Determination of threshold adverse effect doses of percutaneous VX exposure in African green monkeys

• Published in: Toxicology (Amsterdam) 2011-01, Vol.279 (1), p.65-72
• Main Authors: Genovese, Raymond F, Benton, Bernard J, Oubre, John L, Byers, Christopher E, Jakubowski, E. Michael, Mioduszewski, Robert J, Settle, Timothy J, Steinbach, Thomas J
• Format: Article
• Language: English
• Subjects: absorbed dose; acetylcholinesterase; Acetylcholinesterase - drug effects; Acetylcholinesterase - metabolism; AChE; Administration, Cutaneous; adverse effects; African green; Animals; behavior change; Behavior, Animal - drug effects; Biological and medical sciences; blood; Cercopithecus aethiops; Chemical Warfare Agents - pharmacokinetics; Chemical Warfare Agents - toxicity; Cognition; decontamination; Dose-Response Relationship, Drug; Emergency; exposure pathways; Female; Medical sciences; Memory - drug effects; monkeys; nerve tissue; No-Observed-Adverse-Effect Level; Organophosphorus; organothiophosphorus compounds; Organothiophosphorus Compounds - administration & dosage; Organothiophosphorus Compounds - pharmacokinetics; Organothiophosphorus Compounds - toxicity; Percutaneous; Primate; SPR; Time Factors; toxicity; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2010.09.012

Abstract Percutaneous exposure to the chemical warfare nerve agent VX was evaluated in African green monkeys ( n = 9). Doses of VX (7.5–100 μg/kg) were applied to the skin for 60 min and residual agent was quantified (before decontamination) to estimate the absorbed dose. Monkeys were evaluated for the presence or absence of clinical signs of toxicity and blood was sampled periodically (30 min–12 weeks) following exposure to measure the degree of circulating acetylcholinesterase (AChE) inhibition. Monkeys were also evaluated for behavioral changes from VX exposure using a serial probe recognition (SPR) task. The lowest observable adverse effect level (LOAEL) for the production of major clinical signs was determined to be 42.22 μg/kg (absorbed dose estimate = 17.36 μg/kg) and the LOAEL for AChE inhibition was 13.33 μg/kg (absorbed dose estimate = 6.53 μg/kg). Behavioral performance was unaffected at doses that, while producing substantial AChE inhibition, did not produce clinical signs. VX represents a substantial threat as a contact hazard and these results complement previous studies using the percutaneous route of exposure with VX and extend the findings to a non-human primate species.