Health risks associated with inhaled nasal toxicants

Health risks of inhaled nasal toxicants were reviewed with emphasis on chem ically induced nasal lesions in humans, sensory irritation, olfactory and t rigeminal nerve toxicity, nasal immunopathology and carcinogenesis, nasal r esponses to chemical mixtures, in vitro models, and nasal dosimetry- and me tabolism-based extrapolation of nasal data in animals to humans. Conspicuou s 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 ca rcinoma. Objective methods in humans to discriminate between sensory irrita tion and olfactory stimulation and between adaptation and habituation have been introduced successfully, providing more relevant information than sens ory irritation studies in animals. Against the background of chemoperceptio n as a dominant window of the brain on the outside world, nasal neurotoxico logy is rapidly developing, focusing on olfactory and trigeminal nerve toxi city. Better insight in the processes underlying neurogenic inflammation ma y 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 f unction of the nasal passages in brain drainage in rats. The crucial role o f tissue damage and reactive epithelial hyperproliferation in nasal carcino genesis has become overwhelmingly clear as demonstrated by the recently dev eloped biologically based model for predicting formaldehyde nasal cancer ri sk in humans. The evidence of carcinogenicity of inhaled complex mixtures i n 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 ris k of nasal cancer. It is remarkable that these mixtures are aerosols, sugge sting that their "particulate nature" may be a major factor in their potent ial to induce nasal cancer. Studies in rats have been conducted with define d mixtures of nasal irritants such as aldehydes, using a model for competit ive agonism to predict the outcome of such mixed exposures. When exposure l evels in a mixture of nasal cytotoxicants were equal to or below the "No- O bserved-Adverse-Effect-levels" (NOAELs) of the individual chemicals, neithe r 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 t oxicity. However, considering the complexity of the nasal cavity and the ma ny 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 int erpretation of nasal effects in experimental animals with regard to potenti al human health risk. Mapping of nasal lesions combined with airflow-driven dosimetry and knowledge about local metabolism is a solid basis for extrap olation of animal data to humans. However, more research is needed to bette r understand factors that determine the susceptibility of human and animal tissues to nasal toxicants, in particular nasal carcinogens.