Inhalation compounding

Nonetheless, it was not until 1793 that the English scientist and clergyman Joseph Priestley discovered the first modern inhalant compound, the anesthetic gas nitrous oxide. This gas was widely used for recreational purposes by the English aristocracy in private parties, and traveling charlatans expanded... 

The second special case arises from inhalation exposures. Because of the arrangement of the circulatory system, inhaled compounds (and those administered via the buccal route) enter the full range of systemic circulation without any first-pass metabolism by the liver. Kerberle (1971) and O Reilly (1972) have published reviews of absorption, distribution and metabolism that are relevant to acute testing. 

Each situation requires an evaluation of the hypotheses to be tested before the personal monitor can be designed and the identification of the types and duration of exposure that may occur. Once inhaled, the compound may be rapidly metabolized in the body short-term measurements would be appropriate for such processes. The compound may instead have a long residence time at a specific site in the lung or may be stored in an organ or tissue. Thus, the inhaled compound or one or more of its adducts or metabolites could eventually deliver a biologically effective dose to a target organ or cell (13). The monitor must be developed with consideration of the... 

The total surface area of the nasal cavity is about 150 cm2, with the area available for absorption enhanced by the convolutions of the turbinates and the presence of microvilli on the surface of the ciliated and unciliated cells of the respiratory epithelium. The arterial supply of the nose is particularly rich in the respiratory epithelium where the Kiesselbach s plexus lies, an area that is rich in numerous capillary loops. The nasal blood flow has been shown to be sensitive to the action of a variety of inhaled compounds, both locally or systemically acting. Clonidine has been shown to decrease the blood flow whereas histamine and phenylephrine have been shown to induce the converse effect. Such direct changes to blood flow are important in determining the rate and extent of drug absorption from the nasal cavity. 

Gong et al. (1998) assessed the effect of rat strain on susceptibility to anesthesia and convulsions produced by inhaled compounds in five different rat strains. Strain minimally influenced anesthetic and convulsant requirements of inhaled compounds in rats. 

Gong D, Fang Z, Ionescu P et al. (1998) Strain minimally influences anesthetic and convulsant requirements of inhaled compounds in rats. Anesth Analg 87 963-966 Hall RI, Murphy MR, Hug CC (1987) The enfluorane sparing effect of sufentanyl in dogs. Anesthesiol 67 518-525 Ide T, Sakurai Y, Aono M, Nishino T (1998) Minimum alveolar anesthetic concentrations for airway occlusion in cats A new concept of minimum alveolar anesthetic concentration-airway occlusion response. Anaesth Analg 86 191-197... 

The ID50 of aerosolized EA 3580 was calculated to be 8.4 ug/kg, with 95Z confidence limits of 5.8 and 12.2 ug/kg. The time to onset of Incapacitation was about 2 h, and spontaneous recovery from severe effects required about 9 h from their Inception. The effects Induced Inhalation of aerosolized EA 3580 were the same as chose induced by Intramuscular injection of this agent. To judge by comparison of the retained IC50 for the aerosolized material and the ZD50 estimated by Crowell (267) for the Intramuscularly Injected compound, the Inhaled compound seems to have only 46.4Z of the activity of the Injected compound. 

Kharasch ED, Floffman GM,Thorning D, Flan kins DC, Kilty CG. Role of renal cysteine conjugate P-lyase pathway in inhaled compound A nephrotoxicity in rats. Anesthesiology 1998 88 1624-1633. 

In another study, rats were either exposed to hexachlorocyclopentadiene vapors for 1 h, or were dosed orally with " C-hexachlorocyclopentadiene in corn oil. Tissue, urine, and feces samples were analyzed, as well as expired air, to assess the fate and retention time. Approximately 84% of the inhaled compound is retained. Inhaled " C-hexachloro-cyclopentadiene was excreted in the urine orally administered " C-hexachlorocyclopentadiene was eliminated in the feces. In rats exposed by inhalation, the trachea and lung had the highest residue accumulation. In animals receiving oral doses kidneys and liver were major sites of accumulation. These studies indicate that the route of exposure is critical to the pattern of retention and elimination. 

Aliphatic EC5-EC8 Fraction. Studies with humans exposed to vapors of n-hexane indicate that 20-25% of inhaled compound is absorbed and retained (ATSDR 1999b). In studies with rats exposed by inhalation, 12 hours/day for 3 days, to 100 ppm single hydrocarbons in the Ce C10 alkane series in-hexane through n-decane) and a c6-c10 naphthene series (cyclohexane, methylcyclohexane, dimethyl-cyclohexane, trimethylcyclohexane and /-butylcyclohexane), absorption was demonstrated by the measurement of concentrations of hydrocarbons in blood, brain, liver, kidneys, and fat (Zahlsen et al. 1992). Within each series, tissue concentrations (pmol/kg) generally increased with increasing carbon number. 

Hazard Toxic by inhalation compounds are also toxic. Powder form is explosive in air, either dry or wet, with less than 25% water. TLV 0.5 mg/m3. 

Death. The volatility of 1,1,1-trichloroethane, in addition to the rapid and extensive absorption and elimination ofthe inhaled compound, makes acute inhalation in product use situations the most likely lethal exposure scenario in humans. The acute lethal air concentration for human is unknown however, simulations of several lethal exposures suggest that it may be as low as 6,000 ppm (Droz et al. 1982 Jones and Winter 1983 Silverstein 1983). The results of animal studies indicate that the acute lethal exposure concentration decreases substantially with increasing exposure duration. 

The route by which PAHs and other xenobiotics enter the body may determine their fate and organ specificity. For example, an inhaled compound may bypass the first-pass effect of the liver and reach peripheral tissues in concentrations higher than one would see after oral exposures. Enzyme activities among tissues are variable. 

KAROL, M.H. (1992) Occupational asthma and allergic reactions to inhaled compounds, in MILLER, K., TURK, J. NICKLIN, S. (Eds) Principles and Practice of Immunotoxicology, pp. 228-241, Oxford Black well Scientific Publications. 

Dixon et al. (2001) described a preliminary PB-PK model to predict JP-8 concentrations in Air Force fuel-cell maintenance workers. The model used data from PB-PK models of naphthalene inhalation in mice and rats and nonane inhalation in rats. In addition to inhalation, a pathway of dermal exposure and a skin compartment were included. For highly exposed people, the PB-PK model was generally in agreement with exhaled-air naphthalene concentrations however, predictions for the low-exposure scenarios were grossly underestimated, especially in female workers, by a factor of 10. The model did not predict blood and urinary concentrations. The major limitation of the Dixon et al. (2001) study was the lack of appropriate human data (e.g., metabolic measures, blood and tissue partition coefficients, and diffusion rates). The Dixon et al. (2001) model predicted a rapid decline in naphthalene concentrations in all compartments after exposure except liver, fat, and brain. The model predicted accumulation in liver, brain, and fat tissues for a 7-day period that included 4-hr exposures on 5 days. Competition for enzyme does not occur only from interactions of different inhaled compounds. Interactions can also occur between inhaled compounds and metabolites formed in the body that require similar enzymes for biotransformation. Detailed kinetic studies with both benzene and -hexane show inhibition of later metabolic steps, phenol to hydroquinone or methyl -butyl ketone to 2,5-hexane dione, by high concentrations of inhaled benzene or hexane, respectively (Medinsky et al. 1989 Andersen and Clewell 1984). 

Coupling of validated PB-PK models with a better grasp of the constituents or metabolites associated with target organ toxicity makes it possible to assess the effects of phenotypic variants and other forms of variation on tissue doses of inhaled compounds and their metabolites. Such assessments are becoming routine, but in the absence of a model for calculating the consequences of the variants in relation to tissue dose, the presence of the phenotypic variations is impossible to assess quantitatively in a rigorous manner. 

Inhaled compounds may rapidly attain high concentrations in well-perfused organs (brain, heart), while concentrations in muscle and adipose tissue may be very low. Should death occur, this situation is frozen to an extent, but if exposure continues the compound will accumulate in less accessible (poorly perfused) tissues, only to be slowly released once exposure ceases. Thus, the plasma concentrations of... 

Side effects can be the result of unwanted systemic action, toxicity, irritation and hypersensitivity following sensitisation. Both the active substances and excipients can cause side effects and in addition to the chemical nature of the inhaled compounds, also physical properties can be relevant. An example can be given for salbutamol, for which it has been shown that increasing the dose may result... 

The three main exposure pathways to uranium compounds are through the diet, inhalation, or injury, as described earlier. The uptake of uranium after ingestion is affected mainly by soluble uranium compounds (insoluble compounds are excreted through feces with little or no hazardous health effects) as discussed earlier. However, for inhaled compounds, the chemical and physical characteristics determine how long the uranium will be retained in the lungs and what fraction will enter the bloodstream during a given time period. The common practice is to divide these compounds into... 

The site and severity of the respiratory damage caused by inhaled compounds depend mainly on the nature of the agent and the amount inhaled (Schwartz... 

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