Abstract
Purpose. This investigation was conducted to identify the site and characteristics of methanol absorption and to develop an inhalation model relating methanol absorption, blood concentration, and elimination.
Methods. Rats were exposed to methanol in chambers that allowed measurement of methanol uptake, ventilation, and blood concentrations; anesthetized rats with a tracheal cannula were examined to determine tracheal concentrations. In separate experiments, methanol-exposed rats received an iv methanol bolus to examine the effect of blood methanol on ventilation and absorption; ventilation also was manipulated by CO2 or pentobarbital to assess the effect of ventilation rate on methanol absorption. These data were combined to construct a semi-physiologic model of methanol uptake.
Results. Only 1–3% of inhaled methanol reached the trachea, primarily from systemic methanol partitioning into the trachea; blood methanol did not alter methanol absorption. Manipulation of ventilation and application of the pharmacokinetic model indicated that ventilation was less significant than environmental methanol concentration in determining the fraction of inhaled methanol absorbed, although both parameters were important determinants of the total mass absorbed.
Conclusions. These data indicate that methanol uptake is a complex process that depends upon several parameters. Despite these complexities, a relatively simple semi-physiologic model was capable of describing methanol uptake over a wide range of exposure concentrations in the rat.
Similar content being viewed by others
REFERENCES
J. C. Ramsey and M. E. Andersen. A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73:159–175 (1984).
M. L. Gargas, M. A. Medinsky, and M. E. Andersen. Advances in physiological modeling approaches for understanding the disposition of inhaled vapors. In D. E. Gardner (ed.), Toxicology of the Lung, 2d ed., Raven Press, New York, 1993, pp. 461–483.
B. K. Nelson, W. S. Brightwell, D. R. MacKenzie, A. Khan, J. R. Burg, W. W. Weigel, and P. T. Goad. Teratological assessment of methanol and ethanol at high inhalation levels in rats. Fundam. Appl. Toxicol. 5:727–736 (1985).
B. Bolon, D. C. Dorman, D. Janszen, K. T. Morgan, and F. Welsch. Phase-specific developmental toxicity in mice following maternal methanol inhalation. Fundam. Appl. Toxicol. 21:508–516 (1993).
B. Bolon, F. Welsch, and K. T. Morgan. Methanol-induced neural tube defects in mice: Pathogenesis during neurulation. Teratology 49:497–517 (1994).
J. M. Rogers, M. L. Mole, N. Chernoff, B. D. Barbee, C. I. Turner, T. R. Logsdon, and R. J. Kavlock. The developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative doseresponse modeling for estimation of benchmark doses. Teratology 47:175–188 (1993).
Health Research Committee. Automotive methanol vapors and human health: An evaluation of existing scientific information and issues for future research, HEI, Cambridge, 1987.
R. A. Perkins, K. W. Ward, and G. M. Pollack. Measurement of the ventilation of ambulatory rats exposed to methanol vapor in a flow-through exposure system. Inhal. Toxicol. 8:143–162 (1996).
R. A. Perkins, K. W. Ward, and G. M. Pollack. The absorption of methanol vapor by ambulatory rats in a flow-through exposure system. Inhal. Toxicol. (in press).
J. E. Drorbaugh and W. O. Fenn. A barometric method for measuring ventilation in newborn infants. Pediatrics 16:81–87 (1955).
M. A. F. Epstein and R. A. Epstein. A theoretical analysis of the barometric method for measurement of tidal volume. Respir. Physiol. 32:105–120 (1978).
J. P. Jacky. Barometric measurement of tidal volume: Effects of pattern and nasal temperature. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 49:319–325 (1980).
G. M. Pollack and J. L. Kawagoe. Determination of methanol in whole blood by capillary gas chromatography with direct oncolumn injection. J. Chromatogr. Biomed. Appl. 570:406–411 (1991).
G. M. Pollack, K. L. R. Brouwer, and J. L. Kawagoe. Toxicokinetics of intravenous methanol in the female rat. Fundam. Appl. Toxicol. 21:105–110 (1993).
K. W. Ward, R. A. Perkins, J. L. Kawagoe, and G. M. Pollack. Comparative toxicokinetics of methanol in the female mouse and rat. Fundam. Appl. Toxicol. 28:258–264 (1995).
M. E. Andersen, H. J. Clewell, M. L. Gargas, F. A. Smith, and R. H. Reitz. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87:185–205 (1987).
P. G. Welling. Pharmacokinetics, Processes and Mathematics. American Chemical Society, Washington, 1986.
T. R. Tephly and K. E. McMartin. Methanol metabolism and toxicity. In L. D. Stegink and L. J. Filer, Jr. (eds.), Aspartame: Physiology and Biochemistry, Marcel Dekker, New York, 1984, pp. 111–140.
F. J. Miller, J. H. Overton, J. S. Kimbell, and M. L. Russell. Regional respiratory tract absorption of inhaled reactive gases. In D. E. Gardner (ed.), Toxicology of the Lung, 2nd ed., Raven Press, New York, 1993, pp. 485–525.
W. T. Stott and M. J. McKenna. The comparative absorption and excretion of chemical vapors by the upper, lower, and intact respiratory tract of rats. Fundam. Appl. Toxicol. 4:594–602 (1984).
A. R. Dahl, M. B. Snipes, and P. Gerde. Sites for uptake of inhaled vapors in beagle dogs. Toxicol. Appl. Pharmacol. 109:263–275 (1991).
A. R. Dahl, M. B. Snipes, and P. Gerde. A model for the uptake of inhaled vapors in the nose of the dog during cyclic breathing. Toxicol. Appl. Pharmacol. 109:276–288 (1991).
G. Johanson. Modeling of respiratory exchange of polar solvents. Ann. Occup. Hyg. 35:323–339 (1991).
J. B. Morris, D. N. Hassett, and K. T. Blanchard. A physiologically based pharmacokinetic model for nasal uptake and metabolism of nonreactive vapors. Toxicol. Appl. Pharmacol. 123:120–129 (1993).
A. C. M. Schrikker, W. R. de Vries, A. Zwart, and S. C. M. Luijendijk. Uptake of highly soluble gases in the epithelium of the conducting airways. Pfluegers Arch. 405:389–394 (1985).
V. Fiserova-Bergerova and M. L. Diaz. Determination and prediction of tissue-gas partition coefficients. Int. Arch. Occup. Environ. Health 58:75–87 (1986).
W. Wrewsky. Über Zusammensetzung und spannung des dampfes binärer Flüsigkeitsgemische. Z. Physikal. Chem., Stöch., and Verwandschaftslehre. 81:1–29 (1913).
R. N. Harger, B. B. Raney, E. G. Bridwell, and M. F. Kitchel. The partition ration of alcohol between air and water, urine, and blood; estimating and identification of alcohol in these liquids from analysis of air equilibrated with them. J. Biol. Chem. 183:197–213 (1950).
M. Gumbleton, P. J. Nicholls, and G. Taylor. Differential influence of laboratory anaesthetic regimens upon renal and hepatosplanchnic haemodynamics in the rat. J. Pharm. Pharmacol. 42:693–697 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Perkins, R.A., Ward, K.W. & Pollack, G.M. Methanol Inhalation: Site and Other Factors Influencing Absorption, and an Inhalation Toxicokinetic Model for the Rat. Pharm Res 13, 749–755 (1996). https://doi.org/10.1023/A:1016055701736
Issue Date:
DOI: https://doi.org/10.1023/A:1016055701736