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The closed chamber technique — uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapors

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Abstract

The “closed chamber technique” (CCT) is presented. It allows investigation of pharmacokinetics of volatile substances in vivo in animals and in man and in vitro using tissue fractions. During the exposure period only the atmospheric concentrations of the substance are measured. The concentration-time data obtained are pharmacokinetically analyzed by a two compartment model describing uptake, endogenous production and excretion of the unchanged substance and its metabolic elimination. Using this model, pharmacokinetics of ethylene have been determined in rats and man. For both species, the results compared well with an estimation based on an allometric species scaling. Furthermore, the applicability of CCT is demonstrated in vivo on several other gases and vapors of solvents, e.g. trichloroethylene and 1,1,1-trichloroethane, and in vitro on 1,2-epoxybutene-3.

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References

  • Andersen ME, Gargas ML, Jones RA, Jenkins LJ Jr (1979) The use of inhalation techniques to assess the kinetic constants of 1,1-dichloroethylene metabolism. Toxicol Appl Pharmacol 47: 395–409

    CAS  PubMed  Google Scholar 

  • Andersen ME, Gargas ML, Jones RA, Jenkins LJ Jr (1980) Determination of the kinetic constants for metabolism of inhaled toxicants in vivo using gas uptake measurements. Toxicol Appl Pharmacol 54: 100–116

    Article  CAS  PubMed  Google Scholar 

  • Åstrand I (1982) Work load and uptake of solvents in tissues of man. In: Englund A, Ringen K, Mehlman MA (eds) Occupational health hazards of solvents, Vol. II. Princeton Scientific Publishers, INC, Princeton, NJ,pp 141–152

    Google Scholar 

  • Bolt HM, Filser JG (1977) Irreversible binding of chlorinated ethylenes to macromolecules. Environ Health Perspect 21: 107–112

    CAS  PubMed  Google Scholar 

  • Bolt HM, Filser JG (1987) Kinetics and disposition in toxicology. Example: carcinogenic risk estimate for ethylene. Arch Toxicol 60: 73–76

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Link B (1980) Zur Toxikologie von Perchlorethylen. Verh Dtsch Ges Arbeitsmedizin 20: 463–470

    Google Scholar 

  • Bolt HM, Kappus H, Buchter A, Bolt W (1976) Disposition of (1,2-14C vinyl chloride in the rat. Arch Toxicol 35: 153–162

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Buchter A, Wolowski L, Gil DL, Bolt W (1977 a) Incubation of14 C-trichloroethylene vapor with rat liver microsomes: uptake of radioactivity and covalent protein binding of metabolites. Int Arch Occup Environ Health 39: 103–111

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Laib RJ, Kappus H, Buchter A (1977 b) Pharmacokinetics of vinyl chloride in the rat. Toxicology 7: 179–188

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Filser JG, Hinderer RK (1978) Rat liver microsomal uptake and irreversible protein binding of [1,2-14C] vinyl bromide. Toxicol Appl Pharmacol 44: 481–489

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Filser JG, Wiegand M, Buchter A, Bolt W (1979) Studies on liver microsomal metabolism and interaction of vinyl chloride and related compounds in relation to possible carcinogenicity. Arh Hig Rada Toksikol 30: 369–377

    Google Scholar 

  • Bolt HM, Filser JG, Buchter A (1981) Inhalation pharmacokinetics based on gas uptake studies III. A pharmacokinetic assessment in man of “peak concentrations” of vinyl chloride. Arch Toxicol 48: 213–228

    Article  CAS  PubMed  Google Scholar 

  • Bolt HM, Filser JG, Störmer F (1984) Inhalation pharmacokinetics based on gas uptake studies V. Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats. Arch Toxicol 55: 213–218

    CAS  PubMed  Google Scholar 

  • Buchter A, Bolt HM, Filser JG, Goergens HW, Laib RJ, Bolt W (1978) Pharmakokinetik und Karzinogenese von Vinylchlorid. Arbeitsmedizinische Risikobeurteilung. Verh Dtsch Ges Arbeitsmedizin 18: 111–124

    Google Scholar 

  • Buchter A, Filser JG, Peter H, Bolt HM (1980) Pharmacokinetics of vinyl chloride in the rhesus monkey. Toxicol Lett 6: 33–36

    Article  CAS  PubMed  Google Scholar 

  • Csanády GA, Filser JG (1990) SOLVEKIN: a new program for solving pharmaco- and toxicokinetic problems. Presented on the International Workshop on Pharmacokinetic Modelling in Occupational Health, March 4–8, Leysin, Switzerland

  • Daugherty MS, Ludden TM, Burk RF (1988) Metabolism of ethane and pentane to carbon dioxide by the rat. Drug Metab Dispos 16 [No. 5]: 666–671

    CAS  PubMed  Google Scholar 

  • Davidson IWF, Parker JC, Beliles RP (1986) Biological basis for extrapolation across mamalian species. Regul Toxicol Pharmacol 6: 211–237

    Article  CAS  PubMed  Google Scholar 

  • Denk B (1990) Abschätzung des kanzerogenen Risikos von Ethylen und Ethylenoxid für den Menschen durch Speziesextrapolation von der Ratte unter Berücksichtigung der Pharmakokinetik. GSF-Bericht 20/90. Gesellschaft für Strahlen- und Umweltforschung, München

  • Denk B, Filser JG (1990) Abschätzung des durch Ethylen und Ethylenoxid bedingten kanzerogenen Risikos für den Menschen — Vergleich mit dem Risiko durch endogenes Ethylen. Verh Dtsch Ges Arbeitsmedizin 30 (in press)

  • Dogra S, Filser JG, Cojocel C, Greim H, Regel U, Oesch F, Robertson LW (1988) Long-term effects of commercial and congeneric polychlorinated biphenyls on ethane production and malonedialdehyde levels, indicators of in vivo lipid peroxidation. Arch Toxicol 62: 369–374

    Article  CAS  PubMed  Google Scholar 

  • Ehrenberg L, Hiesche KD, Osterman-Golkar S, Wennberg I (1974) Evaluation of genetic risks of alkylating agents: tissue doses in the mouse from air contaminated with ethylene oxide. Mutat Res 24: 83–103

    CAS  PubMed  Google Scholar 

  • Fernandez J, Guberan E, Caperos J (1976) Experimental human exposure to tetrachloroethylene vapor and elimination in breath after inhalation. Am Ind Hyg Assoc J 37: 143–150

    CAS  PubMed  Google Scholar 

  • Filser JG, Bolt HM (1979) Pharmacokinetics of halogenated ethylenes in rats. Arch Toxicol 42: 123–136

    CAS  PubMed  Google Scholar 

  • Filser JG, Bolt HM (1981) Inhalation pharmacokinetics based on gas uptake studies I. Improvement of kinetic models. Arch Toxicol 47: 279–292

    Article  CAS  PubMed  Google Scholar 

  • Filser JG, Bolt HM (1983) Inhalation pharmacokinetics based on gas uptake studies IV. The endogenous production of volatile compounds. Arch Toxicol 52: 123–133

    CAS  PubMed  Google Scholar 

  • Filser JG, Bolt HM (1984) Inhalation pharmacokinetics based on gas uptake studies VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats. Arch Toxicol 55: 219–223

    Article  CAS  PubMed  Google Scholar 

  • Filser JG, Deml E (1989) Pharmakokinetik und Metabolismus leichtflüchtiger chlorierter Verbindungen am Beispiel von Trichlorethylen, Perchlorethylen und 1,1,1-Trichlorethan (Methylchloroform). VDI Berichte 745: 679–711

    Google Scholar 

  • Filser JG, Bolt HM, Muliawan H, Kappus H (1983) Quantitative evaluation of ethane and n-pentane as indicators of lipid peroxidation in vivo. Arch Toxicol 52: 135–147

    CAS  PubMed  Google Scholar 

  • Filser JG, Peter H, Bolt HM, Fedtke N (1987) Pharmacokinetics of the neurotoxin n-hexane in rat and man. Arch Toxicol 60: 77–80

    Article  CAS  PubMed  Google Scholar 

  • Filser JG, Kessler W, Koch R, Denk B, Summer KH (1988) Kompetitive Hemmung der Bildung des n-Hexan-Metaboliten 2,5-Hexandion durch Toluol: Messung von Pyrrolen im Urin von Ratten. Verh Dtsch Ges Arbeitsmedizin 28: 603–605

    Google Scholar 

  • Filser JG, Denk B, Törnqvist M, Kessler W, Ehrenberg L (1991) Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene. Arch Toxicol, submitted for publication

  • Fiserova-Bergerova V, Teisinger J (1965) Pulmonary styrene vapor retention. Industrial Medicine and Surgery 34 [No 8]: 620–622

    CAS  PubMed  Google Scholar 

  • Fisher JW, Whittaker TA, Taylor DH, Clewell HJ III, Andersen ME (1989) Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Toxicol Appl Pharmacol 99: 395–414

    Article  CAS  PubMed  Google Scholar 

  • Frank H, Dürk H (1983) Determination of alkanes in breath to monitor lipid peroxidation in the presence of volatile toxicants and metabolites. An optimized automatic method. Arch Toxicol 53: 213–223

    Article  CAS  PubMed  Google Scholar 

  • Frank H, Hintze T, Bimboes D, Remmer H (1980) Monitoring lipid peroxidation by breath analysis: endogenous hydrocarbons and their metabolic elimination. Toxicol Appl Pharmacol 56: 337–344

    Article  CAS  PubMed  Google Scholar 

  • Freundt KJ, Römer KG, Federsel RJ (1989) Decrease of inhaled toluene, ethyl benzene, m-xylene, or mesitylene in rat blood after combined exposure to ethyl acetate. Bull Environ Contam Toxicol 42: 495–498

    Article  CAS  PubMed  Google Scholar 

  • Gargas ML, Andersen ME, Clewell HJ III (1986) A physiologicallybased simulation approach for determining metabolic constants from gas uptake data. Toxicol Appl Pharmacol 86: 341–352

    Article  CAS  PubMed  Google Scholar 

  • Gargas ML, Clewell HJ III, Andersen ME (1990) Gas uptake inhalation techniques and the rates of metabolism of chloromethanes, chloroethanes, and chloroethylenes in the rat. Inhalation Toxicology 2: 295–319

    CAS  Google Scholar 

  • Garman RH, Snellings WM, Maronpot RR (1984) Brain tumors in F344 rats associated with chronic inhalation exposure to ethylene oxide. Neurotoxicology 6: 117–138

    Google Scholar 

  • Golka K, Peter H, Denk B, Filser JG (1989) Pharmacokinetics of propylene and its reactive metabolite propylene oxide in Sprague-Dawley rats. Arch Toxicol Suppl 13: 240–242

    CAS  PubMed  Google Scholar 

  • Guyton AC (1947) Respiratory volumes of laboratory animals. Am J Physiol 150: 70–77

    Google Scholar 

  • Hartmann M, Kessler W, Denk B, Filser JG (1990) Pharmakokinetik und endogene Produktion von Isopren beim Menschen. Verh Dtsch Ges Arbeitsmedizin 30 (in press)

  • Hallier E, Filser JG, Bolt HM (1981) Inhalation pharmacokinetics based on gas uptake studies II. Pharmacokinetics of acetone in rats. Arch Toxicol 47: 293–304

    Article  CAS  PubMed  Google Scholar 

  • Hefner RE, Watanabe PG, Gehring PJ (1975) Preliminary studies on the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sci 246: 135–148

    CAS  Google Scholar 

  • Igwe OJ, Que Hee SS, Wagner WD (1986) Inhalation pharmacokinetics of 1,2-dichloroethane after different dietary pretreatment of male Sprague-Dawley rats. Arch Toxicol 59: 127–134

    Article  CAS  PubMed  Google Scholar 

  • Johanson G (1986) Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man. Toxicol Lett 34: 23–31

    Article  CAS  PubMed  Google Scholar 

  • Kappus H, Muliawan H (1982) Alkane formation during liver microsomal lipid peroxidation. Biochem Pharmacol 31: 597–600

    Article  CAS  PubMed  Google Scholar 

  • Kappus H, Bolt HM, Buchter A, Bolt W (1976) Liver microsomal uptake of [14C] vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol Appl Pharmacol 37: 461–471

    Article  CAS  PubMed  Google Scholar 

  • Kessler W, Denk B, Filser JG (1989) Species-specific inhalation pharmacokinetics of 2-nitropropane, methyl ethyl ketone, and n-hexane. In: Travic CC (ed) Biologically-based methods for cancer risk assessment. Plenum Publishing Corporation, New York and London, pp 123–139

    Google Scholar 

  • Kessler W, Heilmaier H, Kreuzer P, Shen JH, Filser M, Filser JG (1990) Spectrophotometric determination of pyrrole-like substances in urine of rat and man: an assay for the evaluation of 2,5-hexanedione formed from n-hexane. Arch Toxicol 64: 242–246

    Article  CAS  PubMed  Google Scholar 

  • Kivits GAA, Ganguli-Swarttouw MACR, Christ EJ (1981) The composition of alkanes in exhaled air of rats as a result of lipid peroxidation in vivo. Biochim Biophys Acta 665: 559–570

    CAS  PubMed  Google Scholar 

  • Kreiling R, Laib RJ, Filser JG, Bolt HM (1986) Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics. Arch Toxicol 58: 235–238

    Article  CAS  PubMed  Google Scholar 

  • Kreiling R, Laib RJ, Filser JG, Bolt HM (1987) Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis. Arch Toxicol 61: 7–11

    Article  CAS  PubMed  Google Scholar 

  • Kreuzer PE, Kessler W, Welter HF, Baur C, Filser JG (1991) Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man. Arch Toxicol 65: 59–67

    Article  CAS  PubMed  Google Scholar 

  • Liira J, Johanson G, Riihimäki V (1990) Dose-dependent kinetics of inhaled methylethylketone in man. Toxicol Lett 50: 195–201

    Article  CAS  PubMed  Google Scholar 

  • Link B (1979) Metabolismus von Perchloräthylen in vivo und in vitro. Diplomarbeit an der Fakultät für Chemie und Pharmazie der Universität Tübingen

  • Monster AC, Boersma G, Duba WC (1976) Pharmacokinetics of trichloroethylene in volunteers, influence of workload and exposure concentration. Int Arch Occup Environ Hlth 38: 87–102

    Article  CAS  Google Scholar 

  • Muliawan H, Scheulen ME, Kappus H (1982) Adriamycin stimulates only the iron ion-induced, NADPH-dependent microsomal alkane formation. Biochem Pharmacol 31: 3147–3150

    Article  CAS  PubMed  Google Scholar 

  • Nelder JA, Mead R (1965) A simplex method for function minimization. Comp J 7: 308–313

    Google Scholar 

  • Nolan RJ, Freshour NL, Rick DL, McCarty LP, Saunders JH (1984) Kinetics and metabolism of inhaled methyl chloroform (1,1,1-trichloroethane) in male volunteers. Fundam Appl Toxicol 4: 654–662

    Article  CAS  PubMed  Google Scholar 

  • Nomiyama K, Nomiyama H (1974) Respiratory retention, uptake and excretion of organic solvents in man. Benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate, ethyl alcohol. Int Arch Arbeitsmed 32: 75–83

    CAS  PubMed  Google Scholar 

  • Ottenwälder H, Kappus H, Bolt HM (1983) Covalent protein binding of vinyl chloride metabolites during co-incubation of freshly isolated hepatocytes and hepatic sinusoidal cells of rats. Arch Toxicol Suppl 6: 266–270

    PubMed  Google Scholar 

  • Peter H, Bolt HM (1984) Experimental pharmacokinetics and toxicology of acrylonitrile. G Ital Med Lav 6: 77–81

    CAS  PubMed  Google Scholar 

  • Peter H, Filser JG, v. Szentpály L, Wiegand HJ (1986) Different pharmacokinetics of dichlorofluoromethane (CFC21) and chlorodifluoromethane (CFC 22). Arch Toxicol 58: 282–283

    Article  CAS  PubMed  Google Scholar 

  • Peter H, Wiegand HJ, Bolt HM, Greim H, Walter G, Berg M, Filser JG (1987) Pharmacokinetics of isoprene in mice and rats. Toxicol Lett 36: 9–14

    Article  CAS  PubMed  Google Scholar 

  • Prout MS, Provan WM, Green T (1985) Species differences in response to trichloroethylene. I. Pharmacokinetics in rats and mice. Toxicol Appl Pharmacol 79: 389–400

    Article  CAS  PubMed  Google Scholar 

  • Remmer H, El Majid Gharaibeh A (1984) Measurement of the oxidation rate of volatile alkanes: a new and non-invasive procedure for testing the drug-metabolizing capacity of the liver. Biochem Soc Trans 12: 28–30

    CAS  PubMed  Google Scholar 

  • Robertson LW, Regel U, Filser JG, Oesch F (1985) Absence of lipid peroxidation as determined by ethane exhalation in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Arch Toxicol 57: 13–16

    Article  CAS  PubMed  Google Scholar 

  • Sato A, Nakajima T (1979a) A vial-equilibration method to evaluate the drug-metabolizing enzyme activity for volatile hydrocarbons. Toxicol Appl Pharmacol 47: 41–46

    Article  CAS  PubMed  Google Scholar 

  • Sato A, Nakajima T (1979b) A structure-activity relationship of some chlorinated hydrocarbons. Arch Environ Health Mar./Apr.: 69–75

    Google Scholar 

  • Schwegler U, Jiang X, Kessler W, Johanson G, Filser JG (1990) Pharmakokinetik von Styrol bei Ratte und Maus und Bestimmung von Styrol-7,8-oxid im Blut von Ratten. Verh Dtsch Ges Arbeitsmedizin 30 (in press)

  • Shen J, Kessler W, Denk B, Filser JG (1989) Metabolism and endogenous production of ethylene in rat and man. Arch Toxicol Suppl 13: 237–239

    CAS  PubMed  Google Scholar 

  • Siegers C-P, Filser JG, Bolt HM (1978) Effect of dithiocarb on metabolism and covalent binding of carbon tetrachloride. Toxicol Appl Pharmacol 46: 709–716

    Article  CAS  PubMed  Google Scholar 

  • Simon P, Filser JG, Bolt HM (1985) Metabolism and pharmacokinetics of vinyl acetate. Arch Toxicol 57: 191–195

    Article  CAS  PubMed  Google Scholar 

  • Snellings WM, Weil CS, Maronpot RR (1984) A two-year inhalation study of the carcinogenic potential of ethylene oxide in Fischer 344 rats. Toxicol Appl Pharmacol 75: 105–117

    Article  CAS  PubMed  Google Scholar 

  • Stacey NH, Kappus H (1982) Cellular toxicity and lipid peroxidation in response to mercury. Toxicol Appl Pharmacol 63: 29–35

    Article  CAS  PubMed  Google Scholar 

  • Stewart RD, Hugh C, Dodd AB, Baretta ED, Schaffer AW (1968) Human exposure to styrene vapor. Arch Environ Health 16: 656–662

    CAS  PubMed  Google Scholar 

  • Wigaeus E, Holm S, Åstrand I (1981) Exposure to acetone. Uptake and elimination in man. Scand J Work Environ Health 7: 84–94

    CAS  PubMed  Google Scholar 

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  1. GSF - Forschungszentrum für Umwelt und Gesundheit, Institut für Toxikologie, Ingolstädter Landstraße 1, D-8042, Neuherberg (München), FRG

    J. G. Filser

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Filser, J.G. The closed chamber technique — uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapors. Arch Toxicol 66, 1–10 (1992). https://doi.org/10.1007/BF02307263

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