title: The dose-response effects of repeated subacute sarin exposure on guinea pigs.
abstract: The present study assessed the effects of repeated subacute exposure to the organophosphorous nerve agent, sarin. Guinea pigs were injected five times per week (Monday-Friday) for 2 weeks with fractions of the established LD(50) dose of sarin (42 microg/kg sc). The animals were assessed for the development of cortical EEG seizures. Changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels and neurobehavioral reactions to a functional observational battery were monitored over the 2 weeks of sarin exposure and for an extended postinjection period. There were dose-related changes in body weight and RBC AChE levels. No guinea pigs receiving 0.3, 0.4 or 0.5 x LD(50) of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline. Seizures were evident in animals receiving 0.6 x LD(50) of sarin as early as the second day, and subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD(50) sarin showed obvious signs of cholinergic toxicity, which included a significant increase in their angle of gait. Overall, 2/13 animals receiving 0.5 x LD(50) sarin died before all 10 injections were given. By the 10th day of injections, the animals receiving saline were significantly easier to remove from their cages and handle as compared to the first day of injections. They were also significantly less responsive to an approaching pencil and touch on the rump in comparison to the first day of testing. In contrast, the animals receiving 0.4 x LD(50) sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared to the first day. The 0.5 x LD(50) sarin animals failed to show any significant changes to the approach response and touch response and did not adjust to handling or cage removal from the first day of injections to the last day of handling. In summary, the guinea pigs receiving the 0.4 x LD(50) and 0.5 x LD(50) doses of sarin failed to habituate to some aspects of the functional observational battery testing.
authors.affiliation: Neurotoxicology and Applied Pharmacology Branches, US Army Medical Research Institute of Chemical Defense, MCMR-UV-PN, Aberdeen Proving Grounds, MD 21010-5400, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Hulet
authors.forename: J H
authors.initials: JH
authors.lastname: McDonough
authors.forename: T-M
authors.initials: TM
authors.lastname: Shih
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004912:Erythrocytes / Q000201:enzymology; D005684:Gait / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D009206:Myocardium / Q000473:pathology; D012018:Reflex / Q000187:drug effects; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012524:Sarin; D000110:Acetylcholinesterase