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Toxicologic Pathology
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Toxicologic and Carcinogenic Effects of the Type IV Phosphodiesterase Inhibitor RP 73401 on the Nasal Olfactory Tissue in Rats

Michael V. Pino

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

Marion G. Valerio

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

Glen K. Miller

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

Jeffrey L. Larson

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA, School of Medicine, Philadelphia, Pennsylvania, USA

David L. Rosolia

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

Zaid Jayyosi

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

Christopher N. Crouch

RCC Research and Consulting Services Ltd., Itingen, Switzerland

John Q. Trojanowski

Department of Pathology and Laboratory Medicine, University of Pennsylvania

Lee E. Geiger

Rhône-Poulenc Rorer Research and Development, Collegeville, Pennsylvania, USA

RP 73401, a type IV phosphodiesterase inhibitor, caused toxic effects in the nasal olfactory region of Sprague-Dawley rats when administered by either oral or inhalation exposure. A single oral administration of RP 73401 (at a dose of ≥50 mg/kg) or 5-day inhalation exposure (1 hr/day) at a dose of approximately 1.0 mg/kg per day caused degeneration and sloughing of the olfactory surface epithelium. Degeneration and loss of Bowman's glands were noted in the underlying lamina propria and submucosa. Electron microscopy of these lesions demonstrated that sustentacular cells and the epithelial cells lining Bowman's glands were the primary target cells in the olfactory mucosa. The earliest ultrastructural changes detected in these cells were dilatation and vesiculation of the endoplasmic reticulum, suggesting that metabolic activation is important for the toxic effects. In repeated-dose studies, 13 wk of oral dosing at 2.0 or 6.0 mg/kg per day resulted in subtle disorganization of the olfactory epithelium, whereas basal cell hyperplasia in the olfactory epithelium was identified in a 6-month inhalation study at a dose of 1.0 mg/kg per day. A 2-yr inhalation carcinogenicity study resulted in tumors of the nasal olfactory region in rats treated at 0.5 and 1.0 mg/kg per day. Most tumors were classified as olfactory neuroblastomas, and immunohistochemistry on selected tumors was consistent with their being of neuroectodermal origin. Of the species studied (rat, mouse, and dog), the olfactory toxicity of RP 73401 was confined to the rat, and the toxicity was likely related to metabolic activation by olfactory epithelial cells rather than the phosphodiesterase activity of the compound.

Key Words: Nasal toxicity • olfactory toxicity • neuroblastoma • neuroepithelial carcinoma • phosphodiesterase inhibitor • electron microscopy • immunohistochemistry • rats

References

  • Ashton MJ, Cook DC, Fenton G., Karlsson J-A., Palfreyman MN, Raeburn D., Ratcliffe AJ, Souness JE, Thurairatnam S., and Vicker N. (1994). Selective type IV phosphodiesterase inhibitors as antiasthmatic agents: The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues. J. Med. Chem. 37: 1696-1703.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Bergman K., Muller L., and Weberg Teigen S (1996). The genotoxicity and carcinogenicity of paracetamol: A regulatory (re)view. Mutat. Res. 349: 263-288.[Web of Science][Medline] [Order article via Infotrieve]
  • Bernstein DM, Moss O., and Fleissner H. (1984). A brush fed micronizing jet mill powder aerosol generator for producing a wide range of concentrations of respirable particles. In: "Aerosols" Science, Technology and Industrial Application of Airborne Particles, BYH Liu, DYH Pui, and H Fissan (eds). Elsevier Science, New York, pp. 721-724.
  • Bogdanffy MS, Mazaika TJ, and Fasano WJ (1989). Early cell proliferative and cytotoxic effects of phenacetin on rat nasal mucosa. Toxicol. Appl. Pharmacol. 98: 100-112.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Bonnefoi M., Monticello TM, and Morgan KT (1991). Toxic and neoplastic responses in the nasal passages: Future research needs. Exp. Lung Res. 17: 853-868.[Web of Science][Medline] [Order article via Infotrieve]
  • Brandt I., Brittebo EB, Feil VJ, and Bakke JE (1990). Irreversible binding and toxicity of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in the olfactory mucosa of mice. Toxicol. Appl. Pharmacol. 103: 491-501.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Brown HR (1990). Neoplastic and potentially preneoplastic changes in the upper respiratory tract of rats and mice. Environ. Health Perspect. 85: 291-304.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Brown HR, Monticello TM, Maronpot RR, Randall HW, Hotchkiss JR, and Morgan KT (1991). Proliferative and neoplastic lesions in the rodent nasal cavity. Toxicol. Pathol. 19: 358-372.[Web of Science][Medline] [Order article via Infotrieve]
  • Deamer NJ and Genter MB (1995). Olfactory toxicity of diethyldithiocarbamate (DDTC) and disulfiram and the protective effect of DDTC against the olfactory toxicity of dichlobenil. Chem. Biol. Interact. 95: 215-226.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Emeigh Hart SG, Cartun RW, Wyand DS, Khairallah EA, and Cohen SD (1995). Immunohistochemical localization of acetaminophen in target tissues of the CD-1 mouse: Correspondence of covalent binding with toxicity. Fundam. Appl. Toxicol. 24: 260-274.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Feron VJ, Woutersen RA and Spit BJ (1986). Pathology of chronic nasal toxic responses including cancer. In: Toxicology of the Nasal Passages, CS Barrow (ed). Hemisphere Publishing Corp., Washington, D.C., pp. 67-89.
  • Feron VJ, Woutersen RA, van Garderen-Hoetmer A., and Dreef-van der Muelen HC (1990). Upper respiratory tract tumors in Cpb:WU (Wistar random) rats. Environ. Health Perspect. 85: 305-315.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Gaskell BA (1990). Nonneoplastic changes in the olfactory epithelium—experimental studies. Environ. Health Perspect. 85: 275-280.[Web of Science][Medline] [Order article via Infotrieve]
  • Genter MB, Llorens J., O'Callaghan JP, Peele DB, Morgan KT, and Crofton KM (1992). Olfactory toxicity of β,β'-iminodipropionitrile in the rat. J. Pharmacol. Exp. Ther. 263: 1432-1439.[Abstract/Free Full Text]
  • Gross EA, Swenberg JA, Fields S., and Popp JA (1982). Comparative morphometry of the nasal cavity in rats and mice. J. Anat. 135: 83-88.[Web of Science][Medline] [Order article via Infotrieve]
  • Harkema JR and Morgan KT (1996). Normal morphology of the nasal passages in laboratory rodents. In: Respiratory System (Monographs on Pathology of Laboratory Animals), 2nd ed., TC Jones, DL Dungworth, and U Mohr (eds). Springer-Verlag, New York, pp. 3-17.
  • Haseman JK and Hailey JR (1997). An update of the National Toxicology Program database on nasal carcinogens. Mutat. Res. 380: 3-11.[Web of Science][Medline] [Order article via Infotrieve]
  • Hayes HM and Wilson GP (1983). Comparative aspects of nasal passage carcinoma in dogs with man. In: Nasal Tumors in Animals and Man, G Reznik and SF Stinson (eds). CRC Press Inc., Boca Raton, Florida, pp. 229-238.
  • Hecht SS, Castonguay A., and Hoffmann D. (1983). Nasal cavity carcinogens: Possible routes of metabolic activation. In: Nasal Tumors in Animals and Man, G Reznik and SF Stinson (eds). CRC Press Inc., Boca Raton, Florida, pp. 201-232.
  • Holbrook EH, Mieleszko Szumowski KE, and Schwob JE (1995). An immunochemical, ultrastructural, and developmental characterization of the horizontal basal cells of rat olfactory epithelium. J. Comp. Neurol. 363: 129-146.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Jayyosi Z., Muc M., Knoble D., Pino M., Mirsky M., Toutain H., Cassidy K., Geiger L., and Kelley M. (1998). Mechanism of species specific nasal toxicity of the phosphodiesterase IV inhibitor RP 73401 in the rat. Toxicol. Sci. 42(1-S): 242-243 (abstract).
  • Johansson SL (1981). Carcinogenicity of analgesics: Long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen). Int. J. Cancer 27: 521-529.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kuschner M., Laskin S., Drew RT, Cappiello V., and Nelson N. (1975). Inhalation carcinogenicity of alpha halo ethers. Arch. Environ. Health 30: 73-77.[Web of Science][Medline] [Order article via Infotrieve]
  • Larson JL, Pino MV, Geiger LE, and Simeone CR (1996). The toxicity of repeated exposures to rolipram, a Type IV phosphodiesterase inhibitor, in rats. Pharmacol. Toxicol. 78: 44-49.[Web of Science][Medline] [Order article via Infotrieve]
  • Leong Bkj, Kociba RJ, and Jersey GC (1981). A lifetime study of rats and mice exposed to vapors of bis(chloromethyl)ether. Toxicol. Appl. Pharmacol. 58: 269-281.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Mery S., Gross EA, Joyner DR, Godo M., and Morgan KT (1994). Nasal diagrams: A tool for recording the distribution of nasal lesions in rats and mice. Toxicol. Pathol. 22: 353-372.[Abstract/Free Full Text]
  • Miller RR, Young JT, Kociba RJ, Keyes DG, Bodner KM, Calhoun LL, and Ayres JA (1985). Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice. Drug Chem. Toxicol. 8: 1-42.[Web of Science][Medline] [Order article via Infotrieve]
  • Molenaar WM, Rorke LB, and Trojanowski JQ (1995). Neural tumors. In: Diagnostic Immunopathology, 2nd ed., RB Colvin, AK Bhan, and RT McCluskey (eds). Raven Press, Ltd., New York, pp. 651-68.
  • Molenaar WM and Trojanowski JQ (1994). Primitive neuroectodermal tumors of the central nervous system in childhood: Tumor biological aspects. Crit. Rev. Oncol. Hematol. 17: 1-25.[Medline] [Order article via Infotrieve]
  • Monticello TM and Morgan KT (1997). Chemically-induced nasal carcinogenesis and epithelial cell proliferation: A brief review. Mutat. Res. 380: 33-41.[Web of Science][Medline] [Order article via Infotrieve]
  • Reed CJ (1993). Drug metabolism in the nasal cavity: Relevance to toxicology. Drug Metab. Rev. 25: 173-205.[Web of Science][Medline] [Order article via Infotrieve]
  • Renne RA, Brown HR, and Jokinen MP (1992). Morphology of nasal lesions induced in Osborne-Mendel rats and B6C3F1 mice by chronic inhalation of allyl glycidyl ether. Toxicol. Pathol. 20: 416-425.[Web of Science][Medline] [Order article via Infotrieve]
  • Reznik GK, Reznik-Schuller H., Ward JM, and Stinson SF (1980). Morphology of nasal-cavity tumours in rats after chronic inhalation of 1,2-dibromo-3-chloropropane. Br. J. Cancer 42: 772-781.[Web of Science][Medline] [Order article via Infotrieve]
  • Reznik-Schuller H. (1978). Ultrastructure of N-diethylnitrosamine induced tumours in the nasal olfactory region of the Syrian golden hamster. J. Anat. 124: 161-164.
  • Reznik-Schuller H. (1983). Pathogenesis of tumors induced with N-nitrosomethylpiperazine in the olfactory region of the rat nasal cavity. J. Natl. Cancer Inst. 71: 165-172.[Web of Science][Medline] [Order article via Infotrieve]
  • Sandusky GE, Vodicnik MJ, and Tamura RN (1991). Cardiovascular and adrenal proliferative lesions in Fischer 344 rats induced by long-term treatment with Type III phosphodiesterase inhibitors (positive inotropic agents), isomazole and indolidan. Fundam. Appl. Toxicol. 16: 198-209.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Scherf HR, Frei E., and Wiessler M. (1989). Carcinogenic properties of N-nitrodimethylamine and N-nitromethylamine in the rat. Carcinogenesis 10: 1977-1981.[Abstract/Free Full Text]
  • Schuller HM (1989). Nitrosamine-induced nasal cavity carcinogenesis in rodents. In: Nasal Carcinogenesis in Rodents: Relevance to Human Health Risk: Proceedings of the TNO-CIVO/NYU Nose Symposium, Veldhoven, Netherlands, 24-28 October 1988, VJ Feron and MC Bosland (eds). Pudoc Wageningen, Wageningen, Netherlands, pp. 63-69.
  • Schwartz LW, Hahn FF, Keenan KP, Keenan CM, Brown HR, and Mann PC (1994). Proliferative lesions of the rat respiratory tract. In: Guides for Toxicologic Pathology, Society of Toxicologic Pathologists/American Registry of Pathology/ Armed Forces Institute of Pathology, Washington, D.C., pp. 1-24.
  • Schwob JE, Huard Jmt, Luskin MB, and Youngentob SL (1994). Retroviral lineage studies of the rat olfactory epithelium. Chem. Senses 19: 671-682.[Abstract/Free Full Text]
  • Schwob JE, Youngentob SL, and Mezza RC (1995). Reconstitution of the rat olfactory epithelium after methyl bromide-induced lesion. J. Comp. Neurol. 359: 15-37.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Shibuya K., Tajima M., and Nunoya T. (1996). Olfactory undifferentiated carcinoma with endocranial extension in a Fischer-344 rat. Toxicol. Pathol. 24: 361-364.[Abstract/Free Full Text]
  • Stinson SF (1983). Nasal cavity cancer in laboratory animal bioassays of environmental compounds. In: Nasal Tumors in Animals and Man, G Reznik and SF Stinson (eds). CRC Press, Boca Raton, Florida, pp. 157-169.
  • Thorton-Manning JR and Dahl AR (1997). Metabolic capacity of nasal tissue interspecies comparisons of xenobiotic-metabolizing enzymes. Mutat. Res. 380: 43-59.[Web of Science][Medline] [Order article via Infotrieve]
  • Tucker MJ (1975). Carcinogenic action of quinoxaline 1,4-dioxide in rats. J. Natl. Cancer Inst. 55: 137-146.[Web of Science][Medline] [Order article via Infotrieve]
  • U.S. Environmental Protection Agency (1984). Special Review of Certain Pesticides Products. Alachlor: Position Document 1, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington D.C., PB 85-175503.
  • Vollrath M., Altmannsberger M., Weber K., and Osborn M. (1986). Chemically induced tumors of rat olfactory epithelium: A model for human esthesioneuroepithelioma. J. Natl. Cancer Inst. 76: 1205-1216.[Web of Science][Medline] [Order article via Infotrieve]
  • Westwood FR, Iswaran TJ, and Greaves P. (1990). Pathologic changes in blood vessls following an inotropic vasodilator (ICI 153,110) to the rat. Fundam. Appl. Toxicol. 14: 797-809.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Young JT (1981). Histopathologic examination of the rat nasal cavity. Fundam. Appl. Toxicol. 1: 309-312.[Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 27, No. 4, 383-394 (1999)
DOI: 10.1177/019262339902700401
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