Comparison of Cholinergic and Neuromuscular Toxicity following Acute Exposure to Sarin and VX in Rat

Comparison of Cholinergic and Neuromuscular Toxicity followingAcute Exposure to Sarin and VX in Rat. GUPTA, R. C, PATTERSON,G. T., AND DETTBARN, W-D. (1991). Fundam. Appl. Toxicol. 16,449–458. Male Sprague-Dawley rats injected with a sublethalsc dosage of 110 µg/ kg of sarin (isopropyl methylphosphonofluoridate),or 12 µg/kg of VX (S-{2-diisopropylaminoethyl) O-ethylmethylphosphonothioate), developed severe toxic signs within5–15 min after sarin and 20–50 min after VX lastingfor 5 to 7 hr. Myonecrotic lesions were seen in soleus and diaphragmmuscles within 1 hr. A maximum number of lesions had developedafter 24 hr, and lesions were also present in extensor digitorumlongus (EDL) at this time. Regeneration of muscle fibers wasslow since lesions were still evident past 7 days of treatment.Within 1 hr following VX, AChE activity was reduced to 8, 12,and 17% of control activity in soleus, diaphragm, and EDL, respectively,whereas with sarin the enzyme activity was reduced to 23, 48,and 82% of control. A still greater inhibition was seen 24 hrafter sarin when AChE activity was reduced to 19, 13, and 43%in these muscles. In skeletal muscles the different molecularforms of AChE, such as 16 S, 12 S, 10 S, and 4 S vary in locationand functional importance with the 16 S form highly concentratedat the neuromuscular junction. All forms in a given muscle wereequally sensitive to the inhibitors. In EDL, sarin was the leasteffective in reducing AChE or its molecular forms. In the brainstructures (cortex, brain stem, striatum, and hippocampus),AChE activity was reduced to 1–6% of control by sarinand VX with the exception that following VX striatal AChE wasreduced to only 41% of control activity. AChE activity in thebrain cortex following either of the agents was maximally affected(1%). A slow but significant recovery of brain AChE was evidentafter 24 hr and more so after Day 7. Butyrylcholinesterase (BuChE)activity was less sensitive to inhibition by both inhibitorscompared to AChE activity and showed a rapid recovery. Basedon the equitoxic doses (toxic signs of similar magnitude), VXwas found to be 10 times more toxic than sarin. The mechanismsof this disparity may be due to differences in rate of uptake,circulation, susceptibility to hydrolysis, and reactivity withnonspecific binding sites.