title: An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.
abstract: In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.
authors.affiliation: FOI CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Rocksén
authors.forename: Daniel
authors.initials: D
authors.lastname: Elfsmark
authors.forename: Victoria
authors.initials: V
authors.lastname: Heldestad
authors.forename: Karin
authors.initials: K
authors.lastname: Wallgren
authors.forename: Gudrun
authors.initials: G
authors.lastname: Cassel
authors.forename: Ann
authors.initials: A
authors.lastname: Göransson Nyberg
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*; D009995:Osmosis; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects; D013686:Telemetry / Q000379:methods; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013974:Thyroxine / Q000187:drug effects / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000110:Acetylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D003345:Corticosterone; D009946:Organothiophosphorus Compounds; D013974:Thyroxine; C009680:VX-agent