Effects of inhalation exposures to an M1-receptor agonist on ventilation in rhesus monkeys.
Information was needed on effects of possible occupational inhalation exposure to an M1-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 > or = 0.6 mg/m3 and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m3.
Allen
D L
DL
Toxicology Research Laboratories, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140, USA.
Leiter
P A
PA
Tielking
R L
RL
Hoffman
W P
WP
Vidyashankar
A N
AN
van Lier
R B
RB
Wolff
R K
RK
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001285:Atropine / Q000494:pharmacology; D016084:Bronchoconstriction; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008253:Macaca mulatta; D008297:Male; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000633:toxicity*; D012123:Pulmonary Ventilation / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity*; D012119:Respiration / Q000187:drug effects; D013830:Thiadiazoles / Q000008:administration & dosage / Q000633:toxicity*; D013990:Tidal Volume / Q000187:drug effects
D018721:Muscarinic Agonists; D011725:Pyridines; D013830:Thiadiazoles; D001285:Atropine; C075257:xanomeline