Nasal toxicity

The nose is usually the first site of contact in the respiratory tract for many airborne chemicals of environmental and occupational concern. Examples of human nasal effects include loss of olfactory function (e.g., anosmia and hyposmia), atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or sinonasal cancer related to exposure to certain metal dusts and vapors (Sunderman 2001). 

Differences among species in distribution patterns of histological changes may be caused by species variations in the distribution in the nasal epithelium of chemical-metabolizing enzymes. For example, in rats exposed to methyl methacrylate, nasal lesions were shown to be caused by the carboxylesterase mediated metabolism of methyl methacrylate to methacrylic acid, an irritant and corrosive metabohte. The distribution of these enzymes in the nasal tissues of man, rat, and hamster indicated a lower rate of metabolism in man compared to rat and hamster, suggesting a lower sensitivity to methacrylate in humans (Mainwaring et al. 2001). 

The normal gene expression in the rat nasal epithelium has been studied by using cDNA array technology (Hester et al. 2001). 

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Heck, H. d A., M. Casanova, M.J. McNulty, and C.W. Lam. 1986. Mechanisms of nasal toxicity induced by formaldehyde and acrolein. Pages 235-247 in C.S. Barrow (ed.). Toxicology of the Nasal Passages. Hemisphere Publishing, New York. 

Mery S, Larson JL, Butterworth BE, et al. 1994. Nasal toxicity of chloroform in male F-344 rats and female B6C3Fj mice following a 1-week inhalation exposure. Toxicol Appl Pharmacol 125(2) 214-227. 

Exposure Concentrations (ppm) Used in 3-Day (6 h/day) Inhalation Toxicity Studies in Male Rats with Nasal Toxicants... 

In subcbronic studies HMPA administered by gavage or in tbe drinking water of rats caused lesions in tbe nasal cavity. At 100 ppm in tbe drinking water for 90 days there was epithelial denudation, regeneration, and squamous metaplasia of the nasal cavity. At 1000 ppm nasal toxicity was more severe and testicular atrophy was induced in males. 

Keller DA, Marshall CE, Lee KP Subchronic nasal toxicity of hexamethylphosphoramide administered orally for 90 days. Fundam Appl Toxiro/40(1) 15-29, 1997... 

Ethylene glycols Formulation aid for nasal delivery Single and repeat-dose nasal toxicity (up to 14 days— intranasal rabbit) Mild local toxicity likely to be acceptable in clinical nasal formulations for short-term use 35... 

Feron VJ, Woutersen RA, Spit BJ. 1986. Pathology of chronic nasal toxic responses including cancer. Chem Ind Inst Toxicol Ser 7 67-89. 

Among various nasal toxicity studies, ciliotoxicity studies are of special interest due to the importance of maintaining optimal ciliary beating to protect the lower respiratory system from infections. If the drug formulation inhibits the ciliary beating, such inhibition needs to be completely reversible upon formulation removal [116]. 

Monteiro-Riviere NA, Popp JA. 1986. Ultrastructural evaluation of acute nasal toxicity in the rat respiratory epithelium in response to formaldehyde gas. Fundam Appl Toxicol 6 251-262. 

Sunderman, F. W., Jr. (2001). Nasal toxicity, carcinogenicity, and olfactory uptake of metals. Ann Clin... 

Inhalation of a high concentration of formaldehyde can lead to death. Animal studies indicated that exposure to 700 ppm for 2 hours was fatal to mice cats died of an 8-hours exposure. Chronic exposure to a 40-ppm concentration was lethal to mice, with symptoms of dyspnea, listlessness, loss of body weight, inflammation in the nasal tissues, and pathological changes in the nose, larynx, trachea, and bronchi. In addition to this, pathological changes in ovaries and uterus were observed in female mice. Neurotoxicity studies indicate that acute low-level exposure (5-20 ppm) for 3 h/day for 2 days can result in decreased motor activity in rats associated with neurochemical changes in dopamine [51-61-6] and 5-hydroxytryptamine [50-67-9] neurons. Similar to acrolein, formaldehyde can induce nasal toxicity short-term exposure to... 

Feron VJ Health risle associated with inflated nasal toxicants. Crit Rev Toxicol 2001 31 (3) 313-347. [PMiD 11405443] (Review.)... 

Riechelmann H, Deutschle T, Stuhlmiller A, Gronau S, Burner H (2004) Nasal toxicity of benzalkonium chloride. Am J Rhinol 18(5) 291-299... 

As the mucosa is highly sensitive to irritation, nasal toxicity of active substances and excipients is an important issue in formulating nasal preparations, especially when they are intended for treatment of chronic diseases [11]. Nearly all substances used in nasal preparations have a negative influence on the ciliary beat, and are therefore ciliotoxic. The influence may vary from a temporary (reversible) effect up to an irreversible inhibition of the ciliary beat [30]. In many nasal drops and nasal sprays preservatives cause the toxic effect on cilia [31], but the active substance itself may also have a negative influence on the ciliary epithelium. Nasal drops with decongestants have been shown to exhibit relatively low cUiotoxicity (e.g. Xylometazoline nasal drops 0.025 %, 0.05 % and 0.1 % (see Table 8.4) as well as a number of licensed preparations) [32]. 

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