Vera Fiserova-Bergerova

Determination and prediction of tissue-gas partition coefficients

SummaryThe head space method for determination of tissue-gas partition coefficients was modified to make it suitable for determination of tissue-gas partition coefficients of water soluble solvents. The method was used to determine tissue-gas partition coefficients of acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol and isobutanol for six representative tissues (muscle, kidney, lung, white and gray matter of brain, and adipose tissue). Blood-gas partition coefficients and distribution between plasma and erythrocytes were also determined. Relation between tissue-blood and fat-blood partition coefficients of 35 hydrophilic and hydrophobic substances of different chemical structure is described by linear correlation equations which can be used for prediction of tissue-gas partition coefficients of any chemical for which blood-gas and fat-gas partition coefficients are known. The correlation equations are based on all currently available data.

The Biotransformation of Ēthrane in Man

The biotransformation of Ēthrane was studied in seven healthy female patients by measuring urinary fluorine excretion. The total amount of Ēthrane recovered was 85.1 per cent of the amount absorbed; 82.7 ± 18.8 per cent was recovered as unchanged Ēthrane in exhaled air and 2.4 per cent as nonvolatile fluorinated metabolites in urine. Of the urinary fluorine, 0.5 per cent was excreted in inorganic form and 1.9 per cent in organic form. Following anesthesia, urinary excretion rates of fluoride in reached a maximum in seven hours. Maximum excretion of organic fluorine metabolites was reached on the second day. Urinary excretion then assumed a simple exponential decay, with half-times of 1.53 days for inorganic fluoride and 3.69 days for or-ganic fluorine. The excretion of unaltered Ēthrane in exhaled air assumed a three-term exponential decay, with half-times of 17.8 minutes, 3.2 hours, and 36.2 hours.

Effects of Biosolubility on Pulmonary Uptake and Disposition of Gases and Vapors of Lipophilic Chemicals

Since statistical analysis proved the intercorrelation of tissue-gas partition coefficients of chemicals with similar chemical structures, bioavailability is controlled by one parameter dependent on the physicochemical properties of the chemicals and two constants distinguishing the tissues. Oil-gas partition coefficients are suggested to describe the biosolubility of volatile halogenated aliphatic chemicals. Tissue-gas partition coefficients derived from oil-gas partition coefficients were substituted in a pharmacokinetic model in order to study the effect of biosolubility on uptake, distribution, and elimination of inhaled chemicals. The simulation was focused on occupational exposures (8 h/day, 5 days/wk). Desaturation curves for all tissues show three exponential decays. The analysis of the simulation data indicates three patterns in behavior of inhaled vapors and gases in the body. Tissue uptake of poorly soluble chemicals (oil-gas partition coefficient less than 10) is flow limited at the beginning of exposure, but the partial pressures of such chemicals in the body equilibrate very rapidly with ambient air. Increased pulmonary uptake compensates for metabolic clearance. The rapid response of tissue concentrations to changes in exposure concentrations indicates that the toxic effect can easily be induced by short-term increase of exposure concentration, and that emergence from the reversible effect is rapid when exposure ceases. Tissue uptake of chemicals with oil-gas partition coefficients between 10 and 10(4) is flow limited during the entire 8-h exposure. Tissue concentrations increase slowly. Pulmonary uptake, being restricted by alveolar ventilation, compensates at steady state only for the amount of chemical removed by metabolic clearance. Therefore, tissue concentrations at steady state are lower than biosolubility. Accumulation during occupational exposure is obvious. Dumping of inhaled chemicals in adipose tissue protects the target organ from the occasional short-term increases in the exposure concentration. Tissue uptake of highly soluble chemicals (oil-gas partition coefficients greater than 10(4)) is limited by alveolar ventilation and exposure concentration. The rising and declining of tissue concentrations is very slow, half-times being in the magnitude of months and years. Metabolism reduces the half-time significantly. A lagging acute toxic effect can develop as the chemical accumulates in the body; the effect is most likely to persist long after the termination of the exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Predictable "individual differences" in uptake and excretion of gases and lipid soluble vapours simulation study

A five-compartment pharmacokinetic model with two excretory pathways, exhalation and metabolism, based on first order kinetics is used to outline the effect of body build, pulmonary ventilation, and lipid content in blood on uptake, distribution, and clearance of low solubility gases and lipid soluble vapours during and after exposure. The model shows the extent that individual differences have on altering uptake and distribution, with consequent changes in blood concentration, rate of excretion, and toxicity, even when variations in these parameters are within physiological ranges. The model is also used to describe the concentration variation of inhaled substances in tissues of subjects exposed to concentrations with permitted excursions. During the same course of exposure, the tissue concentrations of low solubility gases fluctuate much more than tissue concentrations of lipid soluble vapours. The fluctuation is reduced by metabolism of inhaled substance. These conclusions are recommended for consideration whenever evaluating the effect of excursions above the threshold limit values used in the control of industrial exposures (by excursion factors).

Simulation and prediction of uptake, distribution, and exhalation of organic solvents

Fiserova-Bergerova, Vera, Vlach, J., and Singhal, K. (1974).British Journal of Industrial Medicine,31, 45-52. Simulation and prediction of uptake, distribution, and exhalation of organic solvents. Presented here is a theory and mathematical solution of the uptake, distribution, and excretion of inhaled lipid soluble noxious gases, which embraces the effects of metabolism. An electrical analogue was employed to explain the theory, since the analogue is described by the same set of differential equations, and much knowledge is available for the mathematical treatment of electrical networks. The model is used to calculate the uptake and exhalation curves of vapours, to explain what happens to the inhaled vapours in the body, and to predict their cumulation in the body in periodic situations such as occur in industrial exposure.

Uptake and clearance of inhalation anesthetics in man.

The uptake, distribution, and clearance of inhaled vapors is governed by rules of partial pressure equilibration in a multicompartmental system. Since halogenated anesthetic agents are not soluble in water, biotransformation is their only clearance pathway during anesthesia. When apparent steady state is reached, the rate of overall metabolism can be determined from the pulmonary uptake rate. As a result of metabolism, pulmonary uptake increases but the concentration of inhaled vapor in blood and tissues decreases, and only a fraction of uptake is exhaled following anesthesia. Uptake and pulmonary clearance of five halogenated anesthetic agents were studied in 45 surgical patients. The susceptibility to biotransformation increases in the following order: isoflurane, enflurane, halothane, fluroxene, methoxyflurane.

Uptake, Distribution, and Excretion of Fluorocarbon FX-80 (Perfluorobutyl Perfluorotetrahydrofuran) during Liquid Breathing in the Dog

The uptake, distribution, and excretion of FX-80, a water-insoluble mixture of isomers of perfluorobutyl perfluorotetrahydrofuran, were studied in 17 dogs subjected to liquid breathing with oxygenated FX-80. The absence of excess fluoride ion in urine suggests that FX-80 is not metabolized, nor is it excreted in urine unchanged. Its distribution in the body depends on the lipid content of tissues. The uptake and desaturation curves are multiple exponential functions, the rate constants of which can be predicted from the ratios of lipid contents of blood and tissues and the fractions of cardiac output supplying the tissue compartments. During liquid breathing the concentration of FX-80 in arterial blood averages 0.43 mg/100 ml. Calculations indicate that at saturation a 13.8-kg dog would absorb 1.25 g of FX-80. Of this amount, 71 per cent would be deposited in adipose tissues and bone marrow, 25 per cent in muscles and skin, and 4 per cent in parenchymatous tissues. Desaturation is delayed because deposits of liquid FX-80 are sequestered in the lungs following liquid breathing.

Metabolism of Methoxyflurane in Man

Excretion of methoxyflurane was studied in 12 patients receiving anesthesia in a closed rebreathing circuit at a constant alveolar concentration of approximately 0.24 per cent. The mean methoxyflurane uptake was 1S g (range 7.6–31 g) during a mean time of anesthesia administration of 2 hours. 1S minutes (range 55–309 minutes). An average of 19 per cent of the uptake was recovered unchanged in the exhaled air after anesthesia. Urinary excretion of organic fluorine, fluoride, and oxalic acid was equivalent to 29, 7.7 and 7.1 per cent of methoxyflurane uptake. respectively. Approximately a third of the uptake remained unrecovered. It is postulated that a portion of the unrecovered drug became permanently bourn to tissues and hence its exeretion was delayed beyond the period of the study.

Biotransformation of Fluroxene in Man

Biotransformation and excretion of fluroxene were studied in nine patients following administration of known quantities. An average of 58 per cent was exhaled unaltered following anesthesia. Ten per cent of the fluorine administered as fluroxene was recovered in urine, mainly as trifluoroacetic acid. In contrast to other species, which excrete trifluoroethanol primarily, in man free and conjugated trifluoroethanol accounted for only 0.6 per cent of the administered dose. Fluoride ion excretion in urine did not exceed normal rates of excretion. The fate of 32 per cent of administered fluroxene remains unknown.

Extrapolation of physiological parameters for physiologically based simulation models

Masses of organs and fluids, pulmonary ventilation and cardiac output and its distribution are the basic input data used in physiologically based pharmacokinetic models. Since these parameters are rarely measured in pharmacokinetic studies, the values found in reference books or extrapolated to meet the specific exposure conditions are used in the models. In this review of the extrapolation of pertinent physiological parameters, power equations for scaling across mammals, adjustments to body build (lean body mass) and physical activity of humans and their significance for risk assessment of human exposure to solvents using animal data are assessed.