Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol.

Our previous report on pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH) examined the biopersistence potential of its metabolites based on data published from single inhalation and occupational 6:2 FTOH exposure studies. We calculated internal exposure estimates of three key metabolites of 6:2 FTOH, of which 5:3 fluorotelomer carboxylic acid (5:3 acid) had the highest internal exposure and the slowest clearance. No oral repeated 6:2 FTOH exposure data were available at the time to fully characterize the biopersistence potential of the metabolite 5:3 acid. We recently received additional data on 6:2 FTOH and 5:3 acid, which included a 90-day toxicokinetic study report on repeated oral 6:2 FTOH exposure to rats. We reviewed the study and analyzed the reported 5:3 acid concentrations in plasma, liver, and fat using one-compartment PK modeling and calculated elimination rate constants (kel), elimination half-lives (t1/2) and times to steady state (tss) of 5:3 acid at three 6:2 FTOH doses. Our results showed that tss of 5:3 acid in plasma and evaluated tissues were approximately close to 1 year, such that the majority of highest values were observed at the lowest 6:2 FTOH dose, indicating its association with the biopersistence of 6:2 FTOH. The results of our PK analysis are the first to characterize biopersistence potential of the 5:3 acid after repeated oral exposure to the parent compound 6:2 FTOH based on steady state PK parameters, and therefore, may have an impact on future study designs when conducting toxicity assays for such compounds.

On the application of Nafion membrane for the preparation of (90)Y skin patches, quality control, and biological evaluation for treatment of superficial tumors.

This article describes the preparation, quality control, and biological evaluation of (90)Y-skin patches based on Nafion(®) membrane as a viable treatment modality for superficial skin tumors such as melanoma. To arrive at the conditions for optimum uptake of (90)Y on the membrane, influence of various experimental parameters, such as pH of the feed solution, inactive yttrium carrier concentration, reaction volume, contact time, and temperature, was systematically investigated. Under the optimized conditions, >95% of the (90)Y activity (37-185 MBq) could be incorporated in the Nafion membranes to prepare (90)Y-skin patches. Quality control tests were carried out to ensure nonleachability, uniform distribution of activity, and stability of the (90)Y-patches. Mice bearing transplanted melanoma tumors that were treated with two doses of 74 MBq (90)Y-Nafion membrane sources showed complete tumor regression. Histopathological examination of the treated area showed absence of tumor. The results of the study indicate the potential of (90)Y-Nafion membrane sources for treatment of superficial skin tumors.

Toxic alveolitis after inhalation of a water repellent.

Inhalation of fluorocarbon polymers can cause pulmonary toxicity. Although multiple cases of lung injury have been reported, cellular characterization of the associated alveolitis occurring acutely after inhalation is limited. We report the case of a previously healthy woman who presented at our Emergency Department with an acute pneumonitis following inhalation of a fluorocarbon polymer-based rain-proofing spray. Bronchoalveolar lavage (BAL) performed shortly after the presentation showed an elevated total cell count, with a high proportion of neutrophils (58%) and eosinophils (9%). In addition, a lipid stain (Oil-Red-O-stain) showed a high level of lipid laden macrophages, a marker that could reflect a direct toxic effect of the spray on alveolar cells. The patient made a full recovery after four days of in-hospital observation with supportive care.

Evaluation of barrier creams against sulphur mustard: (II) In vivo and in vitro studies using the domestic white pig.

Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinated polymers, are effective against the chemical warfare agent sulphur mustard (SM) when evaluated using human skin in vitro. The purpose of this follow-up study was to further evaluate three candidate (perfluorinated) barrier creams against SM (vapour) using the domestic white pig. The severity and progression of the resulting skin lesions were quantified daily for three weeks post-exposure using biophysical measurements of transepidermal water loss (TEWL) and skin reflectance spectroscopy (SRS). Skin biopsies obtained post-mortem were evaluated by light microscopy and additional skin samples were obtained from adjacent (unexposed) skin sites for a comparative in vitro skin absorption study. Samples of SM vapour within the dosing chambers were measured ex vivo to ascertain the exposure dose (Ct). The three creams were highly effective against SM in vivo (Ct approximately 5000 mg.min.m(-3)): After 3 weeks, barrier cream pre-treated sites were not significantly different from control (unexposed) skin when evaluated by TEWL, SRS or histology. In contrast, skin exposed to SM without pre-treatment showed evidence of persistent damage that was consistent with the slow healing time observed in humans. The amount of SM absorbed in vitro in untreated pig skin was similar to that required to cause comparable lesions in human skin (8-20 and 4-10 microg.cm(-2), respectively), further validating the use of pigs as a toxicologically-relevant dermal model for SM exposure.

Use of perfluorocarbon (fluorinert) to enhance reporter gene expression following intratracheal instillation into the lungs of Balb/c mice: implications for nebulized delivery of plasmids.

Perfluorocarbons combine high respiratory gas dissolving capabilities with extreme chemical and biological inertness and therefore offer an attractive option as an excipient in the area of pulmonary therapeutics. Perfluorocarbons have also been shown to "float" mucus, because of their high densities (1.9-2.5 g/mL), which may hold potential in gene delivery for cystic fibrosis patients, in terms of enhancing penetration through highly viscous mucus and thereby providing access to target epithelial cells to correct the gene defect. Additionally, their low surface tension allows for better dispersion. A commonly available perflurocarbon, heptacosafluorotributylamine (Fluorinert), was used to deliver either plasmid DNA (pDNA) alone or cationic-lipid-complexed plasmid DNA to the lungs of Balb/c mice by direct intratracheal instillation. The complexes consisted of supercoiled (SC) plasmid DNA (4.7 Kb, 0.625 mg/mL) and lipid (ethyldimyristoyl phosphatidylcholine [EDMPC]/cholesterol [1:1 mole ratio], with pDNA (3:1 mg pDNA/mM EDMPC in 20 mM Tris-HCl pH 8.0) expressing chloramphenicol acetyl transferase (CAT) or beta-galactosidase (beta-Gal). pDNA alone was supplemented with 14% w/v Fluorinert. Cationic lipid/pDNA complexes were supplemented with 3, 8, and 14% w/v Fluorinert. Results showed that the CAT expression from pDNA alone was enhanced 24 x using 14% w/v Fluorinert, whereas that from the cationic-lipid-formulated pDNA was enhanced 7 x using 14% w/v Fluorinert. Immunohistochemistry showed that beta-Gal expression was primarily from epithelial cells and not from F4/80 or MAC3 antigen-stained cells (predominantly macrophages), indicating efficient delivery.

Mist particle diameters are related to the toxicity of waterproofing sprays: comparison between toxic and non-toxic products.

Although respiratory failures following exposure to waterproofing sprays have been reported worldwide, their mechanism remains unknown. In this study, we sorted each of 12 commercial waterproofing sprays into either the Toxic Group (No 1-4) or the Non-Toxic Group (No 5-12) and compared the pathological changes produced in the lungs of mice after their inhalation. Then we determined the diameters of each product's mist particles and their adhesion rates to cloth. The 4 products in the Toxic Group, reported as toxic to human beings, caused severe damage to mice lungs, whereas the 8 products in the Non-Toxic Group, not reported as toxic, caused little if any damage. The percentage of particle < or = 10 microns were significantly higher in the Toxic Group than in the Non-Toxic Group. The adhesion rate to cloth correlated to the mean particle diameter and was significantly lower in the Toxic Group than in the Non-Toxic Group. The toxic sprays generated mists of smaller particle diameter than the non-toxic sprays, suggesting that the mist particle diameters of waterproofing sprays are related to their toxicity.

Primary vesicoureteric reflux: treatment with subureteric injection of Polytef paste.

A series of 34 children with 40 primary refluxing ureters were treated endoscopically with a subureteric injection of polytetrafluoroethylene paste (Polytef). The amount injected ranged between 0.1 and 0.8 ml (mean 0.3). A single injection cured the reflux in 26 ureters (65%) and the grade of reflux improved in a further 9 ureters. Seven ureters required a second injection and reflux was cured in 6 of these. The overall cure rate was therefore 80% after the second injection. There was one complication due to self-limiting ureteric obstruction following injection. The procedure is quick, easy to perform and effective. We have some reservations about the long-term efficiency and safety of subureteric Polytef injection in children.

Gaseous exchange and acid-base balance in premature lambs during liquid ventilation since birth.

Nine distressed premature lambs were studied before, during, and after ventilation with fluorocarbon liquid (FC-80). It was found that premature lambs, delivered by cesarean section, could be adequately ventilated with oxygenated liquid for period up to 3 hr. Using fluarocarbon liquid in conjunction with the described liquid breathing system, it was possible to maintain remarkably good pulmonary gas exchange and acid-base balance during normothermic conditions. In addition, peak intratracheal pressures measured during recovery from liquid ventilation were significanly reduced (P is less than 0.001) as compared with preliquid ventilation values. This improvement in lung function is in direct contrast to the deterioration in that of the adult animal following liquid ventilation as reported previously.

Liquid ventilation of primates.

Three adult monkeys were anesthetized with ketamine and ventilated with fluorocarbon liquid [perfluoro bis (1, 4-isopropoxy) butane (Caroxin-D)] at 1 atmosphere on two separate occasions. During five runs, liquid ventilation was continued for 60 minutes. The sixth run was continued for ten minutes. Arterial blood gas levels during and after liquid ventilation were adequate for survival. Three years after the first period of liquid ventilation, the animals were killed. Approximately 0.001 mg of fluorocarbon per gram of tissue was present in the kidney, liver, brain, spleen, muscle, and heart. Fat contained approximately seven to nine times this amount, and the lung and pulmonary lymph nodes contained approximately 1,000 times this amount. In no case was it clinically evident that the monkeys had undergone periods of liquid ventilation. We conclude that primates can be ventilated successfully with liquid fluorocarbon on at least two separate occasions and can return to breathing air without obvious deleterious effects, but fluorocarbon is retained in small amounts for at least three years.

Evaluation of fluorochemicals for liquid membrane oxygenation.

An attempt is being made to develop an oxygenator utilizing gaseous oxygen bubbles completely encapsulated with fluorochemical, thereby avoiding the detrimental changes induced by a blood-gas interface. After the feasibility of this method of oxygenation had been proved, the biocompatibility of the fluorochemicals was investigated. No significant changes in human red blood cells, fibrinogen, or platelets were induced by chronic in vitro contact with fluorochemical over a 24-hour peroid. There is no evidence that the fluorochemicals tested extract lipids from plasma. A device which allowed continuous formation of a blood-fluorochemical interface was utilized in vitro with human blood and in vivo with dogs. No significant alterations were induced by fluorochemicals in the human or animal blood or in the canine organs at autopsy. A prototype oxygenator is now undergoing evaluation. A method of analyzing for fluorochemical in blood and other protein solutions is presented.

Perfluorocarbons having a short dwell time in the liver.

Perfluorinated organic liquids are useful as high capacity oxygen and carbon dioxide solvents. After intravenous infusion most of these perfluorinated emulsions are deposited in the liver and spleen in a matter of days, where they remain for the lifetime of the animal. Hence, while they may be useful as isolated organ perfusion media their value as artificial blood is limited. A family of perfluorocarbons has now been discovered, which, although deposited in the liver after circulation in the blood, leave the liver to be excreted via the lungs and skin in a matter of days without apparent harmn to the animal.