Effects of inhalation exposures to an M-1-receptor agonist on ventilation in rhesus monkeys

Information was needed on effects of possible occupational inhalation expos ure to an M-1-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xano meline were carried out in six male rhesus monkeys using a head-dome exposu re system. Exposure concentrations ranged from 0.3 to 10 mg/m(3). The expos ure durations were up to 2 weeks. Decreases in tidal volume and increases i n respiratory frequency were both time and concentration related during acu te exposures.; These effects were blocked with ati-opine pre-treatment. Cor relation with pulmonary resistance measurements in two monkeys suggested th at 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/ m(3) becoming intolerable to the monkeys after approximately 15 minutes, bu t no measurable effects were observed at 0.3 mg/m(3) after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were e xposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3 and 1.2 m g xanomeline/m(3) of air. When compared to the air-only exposure, 0.3 mg/m( 3) caused no significant changes in tidal volume. In contrast, 1.2 mg/m(3) caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occ urred Repeated exposures did not alter the effects seen after a single expo sure. It is concluded that xanomeline, a M-1-receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations g reater than or equal to 0.6 mg/m(3) and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg /m(3).