The relative toxicities of formaldehyde and glutaraldehyde to the rat nasal epithelium were determined following intra-nasal instillation of aqueous solutions of these compounds into one nostril of male Fischer 344 (F-344) rats. Lesions identical in appearance to those resulting from acute inhalation exposure to formaldehyde were induced by both compounds in a concentration-dependent manner. Treatments included-India ink or 1 m methylene blue (for instillation deposition studies); sterile saline (vehicle control); 40, 200, 400, and 800 mm formaldehyde; and 10, 20, and 40 mm glutaraldehyde. Dye-treated rats were sacrificed immediately, and nasal passages were examined to determine the localization of instilled materials. Three days after treatment, all other animals received a single ip injection of 5-bromo-2'-deoxyuridine 2 hr prior to sacrifice, and the nasal passages were prepared for histopathology and cell proliferation studies. While sterile saline and 10 mM glutaraldehyde induced no significant epithelial changes, 20 and 40 mM glutaraldehyde induced extensive lesions in the treated side of the nose. Aldehyde-induced lesions included inflammation, epithelial degeneration, respiratory epithelial hypertrophy, and squamous metaplasia in association with marked increases (3-8-fold) in labeling index for both compounds. Formaldehyde induced similar lesions but required concentrations of 200 mM or more to elicit a toxic response. Thus, glutaraldehyde is approximately an order of magnitude more toxic to the nasal epithelium than formaldehyde. These studies also indicate that the nose is very resistant to the aldehydes studied, requiring instillation of millimolar concentrations before toxic responses occurred.
1. Albert RE, Sellakumar AR, Laskin S, Kuschner M, Nelson N, and Snyder CA (1982). Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat.JNCI68: 597–603.
2.
2. Ballantyne B, Garman RH, Greenspan BJ, and Myers RC (1985). Acute toxicity and irritancy of glutaral-dehyde.The Toxicologist5: 204.
3.
3. Buckley LA, Jiang XZ, James RA, Morgan KT, and Barrow CS (1984). Respiratory tract lesions induced by sensory irritants at the RD50 concentration.Toxicol. Appl. Pharmacol.74: 417–429.
4.
4. Casanova M, Deyo DF, and Heck Hd'A (1989). Co-valent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 rats: Analysis of formaldehyde and DNA by high-performance liquid chromatography and provisional pharmacokinetic interpretation.Fundam. Appl. Toxicol.12: 397–417.
5.
5. Casanova M and Heck Hd'A (1987). Further studies of the metabolic incorporation and covalent binding of inhaled [3H]- and [14C]formaldehyde in Fischer-344 rats: Effect of glutathione depletion.Toxicol. Appl. Pharmacol.80: 105–121.
6.
6. Chang JCF, Gross EA, Swenberg JA, and Barrow CS (1983). Nasal cavity deposition, histopathology and cell proliferation after single or repeated formaldehyde exposure in B6C3F1 mice and F-344 rats.Toxicol. Appl. Pharmacol:82: 1–13.
7.
7. Chien YW and Chang S-F (1987). Intranasal drug delivery for systemic medications. In: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 4, No. 2, SD Bruck (ed). CRC Press, Boca Raton, pp. 67–194.
8.
8. Columbano A, Ledda-Columbano GM, Coni P, and Pani P (1987). Failure of mitogen-induced cell proliferation to achieve initiation of rat liver carcinogenesis.Carcinogenesis8: 345–347.
9.
9. Craddock VM (1976). Cell prolifcration and experimental liver cancer. In: Liver Cell Cancer, HM Cameron, CA Linsell, and GP Warwick, (eds). Elsevier Publishing Co., Amsterdam, pp. 153–201.
10.
10. Craft TR, Bermudez E, and Skopek TR (1987). Formaldehyde mutagenesis and formation of DNA-protein crosslinks in human lymphoblasts in vitro:Mutat. Res.176: 147–155.
11.
11. Dudley RE, Muggenburg BA, Cuddihy RG, and Mc-Clellan RO (1980). Nasal absorption of DTPA in rats.Health Physics38: 763–768.
12.
12. Farber E (1982). Chemical carcinogenesis. A biologic perspective.Am. J. Pathol.106: 271–296.
13.
13. Greenspan BJ, Ballantyne B, Fowler EH, and Snellings \VM (1985). Subchronic inhalation toxicity of glutaraldehyde.The Toxicologist5: 29.
14.
14. Gorman SP, Scott EM, and Russell AD (1980). A review: Antimicrobial activity, uses, and mechanism of action of glutaraldehyde.J. Appl. Bacteriol.48: 161–190.
15.
15. Hemminki K and Suni R (1984). Sites of reaction of glutaraldehyde and acctaldehyde with nucleosides.Arch. Toxicol.55: 186–190.
16.
16. Kerns WD, Pavkov KL, Donofrio DJ, Gralla EJ, and Swenberg JA (1983). Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure.Cancer Res.43: 4382–4392.
17.
17. Levin DE, Hollstein M, Christman MF, Schwiers EA, and Ames BN (1982). A new Salmonella tester strain (TA102) with A-T base pairs at the site of mutation detects oxidative mutagens. Proc. Natl. Acad. Sci. USA79: 7445–7449.
18.
18. Luna LG (ed). (1968). Manual of Histologic Staining Methods, 3rd ed.McGraw-Hill Book Co., New York, p. 5.
19.
19. Marnett LJ, Hurd HK, Hollstein MC, Levin DE, Es-terbauer H, and Ames BN (1985). Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104.Mutat. Res.148: 25–34.
20.
20. Miller FJ and Graham JA (1988). Research needs and advances in inhalation dosimetry identified through the use of mathematical dosimetry models of ozone.Toxicol. Lett.44: 231–246.
21.
21. Monticello TM and Morgan KT (1990). Cell proliferation in rat nasal respiratory epithelium following three months exposure to formaldehyde gas.The Toxicologist10: 181.
22.
22. Monticello TM, Morgan KT, Everitt JI, and Popp JA (1989). Effects of formaldehyde gas on the respiratory tract of rhesus monkeys. Pathology and cell proliferation.Am. J. Pathol.134: 515–527.
23.
23. Monticello TM, Morgan KT, and Hum ME (1989). An alternative denominator in the labeling index equation for rapid determination of cell proliferation rates in nasal epithelia.Toxicol. Pathol.18: 24–31.
24.
24. Morgan KT, Jiang XZ, Starr TB, and Kerns WD (1986). More precise localization of nasal tumors associated with chronic exposure of F-344 rats to formaldehyde gas.Toxicol. Appl. Pharmacol.82: 264–271.
25.
25. Morgan KT and Monticello TM (1990). Airflow, gas deposition, and lesion distribution in the nasal passages.Environ. Health Perspect.88: 209–218.
26.
26. Morgan KT and Monticello TM (1989). Airflow, mu- cociliary clearance, and lesion distribution in the nasal passages of experimental animals. In: Nasal Carcinogenesis in Rodents: Relevance to Human Health Risk, VJ Feron and MC Bosland (eds). Pudoc Publishing, Wageningen, The Netherlands, pp. 36–41.
27.
27. Morgan KT, Monticello TM, Fleishman A, and Patra AL (1989). Preparation of rat nasal airway casts and their application to studies of nasal airflow. In: Extrapolation of Dosimetric Relationships for Inhaled Particles and Gases, JD Crapo, ED Smolko, FJ Miller, and AW Hayes (eds). Academic Press, San Diego, pp. 45–58.
28.
28. Morgan KT, Patterson DL, and Gross EA (1986). Responses of the nasal mucociliary apparatus of F-344 rats to formaldehyde gas.Toxicol. Appl. Pharmacol.82: 1–13.
29.
29. Morris JB and Cavanagh DG (1986). Deposition of ethanol and acetone vapors in the upper respiratory tract of the rat.Fundam. Appl. Toxicol.6: 78–88.
30.
30. Morris JB, Clay RJ, and Cavanagh DG (1986). Spe- cies differences in upper respiratory tract deposition of acetone and ethanol vapors.Fundam. Appl. Toxicol.7: 671–680.
31.
31. Munton RJ and Russell AD (1973). Effect of glutar-aldehyde on cell viability, triphenyl tetrazolium reduction, oxygen uptake and β-galactosidase activity inEscherichia coli. J. Appl. Microbiol.26: 508–511.
32.
32. Petridou-Fischer J, Whaley SL, and Dahl AR (1987). In vivo metabolism of nasally instilled dihydrosafrole [l-(3,4-methylenedioxyphenyl)-propane] in dogs and monkeys.Chem.-Biol. Interactions64: 1–12.
33.
33. Petridou-Fischer J, Whaley SL, and Dahl AR (1988). In vivo metabolism of nasally instilled ben-zo[a]pyrene in dogs and monkeys.Toxicology48: 31–40.
34.
34. Proetz AW (1951). Air currents in the upper respiratory tract and their clinical importance.Ann. Otol. Rhinol. Laryngol.60: 439–467.
35.
35. Sabatini DD, Bensch K, and Barrnett RJ (1963). Cytochemistry and electron microscopy. The preservation of cellular ultrastructure and enzymatic activity by aldehyde fixation.J. Cell Biol.17: 19–58.
36.
36. Starr TB, Gibson JE, Barrow CS, Boreiko CJ, Heck Hd'A, Levine RJ, Morgan KT, and Swenberg JA (1985). Estimating human cancer risk from formaldehyde: Critical issues. In: Advances in Chemistry Series, Formaldehyde Analytical Chemistry and Toxicology, V Turoski (ed). American Chemical Society, Washington, D.C., pp. 299–333.
37.
37. Stott WT and McKenna MJ (1984). The comparative absorption and excretion of chemical vapors by the upper, lower, and intact respiratory tract of rats.Fundam. Appl. Toxicol.4: 594–602.
38.
38. Stott WT, Reitz RH, Schumann AM, and Watanbe PG (1981). Genetic and nongenetic events in neoplasia.Fd. Cosmet. Toxicol.19: 567–576.
39.
39. Swenberg JA, Barrow CS, Boreiko CJ, Heck Hd'A, Levine RJ, Morgan KT, and Starr TB (1983). Nonlinear biological responses to formaldehyde and their implications for carcinogenic risk assessment.Carcinogenesis4: 945–952.
40.
40. Swenberg JA, Gross EA, and Randall HW (1986). Localization and quantitation of cell proliferation following exposure to nasal irritants. In: Toxicology of the Nasal Passages, CS Barrow (ed). Chemical Industry Institute of Toxicology Series, Hemisphere Publishing Co., New York, pp. 291–300.
41.
41. Swenberg JA, Kerns WD, Mitchell RI, Gralla EJ, and Pavkov KL (1980). Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor.Cancer Res.40: 3398–3402.
42.
42. Woutersen, RA, Appelman, LM, Wilmer, JWGM, Flake, HE, and Feron, VJ, (1987). Subchronic (13-week) inhalation toxicity study of formaldehyde in rats.J. Appl. Toxicol.7: 43–49.
43.
43. Young JT (1981). Histopathologic examination of the rat nasal cavity.Fundam. Appl. Toxicol.1: 309–312.
