RESUMEN
Squamous metaplasia is a nonspecific adaptive response to chronic irritation in the larynx and is often diagnosed as a test item-related change in rat inhalation studies. Investigating scientists are frequently asked to assess the adversity of laryngeal squamous metaplasia and to interpret its relevance to human risk. One factor in predicting relevance to human risk is the kinetics (degree and speed) of recovery following the cessation of exposure to the test item. Most reports describing recovery from squamous metaplasia in the rat larynx discuss the more severe end of the spectrum of metaplastic change (moderate to severe) and include relatively long (6 weeks or more) recovery periods. We conducted 2 studies to evaluate the toxicity and recovery from any potential effects of 4-(Chloro-2-methylphenoxy) butyric (MCPB) acid, a herbicide, when administered by inhalation to young male Sprague Dawley rats for 3 to 4 weeks. The studies resulted in minimal to moderate laryngeal squamous metaplasia for which we describe the kinetics of recovery over 1 to 4 weeks. We found that the microscopic change epithelial alteration, which is normally considered to be a precursor in the development of squamous metaplasia, can occur as a transitional stage between squamous and normal epithelium during recovery.
Asunto(s)
Carcinoma de Células Escamosas , Laringe , Animales , Cinética , Masculino , Metaplasia , Ratas , Ratas Sprague-DawleyRESUMEN
Developing inhaled drugs requires knowledge of lung anatomy, cell biology, respiratory physiology, particle physics, and some plumbing. Although dose makes the poison, in the context of an inhaled drug, the "dose" is not easily defined. This lack of clarity around dose poses issues and challenges in the design of inhalation toxicology programs. To better understand dose, the influence of ventilation is discussed as are the perturbations in pulmonary function observed with inhalation exposure that can affect dose. Methods for determining inhaled drug deposition to arrive at an estimate of lung dose are examined. Equally important to understanding dose are the techniques used to deliver aerosols to animals. With a better understanding of dose and inhalation exposure, species-specific histopathologic lesions, both common background and toxicologically significant lesions, are reviewed. Finally, insight into how regulators synthesize and evaluate these complex findings to assess clinical safety risks is presented.