Effects of Inhalation Exposures to an M1-Receptor Agonist on Ventilation in Rhesus Monkeys

• Published in: Drug and chemical toxicology (New York, N.Y. 1978) N.Y. 1978), 1999, Vol.22 (4), p.595-611
• Main Authors: Allen, Darrel L., Leiter, Paula A., Tielking, Richard L., Hoffman, Wherly P., Vidyashankar, Anand N., van Lier, Robert B. L., Wolff, Ronald K.
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Airway Resistance - drug effects; Animals; Atmosphere Exposure Chambers; Atropine - pharmacology; Biological and medical sciences; Bronchoconstriction; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug toxicity and drugs side effects treatment; Macaca mulatta; Male; Medical sciences; Muscarinic Agonists - administration & dosage; Muscarinic Agonists - toxicity; Pharmacology. Drug treatments; Pulmonary Ventilation - drug effects; Pulmonary Ventilation - physiology; Pyridines - administration & dosage; Pyridines - toxicity; Respiration - drug effects; Thiadiazoles - administration & dosage; Thiadiazoles - toxicity; Tidal Volume - drug effects; Toxicity: respiratory system, ent, stomatology
• ISSN: 0148-0545; 1525-6014
• DOI: 10.3109/01480549908993170

ABSTRACT Information was needed on effects of possible occupational inhalation exposure to an M]-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xanomeline were carried out in six male rhesus monkeys using a head-dome exposure system. Exposure concentrations ranged from 0.3 to 10 mg/m3. The exposure durations were up to 2 weeks. Decreases in tidal volume and increases in respiratory frequency were both time and concentration related during acute exposures. These effects were blocked with atropine pre-treatment. Correlation with pulmonary resistance measurements in two monkeys suggested that these were bronchoconstrictive changes that increased with severity with time at a given concentration and with concentration when measured after a constant exposure time. The dose-response was relatively steep with 10 mg/m3 becoming intolerable to the monkeys after approximately 15 minutes, but no measurable effects were observed at 0.3 mg/m3 after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were exposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3, and 1.2 mg xanomeline/m3 of air. When compared to the air-only exposure, 0.3 mg/m3 caused no significant changes in tidal volume. in contrast, 1.2 mg/m3 caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occurred. Repeated exposures did not alter the effects seen after a single exposure. It is concluded that xanomeline, a M1 - receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations ≥0.6 mg/m3 and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m3.