The nasal cavity is an important target organ for toxicity, and many chemicals induce site-specific lesions in this region. The factors responsible for this site-selectivity have not been unequivocally identified, but probably include regional dosimetry and bioactivation. The purpose of this study was to map, in 3 dimensions, the lesions induced by β-β'-iminodipropionitrile (IDPN), methyl iodide (MeI) and methyl methacrylate (MMA) in the rat nasal cavity. Animals were administered IDPN (150 mg/kg, IP) or exposed via inhalation to MeI (100 ppm, 2 hours) or MMA (400 ppm, 4 hours) and sacrificed after 24 hours. Heads were decalcified, step-sections (1 every 400 μm) cut and stained, and the severity of the epithelial lesion graded as mild (vacuolation and pyknosis), moderate (undulation and mild stripping), or marked (complete stripping). These grades were mapped onto a 3D-model of a rat nasal cavity using the KS400 imaging system (Imaging Associates, Thame, UK). Despite the different routes of exposure the lesions induced by the 3 compounds had very similar distributions, predominantly affecting the dorsal-medial aspects of the ethmoturbinates and, in the case of MMA, the organ of Rodolfo Masera. These results suggest that, with these chemicals, local bioactivation plays a more important role than dosimetry in determining lesion distribution.
Adams JD, Laegreid WW, Huijzer JC, Hayman C., Yost GS ( 1988). Pathology and glutathione status in 3-methylindole-treated rodents. Res Commun Chem Pathol Pharmacol60: 323—336.
2.
Banger KK, Foster JR, Lock EA, Reed CJ ( 1994). Immunohistochemical localisation of six glutathione S-transferases within the nasal cavity of the rat. Arch Toxicol69: 91—98.
3.
Bogdanffy MS , Randall HW, Morgan KT (1986). Histochemical localisation of aldehyde dehydrogenase in the respiratory tract of the Fischer-344 rat . Toxicol Appl Pharmacol82: 560—567.
4.
Bogdanffy MS , Randall HW, Morgan KT (1987). Biochemical quantitation and histochemical localisation of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicol Appl Pharmacol88: 183—194.
5.
Brandt I., Brittebo EB, Feil VJ, Bakke JE (1990). Irreversible binding and toxicity of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in the olfactory mucosa of mice. Toxicol Appl Pharmacol103: 491—501.
6.
Chamberlain MP, Lock EA, Reed CJ (1998). Investigations of the pathways of toxicity of methyl iodide in the rat nasal cavity. Toxicology129: 169—181.
7.
Chamberlain MP, Lock EA, Rimmel BA, Reed CJ (1998). The role of glutathione S-transferase and cytochrome P450-dependent metabolism in the olfactory toxicity of methyl iodide in the rat. Arch Toxicol72: 420—428.
8.
Dahl AR, Hadley WM (1991). Nasal cavity enzymes involved in xenobiotic metabolism—Effects on the toxicity of inhalants. CRC Crit Rev Toxicol21: 345—372.
9.
Foster JR, Elcome CR, Boobis AR, Davies DS, Sesardic D., McQuade J., Robson RT, Howard C., Lock EA ( 1986). Immunohistochemical localisation of cytochrome P450 in hepatic and extra-hepatic tissues of the rat with a monoclonal antibody against cytochrome P450c. Biochem Pharmacol35: 4543—4554.
10.
Gaskell BA, Hext PM, Pigott GH, Hodge MCH, Tinston DJ (1988). Olfactory and hepatic changes following inhalation of 3-trifluoromethyl pyridine in rats. Toxicology50: 57—68.
11.
Genter MB, Deamer NJ, Cao Y., Levi PE ( 1994). Effects of p450 inhibition and induction on the olfactory toxicity of beta,beta'-iminodipropionitrile (IDPN) In the rat. J Biochem Toxicol9: 31—39.
12.
Genter MB, Llorens J., O'Callaghan JP, Peele DB, Morgan KT, Crofton KM (1992). Olfactory toxicity of b,b'-iminodipropionitrile in the rat. J Pharmacol Exp Ther263: 1432—1439.
13.
Hart SE, Cartun RW, Wyand DS, Khairallah EA, Cohen SD (1995). Immunohistochemical localization of acetaminophen in target tissues of the CD-1 mouse: Correspondence of covalent binding with toxicity. Fundam Appl Toxicol24: 260—274.
14.
Hext PM, Pinto PJ, Gaskell BA (2001). Methyl methacrylate toxicity in rat nasal epithelium: Investigation of the time course of lesion development and recovery from short term vapour inhalation. Toxicology156: 119—128.
15.
Hext PM, Pinto PJ, Rimmel BA, Green T. (1998). Inhalation studies on the short term effects of inhaled methylmethacrylate on the rat nasal epithelium. Toxicol Sci42: 241.
16.
Hubal EA, Schlosser PM, Conolly RB, Kimbell JS (1997). Comparison of inhaled formaldehyde dosimetry predictions with DNA-protein crosslink measurements in the rat nasal passages. Toxicol Appl Pharmacol143: 47—55.
17.
Johansson SL (1981). Carcinogenicity of analgesics: Long-term treatment of Sprague—Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetaminophen). Int J Cancer27: 521—529.
18.
Johnson NF, Hotchkiss JA, Harkema JR, Henderson RF (1990). Proliferative responses of rat nasal epithelia to ozone. Toxicol Appl Pharmacol103: 143— 155.
19.
Keenan CM, Kelly DP, Bogdanffy MS (1990). Degeneration and recovery of rat olfactory epithelium following inhalation of dibasic esters. Fundam Appl Toxicol15: 381—393.
20.
Kimbell JS, Godo MN, Gross EA, Joyner DR, Richardson RB, Morgan KT (1997). Computer simulation of inspiratory airflow in all regions of the F344 rat nasal passages. Toxicol Appl Pharmacol145: 388—398.
21.
Kimbell JS, Gross EA, Joyner DR, Godo MN, Morgan KT (1993). Application of computational fluid dynamics to regional dosimetry of inhaled chemicals in the upper respiratory tract of the rat. Toxicol Appl Pharmacol121: 253—263.
22.
Llorens J., Dememes D. (1994). Hair cell degeneration resulting from 3,3'iminodipropionitrile toxicity in the rat vestibular epithelia. Hear Res76: 78—86.
23.
Mainwaring G., Foster JR, Lund V., Green T. (2001). Methyl methacrylate toxicity in rat nasal epithelium: Studies of the mechanism of action and comparisons between species. Toxicology158: 109—118.
24.
Mery S., Gross EA, Joyner DR, Godo MN, Morgan KT (1993). Nasal diagrams—A tool for recording the distribution of nasal lesions in rats and mice. Toxicol Pathol22: 353—372.
25.
Monticello TM, Miller FJ, Morgan KT (1991). Regional increases in rat nasal epithelial cell proliferation following acute and sub-chronic inhalation of formaldehyde. Toxicol Appl Pharmacol111: 409—421.
26.
Morgan KT (1984). Nasal dosimetry, lesion distribution, and the toxicological pathologist: A brief review. Inhal Toxicol6: 41—57.
27.
Morgan KT (1997). A brief review of formaldehyde carcinogenesis in relation to rat nasal pathology and human health risk assessment. Toxicol Pathol25: 291—307.
28.
Morgan KT, Gross EA, Joyner DR, Ishmael J., Thake D. (1997). Proliferative nasal lesions induced in rats by alachlor, acetochlor and butachlor originate in specific regions of the olfactory mucosa. Toxicologist36: 112.
29.
Morgan KT, Kimbell JS, Monticello TM, Patra AL, Fleishman A. (1991). Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: Relevance to formaldehyde toxicity. Toxicol Appl Pharmacol110: 223—240.
30.
Niosh.Monohalomethanes. methyl chloride CH3Cl, methyl bromide CH3Br and methyl iodide CH3I. Current Intelligence Bulletin No. 43. 1984. Cincinnati, Ohio, National Institute for Occupational Safety and Health DHSS (NIOSH) Publication No. 84—117.
31.
Reed CJ (1993). Drug metabolism in the nasal cavity: Relevance to toxicology. Drug Met Rev25: 173—205.
32.
Reed CJ, Gaskell BA, Banger KK, Lock EA ( 1995). Olfactory toxicity of methyl iodide in the rat. Arch Toxicol70: 51—56.
33.
Robinson DA , Foster JR, Nash J., Reed CJ (2002). Development of methodology for the three dimensional modelling of the metabolic capacity of the rat nasal cavity using glutathione S-transferase 3-3 as an example. Toxicol Pathol31(3): 333—340.
34.
Thornton-Manning JR, Dahl AR (1997). Metabolic capacity of nasal tissue interspecies comparisons of xenobiotic-metabolizing enzymes. Mutat Res380: 43—59.
35.
Turk MAM , Henk WG, Flory W. (1987). 3-Methylindole-induced nasal mucosal damage in mice. Vet Pathol24: 400—403.
36.
Young JT (1981). Histopathological examination of the rat nasal cavity. Fundam Appl Toxicol1: 309—312.
