An assessment of beclomethasone dipropionate clathrate formation in a model suspension metered dose inhaler.

The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and changes in surface energy after size reduction (micronization) were determined. Although CFC-11 has largely been phased out of use in pMDIs due to its ozone depletion potential, the BDP CFC-11 clathrate is a stable entity and thus suitable as a model for our initial investigations. In addition, although propellant clathrates have been known for sometime, as far as the authors are aware, their surface energies and adhesive interactions have not been reported. The structure of the clathrate was investigated using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (X-RPD). In addition, atomic force microscopy (AFM) was employed to determine the dispersive surface free energy (SE) and force of adhesion (F(adh)) of the BDP CFC-11 clathrate with different pMDI components in a model propellant (decafluoropentane). The dispersive surface free energies for anhydrous BDP (micronized), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are (47.5+/-4.9) mJ m(-2), (11.3+/-4.1) mJ m(-2) and (15.2+/-1.3) mJ m(-2) respectively. Force of adhesion results shows that BDP CFC-11 clathrates, even after being ball-milled for 2.5h, have a lower F(adh) compared to micronized anhydrous BDP with different pMDI components. This shows that the formation of the crystalline CFC-11 clathrate is advantageous when compared to the micronized anhydrous form, in terms of its surface energy and potential interactions within a suspension MDI formulation. In the wider context, this work has implications for the future development of HFA formulations with APIs which are prone to the formation of propellant clathrates.

Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling.

Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.

An overview of the risk assessment of hazardous materials and the role of toxicology.

The chemical risk assessment process and the need for health-based approaches to identify and characterize potential hazardous substances will be discussed. The risk assessment process can be applied to both workplace and environmental settings. Toxicology will be defined and related to the risk assessment process. A brief overview of toxicity screens and tests will be presented in order to help make toxicity data more meaningful. Toxicity data for Halon 1301 replacements and trichloroethylene (TCE) will be presented as examples. The paper will conclude with a description of tri-service toxicology; what it is and what this laboratory provides to the Department of Defense (DOD), industry, and academia.

Synthesis and analysis of mixed chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans and assessment of formation and occurrence of the fluorinated and chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans.

Various mixtures of chlorinated-fluorinated dibenzodioxins (PCFDD), dibenzofurans (PCFDF) and biphenyls (PCFB) were synthesized. For trace analysis, we compared the behavior of PCFDD/PCFDF and chlorinated congeners in extraction, enrichment and clean-up steps. To establish GC/MS analysis, various columns were tested, temperature programs were optimized and for MS-identification specific masses were selected from the mass spectra. To evaluate the possibility of formation of these compounds in thermal processes, samples from the aluminum-producing industry and products of pyrolysis of chlorofluoro- hydrocarbons (FCKW) on a laboratory scale were analyzed. At present, the most important potential sources of fluorinated or mixed chlorinated-fluorinated dioxins, furans and biphenyls - combustion processes and large scale chemical production - do not cause significant environmental contamination at least in the areas considered. However, in a sample of filter dust from the refining process of aluminum using freon 12 we found high amounts (4.5 g/kg !) of chlorinated and chlorinated-fluorinated aromatic compounds including chlorinated-fluorinated dibenzofurans and biphenyls. Since the FCKW ban in Europe, this procedure was modified in 1992, replacing freon 12 by a mixture of chlorine and argon. The PFDD/PFDF concentration in the fluorophenols was between 0.45 and 120 micrograms/kg. The fluorobenzenes analyzed contained between 15 and 70 mg/kg fluorinated biphenyls.

Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes.

BACKGROUND: Water chlorination has been one of the major disease prevention treatments of this century. While epidemiologic studies suggest an association between cancer in humans and consumption of chlorination byproducts in drinking water, these studies have not been adequate to draw definite conclusions about the carcinogenic potential of the individual byproducts. PURPOSE: The purpose of this study was to investigate the carcinogenic potential of chlorinated or chloraminated drinking water and of four organic trihalomethane byproducts of chlorination (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) in rats and mice. METHODS: Bromodichloromethane, chlorodibromomethane, bromoform, chlorine, or chloramine was administered to both sexes of F344/N rats and (C57BL/6 x C3H)F1 mice (hereafter called B6C3F1 mice). Chloroform was given to both sexes of Osborne-Mendel rats and B6C3F1 mice. Chlorine or chloramine was administered daily in the drinking water for 2 years at doses ranging from 0.05 to 0.3 mmol/kg per day. The trihalomethanes were administered by gavage in corn oil at doses ranging from 0.15 to 4.0 mmol/kg per day for 2 years, with the exception of chloroform, which was given for 78 weeks. RESULTS: The trihalomethanes were carcinogenic in the liver, kidney, and/or intestine of rodents. There was equivocal evidence for carcinogenicity in female rats that received chlorinated or chloraminated drinking water; this evidence was based on a marginal increase in the incidence of mononuclear cell leukemia. Rodents were generally exposed to lower doses of chlorine and chloramine than to the trihalomethanes, but the doses in these studies were the maximum that the animals would consume in the drinking water. The highest doses used in the chlorine and chloramine studies were equivalent to a daily gavage dose of bromodichloromethane that induced neoplasms of the large intestine in rats. In contrast to the results with the trihalomethanes, administration of chlorine or chloramine did not cause a clear carcinogenic response in rats or mice after long-term exposure. CONCLUSION: These results suggest that organic byproducts of chlorination are the chemicals of greatest concern in assessment of the carcinogenic potential of chlorinated drinking water.

Assessment of the reproductive toxicology of bromochlorodifluoromethane (BCF, halon 1211) in the rat.

The effect of bromochlorodifluoromethane (BCF) on reproduction in the rat has been investigated in two studies. Pregnant female rats were exposed by inhalation to 1000, 10,000, or 50,000 ppm BCF for six hours a day on days six to 15 of gestation (day of mating = day 0). Exposure to 50,000 ppm BCF caused a reduction in maternal weight gain over the exposure period but there was no evidence of either teratogenicity or embryo/fetotoxicity at any concentration. In a study designed to assess the potential effect of BCF during a complete reproductive cycle male and female rats were exposed to 5000 ppm or 25,000 ppm BCF for six hours a day for five days a week for 10 weeks (males) or three weeks (females) before mating. Exposure to BCF continued during mating and up to day 20 of gestation for half the females which were subsequently allowed to litter and the development of their offspring monitored. The remaining females were removed from exposure to BCF after mating and killed on day 20 of gestation for examination of their uterine contents. There were no effects on adult fertility, pup numbers, survival, or pup development. It was concluded that BCF had no reproductive toxicity potential in the rat.

Pulmonary blood flow and tissue volume. Assessment of a non-invasive technique of measurement.

Pulmonary blood flow and tissue have been measured by a rebreathing technique in which the disappearance of soluble and insoluble gases from an inhaled mixture is followed continuously using a respiratory mass spectrometer. Although measurements made with diethyl ether are more reproducible than those made with freon-22, they are inaccurate because ether (the more soluble gas) is taken up by the tissues surrounding the respiratory dead space. Experiments carried out on four normal subjects demonstrate that measurements of both pulmonary blood flow and tissue volume are influenced by the volume of gas in the lungs during the manoeuvre. Possible reasons for this are discussed and an exponential relationship between the two variables and lung volume is suggested.