The dose–response effects of repeated subacute sarin exposure on guinea pigs

• Published in: Pharmacology, biochemistry and behavior Vol. 72; no. 4; pp. 835 - 845
• Main Authors: Hulet, S.W, McDonough, J.H, Shih, T.-M
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-07-2002; Elsevier Science
• Subjects: Acetylcholinesterase; Acetylcholinesterase - blood; Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Body Weight - drug effects; Brain - pathology; Chemical and industrial products toxicology. Toxic occupational diseases; Chemical Warfare Agents - toxicity; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - toxicity; Dose-Response Relationship, Drug; Electrodes, Implanted; Electroencephalography - drug effects; Erythrocytes - enzymology; Functional observational battery; Gait - drug effects; Guinea Pigs; Male; Medical sciences; Myocardium - pathology; Nerve agents; Organophosphate; Reflex - drug effects; Sarin; Sarin - administration & dosage; Sarin - toxicity; Toxicology; Various organic compounds; Acetylcholinesterase inhibitors; Organophosphate; Acetylcholinesterase; Nerve agents; Sarin; Functional observational battery; Toxicity; Central nervous system; Esterases; Hemopathy; Behavioral disorder; Chemical warfare agent; Guinea pig; Subcutaneous administration; Anticholinesterase agent; Nervous system diseases; Enzyme; Rodentia; Red blood cell; Enzyme inhibitor; Long term; Open field behavior; Carboxylic ester hydrolases; Cerebral disorder; Vertebrata; Blood cell; Mammalia; Animal; Central nervous system disease; Hydrolases; Organophosphorus compounds; Brain (vertebrata)
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(02)00761-X

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 μg/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×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×LD
50 of sarin as early as the second day, and subsequent injections led to incapacitation and death. Animals receiving 0.5×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×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×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×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×LD
50 and 0.5×LD
50 doses of sarin failed to habituate to some aspects of the functional observational battery testing.