Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Abstract

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.

Assessment of the Medicines Lidocaine, Prilocaine, and Their Metabolites, 2,6-Dimethylaniline and 2-Methylaniline, for DNA Adduct Formation in Rat Tissues

“…Prilo formed a relatively high level of MA-derived DNA adduct in the liver, but no adduct was detected in UBE DNA in prilo-or MA-dosed or multidose groups, suggesting that MA is mainly bioactivated in the liver. The enzyme activities for both cytochrome P450 and sulfotransferase are the highest in the liver (DeBaun et al, 1970;Guengerich and Liebler, 1985), which is consistent with the relatively high adduct yield at this site (Gonçalves et al, 2001;Jeffrey et al, 2002Jeffrey et al, , 2006. The absence of MA adducts in the NM may indicate that the tissue concentration or metabolism of MA is different from DMA in the NM.…”

“…This indicates, as have other studies (Jeffrey et al, 2006), that formation of adducts is insufficient for carcinogenicity. Prilo formed a relatively high level of MA-derived DNA adduct in the liver, but no adduct was detected in UBE DNA in prilo-or MA-dosed or multidose groups, suggesting that MA is mainly bioactivated in the liver.…”

“…We previously reported, as did Short et al (1989), that DMA formed DNA adducts in the NM, the major target organ for its carcinogenicity, at higher levels than in the liver or testes (Jeffrey et al, 2002). Either DMA is concentrated in NM, readily activated there, or both, as shown for other chemicals of this type (reviewed in Jeffrey et al, 2006). Lido similarly formed DNA adducts in the NM, although to a lower level than DMA and with less dmd.aspetjournals.org tissue specificity than with DMA, the NM/liver DNA adduct ratio being approximately only 1:1 for lido compared with 10:1 for DMA.…”

Proliferative and Nonproliferative Lesions of the Rat and Mouse Respiratory Tract

“…Identification of metabolic functions of nasal epithelia has sparked considerable interest in the morphology of the nasal passages, and consequently, the recognition of chemically induced lesions has become more commonplace in recent years (Bond 1986;Dahl 1986;Reed 1993;C. Keenan, Kelly, and Bogdanffy 1990;Adams et al 1991;Jeffrey, Iatropoulos, and Williams 2006). In addition, there has been considerable recent interest in transport of toxicants into the brain via the olfactory nerves (Dorman et al 2002;Harkema, Carey, and Wagner 2006).…”

Toxicity of 4-methylimidazole on isolated brain mitochondria: using bothin vivoandin vitromethods

“…Other studies revealed that 4MI produced alveolar/bronchiolar adenoma and carcinoma in male and female mice (Cunha et al 2011). Hepatic histiocytosis, hepatocellular eosinophilic, and mixed cell foci in male and female rats were also noted (Jeffrey, Iatropoulos, and Williams 2006). However, the mechanisms underlying the 4MI-induced toxicity of 4MI is not known.…”