Methacholine: a 7-day inhalation toxicity study with primates.

The acute and sub-acute inhalation toxicity of methacholine to cynomolgus monkeys was assessed by exposure of animals to an aerosol of a 2% solution of the material in sterile saline. The acute response was characterized by a decrease in tidal volume, increase in respiratory rate, a fall in dynamic compliance and an increased pulmonary resistance. Onset of the acute response was rapid, reached a peak after 2-3 min of exposure and recovery appeared to be complete after 30 min following termination of an exposure. The sub-acute inhalation toxicity of methacholine was assessed by single daily aerosol exposure of primates to graded doses of the compound for 7 days. Pre- and post-exposure measurements of haematology and blood biochemistry, urinalysis, blood gas analysis and ECG showed no changes which could be attributed to exposure to methacholine. Nor were treatment-related histopathological changes observed in exposed animals. Distinct changes were seen in the mechanical characteristics of the lungs of exposed animals. Pulmonary resistances, measured on the day following final exposure, were increased in all animals exposed to the methacholine aerosol. During 9 weeks following the last of the daily exposures, increased pulmonary resistance values persisted in the animals retained for this period, although there was some indication of a gradual return to pre-exposure resistance values.