Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Click here to sign up for SAGE Journal Email Alerts today!

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Robinson, D. A.
Right arrow Articles by Reed, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Robinson, D. A.
Right arrow Articles by Reed, C. J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Three-Dimensional Mapping of the Lesions Induced by β-β'-Iminodiproprionitrile, Methyl Iodide and Methyl Methacrylate in the Rat Nasal Cavity

Darren A. Robinson

School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom

John R. Foster

AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

John A. Nash

Syngenta CTL, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom

Celia J. Reed

School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom, c.j.reed{at}livjm.ac.uk

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.

Key Words: 3D mapping • methyl iodide • methyl methacrylate • β-β'-iminodipropionitrile • rat • nasal cavity.

References

  • Adams JD, Laegreid WW, Huijzer JC, Hayman C., Yost GS ( 1988). Pathology and glutathione status in 3-methylindole-treated rodents. Res Commun Chem Pathol Pharmacol 60: 323—336.[Web of Science][Medline] [Order article via Infotrieve]
  • Banger KK, Foster JR, Lock EA, Reed CJ ( 1994). Immunohistochemical localisation of six glutathione S-transferases within the nasal cavity of the rat. Arch Toxicol 69: 91—98.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Bogdanffy MS, Randall HW, Morgan KT (1986). Histochemical localisation of aldehyde dehydrogenase in the respiratory tract of the Fischer-344 rat. Toxicol Appl Pharmacol 82: 560—567.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pharmacol 88: 183—194.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pharmacol 103: 491—501.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Chamberlain MP, Lock EA, Reed CJ (1998). Investigations of the pathways of toxicity of methyl iodide in the rat nasal cavity. Toxicology 129: 169—181.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Toxicol 72: 420—428.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Dahl AR, Hadley WM (1991). Nasal cavity enzymes involved in xenobiotic metabolism—Effects on the toxicity of inhalants. CRC Crit Rev Toxicol 21: 345—372.[CrossRef]
  • 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 Pharmacol 35: 4543—4554.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Gaskell BA, Hext PM, Pigott GH, Hodge MCH, Tinston DJ (1988). Olfactory and hepatic changes following inhalation of 3-trifluoromethyl pyridine in rats. Toxicology 50: 57—68.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Toxicol 9: 31—39.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Ther 263: 1432—1439.[Abstract/Free Full Text]
  • 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 Toxicol 24: 260—274.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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. Toxicology 156: 119—128.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Sci 42: 241.
  • 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 Pharmacol 143: 47—55.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Johansson SL (1981). Carcinogenicity of analgesics: Long-term treatment of Sprague—Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetaminophen). Int J Cancer 27: 521—529.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Johnson NF, Hotchkiss JA, Harkema JR, Henderson RF (1990). Proliferative responses of rat nasal epithelia to ozone. Toxicol Appl Pharmacol 103: 143— 155.
  • Keenan CM, Kelly DP, Bogdanffy MS (1990). Degeneration and recovery of rat olfactory epithelium following inhalation of dibasic esters. Fundam Appl Toxicol 15: 381—393.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pharmacol 145: 388—398.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pharmacol 121: 253—263.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Llorens J., Dememes D. (1994). Hair cell degeneration resulting from 3,3'iminodipropionitrile toxicity in the rat vestibular epithelia. Hear Res 76: 78—86.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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. Toxicology 158: 109—118.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pathol 22: 353—372.[Web of Science]
  • 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 Pharmacol 111: 409—421.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Morgan KT (1984). Nasal dosimetry, lesion distribution, and the toxicological pathologist: A brief review. Inhal Toxicol 6: 41—57.
  • Morgan KT (1997). A brief review of formaldehyde carcinogenesis in relation to rat nasal pathology and human health risk assessment. Toxicol Pathol 25: 291—307.[Abstract/Free Full Text]
  • 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. Toxicologist 36: 112.
  • 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 Pharmacol 110: 223—240.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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.
  • Reed CJ (1993). Drug metabolism in the nasal cavity: Relevance to toxicology. Drug Met Rev 25: 173—205.[Web of Science][Medline] [Order article via Infotrieve]
  • Reed CJ, Gaskell BA, Banger KK, Lock EA ( 1995). Olfactory toxicity of methyl iodide in the rat. Arch Toxicol 70: 51—56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 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 Pathol 31(3): 333—340.
  • Thornton-Manning JR, 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]
  • Turk MAM, Henk WG, Flory W. (1987). 3-Methylindole-induced nasal mucosal damage in mice. Vet Pathol 24: 400—403.[Abstract]
  • Young JT (1981). Histopathological examination of the rat nasal cavity. Fundam Appl Toxicol 1: 309—312.[Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 31, No. 3, 340-347 (2003)
DOI: 10.1080/01926230390204388
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Toxicol PatholHome page
S. A. Carey, K. R. Minard, L. L. Trease, J. G. Wagner, G. J. M. Garcia, C. A. Ballinger, J. S. Kimbell, C. G. Plopper, R. A. Corley, E. M. Postlethwait, et al.
Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques
Toxicol Pathol, January 1, 2007; 35(1): 27 - 40.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
J. R. Harkema, S. A. Carey, and J. G. Wagner
The Nose Revisited: A Brief Review of the Comparative Structure, Function, and Toxicologic Pathology of the Nasal Epithelium
Toxicol Pathol, April 1, 2006; 34(3): 252 - 269.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
K. Kai, H. Satoh, T. Kajimura, M. Kato, K. Uchida, R. Yamaguchi, S. Tateyama, and K. Furuhama
Olfactory Epithelial Lesions Induced by Various Cancer Chemotherapeutic Agents in Mice
Toxicol Pathol, October 1, 2004; 32(6): 701 - 709.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Robinson, D. A.
Right arrow Articles by Reed, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Robinson, D. A.
Right arrow Articles by Reed, C. J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?