Validation of intratracheal instillation as an alternative for aerosol inhalation toxicity testing

In collecting inhalation toxicity data for the evaluation of the health hazard from occupational exposure to the aerosols of a drug or a chemical, the determination of the inhaled dose in relation to the animal response is most desirable. Intratracheal administration is most likely to deliver an exact dose of a compound to the lungs of an experimental animal. In a series of tests, microliter (microl) quantities of a solution or a suspension of a test material were nebulized into the trachea of an anesthetized rat using an intratracheal fast instillation (ITFI) method. The dose-response in terms of the minimal effective dose (MED) and the median lethal dose (LD50) were determined. The ITFI dose-response for four drugs, five chemicals or chemical intermediates and four pesticides were compared with those obtained via inhalation (IH) and ingestion (p.o.). In addition, the dose-responses of the four pesticides were compared with two additional parameters, intranasal instillation (IN) and intravenous injection (i.v.). The MED end-points for studies via the respiratory administration route were no pharmacotoxic signs other than transient respiratory rales and/or dyspnea and no gross lesions, whereas those for the intranasal, oral and the intravenous administration routes were transient and slight body weight loss and no pharmacotoxic signs and/or gross lesions. The MED ratios between ITFI, IH and p.o. were 1 : 9.3+/-6.5 : 201.4+/-133.3, respectively, for the drugs, chemicals and chemical intermediates. The MED ratios for ITFI, IH, IN, i.v. and p.o. for the four pesticides were 1 : 2.2+/-1.4 : 2.1+/-1.3 : 1.1+/-0.7 : 1.4+/-0.9. The MED ratios for the two categories of test materials were fairly consistent between different routes of administration. Thus, the ITFI dose can be used for extrapolating the IH dose. The simplicity of the ITFI procedure and its requirement of only microliters of a compound to generate a meaningful and reliable dose-response suggests that ITFI may be an alternative method for acute inhalation toxicity evaluation of materials that may present inhalation hazards from liquid or solid aerosols.