Development of a Rat Model for Subacute Exposure to the Toxic Organophosphate VX

An animal model was developed to examine the pharmacology of the highly toxic organophosphorus compound (OP) ethyl-S-diisopropylaminoethyl methylphosphonothiolate (VX) in rats after a subacute exposure in the absence of supporting therapy, such as atropine or an oxime. Male rats (200-220 g: n = 10 per dose level) were continuously exposed via an Alzet osmotic pump to VX in PEG-400 for 14 days at doses of 43, 54, 69, 89, or 109 mu g/kg/day (acute sc LD sub(50) = 45 mu g/kg). Controls received only PEG-400. At the two highest doses, all animals died within 2 days. Surviving animals lost weight for 4 days and then resumed weight gain at the same rate as controls. Blood acetylcholinesterase (AChE) activity in al VX dosed rats was depressed to zero within 2 days and remained depressed throughout the experiment. At 14 days, AChE activity in cortex, brainstem, midbrain, diaphragm, and soleus was depressed between 30 to 60%, depending on the tissue. When rats were exposed to VX at a rate of 57 mu g/kg/day (1.3 median lethal dose/day) and examined at 7 or 14 days, the neurotoxic esterase activity in brainstem, midbrain, and soleus muscle was depressed 75 to 90%. These same animals exhibited muscle myopathy in the soleus muscle. The described model is an initial effort to evaluate the pharmacological and physiological responses that may result when mammals are exposed to VX over a long time in the absence of any supporting therapy.