title: Health risks associated with inhaled nasal toxicants.
abstract: Health risks of inhaled nasal toxicants were reviewed with emphasis on chemically induced nasal lesions in humans, sensory irritation, olfactory and trigeminal nerve toxicity, nasal immunopathology and carcinogenesis, nasal responses to chemical mixtures, in vitro models, and nasal dosimetry- and metabolism-based extrapolation of nasal data in animals to humans. Conspicuous findings in humans are the effects of outdoor air pollution on the nasal mucosa, and tobacco smoking as a risk factor for sinonasal squamous cell carcinoma. Objective methods in humans to discriminate between sensory irritation and olfactory stimulation and between adaptation and habituation have been introduced successfully, providing more relevant information than sensory irritation studies in animals. Against the background of chemoperception as a dominant window of the brain on the outside world, nasal neurotoxicology is rapidly developing, focusing on olfactory and trigeminal nerve toxicity. Better insight in the processes underlying neurogenic inflammation may increase our knowledge of the causes of the various chemical sensitivity syndromes. Nasal immunotoxicology is extremely complex, which is mainly due to the pivotal role of nasal lymphoid tissue in the defense of the middle ear, eye, and oral cavity against antigenic substances, and the important function of the nasal passages in brain drainage in rats. The crucial role of tissue damage and reactive epithelial hyperproliferation in nasal carcinogenesis has become overwhelmingly clear as demonstrated by the recently developed biologically based model for predicting formaldehyde nasal cancer risk in humans. The evidence of carcinogenicity of inhaled complex mixtures in experimental animals is very limited, while there is ample evidence that occupational exposure to mixtures such as wood, leather, or textile dust or chromium- and nickel-containing materials is associated with increased risk of nasal cancer. It is remarkable that these mixtures are aerosols, suggesting that their "particulate nature" may be a major factor in their potential to induce nasal cancer. Studies in rats have been conducted with defined mixtures of nasal irritants such as aldehydes, using a model for competitive agonism to predict the outcome of such mixed exposures. When exposure levels in a mixture of nasal cytotoxicants were equal to or below the "No-Observed-Adverse-Effect-Levels" (NOAELs) of the individual chemicals, neither additivity nor potentiation was found, indicating that the NOAEL of the "most risky chemical" in the mixture would also be the NOAEL of the mixture. In vitro models are increasingly being used to study mechanisms of nasal toxicity. However, considering the complexity of the nasal cavity and the many factors that contribute to nasal toxicity, it is unlikely that in vitro experiments ever will be substitutes for in vivo inhalation studies. It is widely recognized that a strategic approach should be available for the interpretation of nasal effects in experimental animals with regard to potential human health risk. Mapping of nasal lesions combined with airflow-driven dosimetry and knowledge about local metabolism is a solid basis for extrapolation of animal data to humans. However, more research is needed to better understand factors that determine the susceptibility of human and animal tissues to nasal toxicants, in particular nasal carcinogens.
authors.affiliation: Toxicology Division, TNO Nutrition and Food Research, Zeist, The Netherlands. v.jferon@freeler.nl
authors.forename: V J
authors.initials: VJ
authors.lastname: Feron
authors.forename: J H
authors.initials: JH
authors.lastname: Arts
authors.forename: C F
authors.initials: CF
authors.lastname: Kuper
authors.forename: P J
authors.initials: PJ
authors.lastname: Slootweg
authors.forename: R A
authors.initials: RA
authors.lastname: Woutersen
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015386:Hazardous Substances / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology; D019570:Inhalation Exposure / Q000009:adverse effects*; D009296:Nasal Cavity / Q000187:drug effects / Q000473:pathology; D009668:Nose Diseases / Q000139:chemically induced*; D009669:Nose Neoplasms / Q000139:chemically induced / Q000473:pathology; D010316:Particle Size; D012307:Risk Factors; D015262:Xenobiotics / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D015386:Hazardous Substances; D015262:Xenobiotics