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Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

New York Medical College, Department of Pathology, Valhalla, New York 10595, USA

Correspondence: Address correspondence to Gary M. Williams, Department of Pathology New York Medical College, Valhalla, NY 10595; e-mail: GaryWilliams{at}nymc.edu

Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

Key Words: Nose • cancer • toxicity • DNA adducts • mutagens • metabolism • safety assessment

Abbreviations: 2,6-DMA, 2,6-dimethylaniline • 3-MI, 3-methylindole • ADCP, 3,5-aminodichloropyridine • APAP, acetaminophen • BGs, Bowman’s glands • CYP(s), cytochrome P450(s) • DCB(s), dichlorobenzene(s) • DCBN, 2,6-dichlorobenzonitrile • GSH, glutathione (reduced) • HMPA, hexamethylphosphoramide • IARC, International Agency for Research on Cancer • IDPN, β,β'-iminodipropionitrile • NM, nasal mucosa • NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone • NPIP, N-nitrosopiperidine • NTP, National Toxicology Program • OE, olfactory epithelium • OM, olfactory mucosa • PA, phenacetin • PCB(s), polychlorinated biphenyl(s) • PDR, Physicians’ Desk Reference • RE, respiratory epithelium, ciliated pseudostratified • SD, Sprague

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