantly increased from 124 +/- 86 SD (range 57 to 367) mm Hg before transport to 297 +/- 168 SD (range 65 to 537) mm Hg during (P< .001). No transportation associated clinical adverse events were noted. Several previous investigations have shown that portable ventilators are safe and effective in intrahospital transport of mechanically ventilated patients. This study showed that the portable pressure-cycled RTP also allows safe transportation of mechanically ventilated ICU patients. By analogy, the RTP is potentially useful as an automatic resuscitator for emergency medical care. This RTP is a disposable resuscitator/ventilator device that provides an inexpensive alternative for transporting ventilator-dependent patients.

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In this study, the mouse was used to evaluate paternal germline exposure to the organophosphate methamidophos for its potential to produce adverse effects on spermatozoa and in the offspring. There have been reports that organophosphate exposure can increase abnormal sperm morphology in mice. However, effects transmitted to the offspring following paternal exposure have not been reported previously. The maximum tolerated dose (MTD) was 7.5 mg kg(-1) body weight and this dose resulted in no deaths, although blood plasma cholinesterase activity was still decreased. Males were euthanized 4 weeks after an acute intraperitoneal injection of methamidophos (0.5, 3.75, 5.0, and 7.5 mg kg(-1) body wt) and the number of spermatids per gram testes and sperm morphology were analyzed. In this study, abnormal sperm morphology on a per group basis exhibited a dose-response significantly related to increased methamidophos exposure as indicated by regression analysis and a nested ANOVA (p < 0.0001). Preimplantation embryos that were conceived 6 weeks after paternal methamidophos exposure (5 mg kg(-1) body wt) exhibited a significant increase in cleavage arrest. Fertility of males was also affected as shown by a decrease in the number of two- to four-cell embryos per male (postexposure week 6) and an increase in the number of degenerated embryos (postexposure weeks 4-6). We conclude that methamidophos may have the potential to produce transmissible adverse embryonic effects following an acute paternal germline exposure.

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BACKGROUND: Various studies have demonstrated the benefits of continuous nebulization therapy for delivering aerosols of the beta2 agonists such as terbutaline sulfate or albuterol sulfate to patients with severe asthma and/or impending respiratory failure. OBJECTIVE: The purpose of this investigation was to explicate the operational factors associated with the use of nebulizers for extended aerosol respiratory therapy including those factors that affect the prescribed aerosol dosages and the relationship to actual delivery of prescribed drugs to the respiratory airways of the lungs of a patient under treatment conditions. METHODS: Operational characteristics and methods have been investigated for use of long-running nebulizers for continuous nebulization therapy. Factors considered were particle size distribution, setup conditions, aerosolization concentrations and rates, delivery fraction of aerosol reaching patient, and changes in medication concentration during extended operation. With a large volume nebulizer, aerosols can be delivered to the patient without dilution via a standard open mask for up to eight hours without refill. The pneumatic HEART nebulizer with 240 mL reservoir was evaluated. RESULTS: The nebulizer was operated from a single compressed air or oxygen source and found to provide from 10 to 15 L/min of aerosol with 38 to 50 microL of aerosolized medicine per liter of air (or oxygen) and utilize from 30 to 56 mL/hour of medicinal liquid. The mass median aerodynamic diameter of the aerosol droplets was found to be about 2.0 microm (sigma(g) = 2.7). Delivery efficiency to the patient mask was about 90%. The aerosolized medicine delivered to the patient can be increased by adjusting the flow rate of the gas source or changing the solution concentration of medicine. Typically, several milligrams of drug can be delivered to the patient as inhaled aerosol per hour of treatment of which about one-quarter can be expected to be deposited in the lungs. During eight hours of operation the concentration of medicinal solution increased by about a factor of two because of water evaporation. CONCLUSIONS: Continuous nebulization therapy is an important means of treating patients with severe asthma. Dosage criteria can be established based on the operating characteristics of the nebulizer system, drug solution concentration, and patient respiration.

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PURPOSE: The potential use of aerosol delivery for non-viral gene therapy was tested by nebulization of lipid:DNA complexes to the lungs of rhesus monkeys. METHODS: Four female rhesus monkeys were dosed with lipid:DNA formulations via aerosol inhalation, where the DNA coded for the human Cystic Fibrosis Transmembrane Conductance Regulator (hCFTR) protein. Delivery of DNA was determined in lung samples by polymerase chain reaction (PCR) by qualitative and quantitative methods. Transgene specific messenger RNA was measured by reverse transcriptase PCR (RT-PCR) and protein expression and localization were evaluated by immunohistochemistry (IHC). RESULTS: Approximately four mg of DNA, complexed with cationic lipid 1.2-dimyristoyl-sn-glycero-3-ethylphosphatidylcholine (EDMPC) and cholesterol were delivered to the lungs of animals by airjet nebulizer. Three days after dosing, tissue samples from the lung were collected and shown to have vector specific DNA, RNA and the presence of CFFR protein. Specifically, the hCFTR protein was distributed widely, although non-uniformly, throughout airway epithelium being located on the apical surface of epithelial cells. Importantly, no adverse clinical effects were observed and the lungs showed no histological abnormalities or signs of acute inflammation. CONCLUSIONS: This study shows that lipid:DNA formulations based on EDMPC and cholesterol can be administered to primates by nebulization resulting in measurable expression of the hCFTR protein. The absence of inflammation is also encouraging and such systems may have utility for delivery of genes to the lungs for the treatment of a variety of pulmonary diseases including cystic fibrosis.

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Previous studies suggest that the spermatozoa from acutely irradiated male mice exhibit a reduced fertilization rate in vitro with the maximum decrease occurring for spermatozoa produced 6 weeks after irradiation (Y. Matsuda et al., Mutation Res. 142 (1985) 59-63). We have found that spermatozoa from unirradiated F1 males conceived 6 weeks after paternal F0 irradiation also exhibit a significantly reduced fertilization rate in vitro. After acute 137Cs gamma-irradiation yielding an absorbed dose of 1.0 Gy, adult CD1 F0 male mice were mated at weekly intervals with unirradiated female CD1 mice. Unirradiated adult males from F1 litters conceived 5 and 6 weeks after paternal F0 irradiation were allowed to mature. Their epididymal spermatozoa were evaluated for in vitro fertilization rates using oocytes from unirradiated 8-12-week-old CD1 females. The mean fertilization rate for spermatozoa from F1 males conceived 5 weeks after paternal F0 irradiation (80.74 +/- 15.74 SD %, n = 5) did not differ significantly from the control fertilization rate (89.40 +/- 10.94 SD %, n = 8). However, the fertilization rate for spermatozoa from F1 males conceived 6 weeks after paternal F0 irradiation (56.14 +/- 21.93 SD %, n = 5) was significantly less than the fertilization rate for control spermatozoa (p < 0.006) or for that of the F1 males conceived 5 weeks after paternal F0 irradiation (p < 0.04). These data suggest that spermatozoa obtained 6 weeks after paternal F0 irradiation can transmit a decrease in fertilization rate to the F1 generation males as well as exhibit decreased fertilization rate themselves when tested directly in vitro.

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Irradiation of male F0 mice 6 to 7 weeks prior to mating causes significant changes in the proliferation of F1 and F2 embryonic cells. These changes are revealed as a competitive cell proliferation disadvantage in chimera assays when the affected embryo is paired with a normal embryo in an aggregation chimera. This effect has been observed previously to be transmitted to F1 embryos for absorbed doses from 0.01 to 1.0 Gy; 0.01 Gy is about 100-fold lower than detectable using conventional germline mutation assays. However, until now there has been no reported cross-generation heritability. We now report that this competitive cell proliferation disadvantage persists without degradation in the F2 generation of embryos when F0 males received 1.0 Gy from gamma irradiation 6 and 7 weeks prior to conception of F1 males.

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This study was conducted to test the hypothesis that a nuclear target is involved in the embryonic cell proliferation disadvantage transmitted by irradiated mouse oocytes and detected by the chimera assay. In this assay, the cells from the irradiated embryo exhibit a competitive cell proliferation disadvantage when they are challenged by direct cell-cell contact with cells from a normal embryo in an aggregation chimera. Here, six pregnant CD-1 mice received a total of 1.85 TBq tritiated thymidine (TdR) delivered by multiple intraperitoneal injections during days 13-15 postconception. Six more pregnant mice were sham-injected to provide control embryos. Sixty randomly selected female progeny were mated at 47 days of age and their 4-cell embryos tested in the chimera assay. The mean proliferation ratio (PR, number of cells from the experimental embryo divided by total cell number of the chimera) for experimental chimeras was 0.45 +/- 0.02 SE (n = 43), which was significantly less than the mean PR of 0.49 +/- 0.01 SE (n = 47; p = 0.02) for control chimeras. This entire experiment was repeated, with similar results. A comparison for TdR confined to the nucleus (i.e., mean beta-ray range is only 0.7 microm) with the relationship for uniform irradiation by 137Cs gamma-rays demonstrates that these two very different modes of dose delivery produce essentially identical PRs. These results in vivo suggest a nuclear DNA target for embryonic cell proliferation disadvantage consistent with our previous findings in vitro.

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In this study, the safety and efficacy of aerosol delivery to non-human primates of an adenoviral vector encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) were evaluated. The technique of concurrent flow spirometry was used to determine the deposited dose of Ad2/CFTR-2, which ranged from 3 to 8 x 10(10) I.U. Transgene DNA was detected by the polymerase chain reaction (PCR) in lung tissue from all treated animals, and human CFTR mRNA was detected on days 3, 7, and 21 post-exposure. The treatment was well tolerated, with no evidence of respiratory distress. Histologic changes in the lungs from Ad2/CFTR-2-treated animals were mild and, overall, indistinguishable from animals exposed to aerosolized vehicle. One vector-treated animal demonstrated an increase in lavage lymphocyte numbers 3 days after treatment and another had an abnormal chest radiograph 14 days after treatment. A third vector-treated animal had histologic evidence of a bronchointerstitial pneumonia 7 days after aerosol treatment that resolved by day 21. This study demonstrated that Ad2/CFTR-2 can effectively be delivered to the lungs of nonhuman primates and result in minimal adverse effects.

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A previous study using the mouse-preimplantation-embryo-chimera assay demonstrated a reproducible transmitted effect (proliferation disadvantage observed in early embryos) from females irradiated as 49-day-old adults using 0.15 Gy of gamma rays and then mated seven weeks later, i.e., embryos were from oocytes that were immature at time of irradiation. Because mouse immature oocytes are known to be much more radiosensitive to cell killing in juveniles than in adults, a follow-on study was performed here using 14-day-old juvenile mice. In contrast to adults, the exposure of juveniles to 0.15 Gy of gamma rays did not result in a detectable transmitted proliferation disadvantage when animals were mated 7 or 12 weeks later. This observation is discussed in light of previous studies on mouse immature oocytes and embryo chimeras.

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The Farallon Islands Nuclear Waste Dump Site (FINWDS), approximately 30 miles west of San Francisco, California, received at least 500 TBq encapsulated in more than 47,500 containers from approximately 1945 to 1970. During several seasons in 1986/87 deep-sea bottom feeding fishes (Dover sole = Microstomus pacificus; sablefish = Anoplopoma fimbria; thornyheads = Sebastolobus spp.) and intertidal mussels (Mytilus californianus) were collected from the vicinity of the FINWDS and from comparable depths at a reference site near Point Arena, CA. Tissues were analyzed for several radionuclides (137Cs, 238Pu, 239+240Pu, and 241Am). Radionuclide concentrations for fish mussel tissue ranged from non-detectable to 4,340 mBq kg(-1) wet weight, with the following means for Farallon fishes: 137Cs = 1,110 mBq kg(-1); 238Pu = 390 mBq kg(-1); 239+240Pu = 130 mBq kg(-1); and 241Am = 1,350 mBq kg(-1). There were no statistically significant differences in the radionuclide concentrations observed in samples from the Farallon Islands compared to reference samples from Point Arena, CA. Concentrations of both 238Pu and 241Am in fish tissues (from both sites) were notably higher than those reported in literature from any other sites world-wide, including potentially contaminated sites. Concentrations of 239+24OPu from both sites were typical of low values found at some contaminated sites worldwide. These results show approximately 10 times higher concentrations of 239+240Pu and approximately 40-50 times higher concentrations of 238Pu than those values reported for identical fish species from 1977 collections at the FINWDS. Radionuclide concentrations were converted to a hypothetical per capita annual radionuclide intake for adults, yielding the following values of annual Committed Effective Dose Equivalent (CEDE) from ionizing radiation emitted from these radionuclides: 0.000 mSv y(-1) for 137Cs, 0.009 mSv Y(-1) for 228Pu, and 0.003 mSv y(-1) for 239+240Pu. For 241Am, projected CEDE for Dover sole, sablefish, and thornyheads were higher, averaging 0.03 mSv y(-1). The observed isotopic ratio of 238Pu/239+240Pu was about 4 (which is two orders of magnitude higher than the ratio of 0.03 associated with fallout from weapons tests and accidental releases in the north temperate zone of the earth), indicating a considerably higher environmental mobilization for 238Pu compared to 239+240Pu. Likewise, the observed ratio of 241Am/239+240Pu of about 30 was nearly two orders of magnitude higher than the fallout ratio of 0.43 in the north temperate zone of the earth. The projected ionizing radiation CEDE to people from the ingestion of fish with fallout radionuclides was three times higher for 241Am than from the plutonium isotopes.

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The dose-dependent elimination of formate was investigated in the rat using both in vitro and in vivo systems. The in situ perfused liver was used to define the kinetics of hepatic metabolism and obtain initial in vitro estimates of the hepatic metabolism kinetic parameters. Formate was eliminated from the perfused rat liver following Michaelis-Menten kinetics. Estimates of the Michaelis-Menten parameters obtained from the perfused liver studies were used in a two-compartment pharmacokinetic model of the dose-dependent elimination of formate in vivo. This model consisted of a central, well-mixed compartment and a urine compartment. Other features of the model included (1) endogenous production of formate, (2) Michaelis-Menten hepatic metabolism of formate, and (3) renal excretion consisting primarily of glomerular filtration and saturable tubular reabsorption. A good fit of the model to the observed in vivo data was obtained (overall r2 = 0.978). AR dose dependencies of the data could be adequately fitted using a single set of model parameters. Initial estimates of the Michaelis-Menten parameters, Vmax and Km, obtained from the perfused liver system, were within 40% of the final fitted values of these parameters in the in vivo model, indicating the utility of the perfused liver system for performing in vitro-in vivo correlations.

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A knowledge of the methods used to obtain partition coefficients, Vmax, and Km values, and the use of allometric relationships is essential to understanding their role in physiologically based pharmacokinetic (PBPK) models. Vial equilibration methods for obtaining the partition coefficients of volatile and nonvolatile compounds were presented using the results from studies with p-chlorobenzotrifluoride (PCBTF) and isofenphos, respectively. Partition coefficients for volatile and nonvolatile compounds from published studies were included. Several published in vivo inhalation (gas uptake) studies and in vitro enzyme studies were presented to demonstrate several methods for obtaining Vmax and Km values. Allometric equations used in PBPK models for body weight scaling of respiration and cardiac rates between species were presented along with equations for within species body weight scaling of Vmax.

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Several inhalability curves for nose breathing in humans have been developed. No studies have been designed specifically to develop inhalability functions for animals, although it has been shown that pulmonary deposition of large particles (> 4-5 microns) via inhalation is minimal in laboratory animals [Raabe et al., Inhaled Particles VI, pp. 53-63. Pergamon Press, Oxford (1988)]. The logistic function was fitted to these animal deposition data of Raabe et al. (1988) to estimate an inhalability curve for laboratory animals. The logistic function was also fitted to the human data of Breysse and Swift [Aerosol Sci. Technol. 13, 459-464 (1990)] for comparison. The results suggest that ambient concentration is a good predictor (inhalability > 95%) of inhaled concentration for humans for particles < 11 microns dae. In small laboratory animals, however, the inhalable portion of the ambient concentration is predicted to be 95% for 0.7 microns dae particles but declines to 45% for 10 microns dae particles. It is, therefore, important to consider the effects of inhalability when estimating dose delivered to the target tissue in animals. In comparing delivered doses between animals and humans, adjusting for inhalability may change not only the magnitude of the difference but also which species is predicted to receive a greater delivered dose.

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