Evidence of Necrosis in Human Intercostal Muscle following Inhalation of an Organophosphate Insecticide

Evidence of Necrosis in Human Intercostal Muscle following Inhalationof an Organophosphate Insecticide. WECKER, L, MRAK R. E., ANDDETTBARN, W-D. (1986). Fundam Appl. Toxicol. 6, 172–174.Intercostal muscle samples obtained from autopsy of a 51-year-oldmale exposed to an organophosphate insecticide were analyzedfor cholinesterase activity and muscle fiber integrity. Musclecholinesterase activity, 5 days after exposure, was reducedto 53% of control values. Histological analysis indicated thepresence of muscle fibers with subsarcolemmal grouped granularbasophilic inclusions and scattered necrotic fibers. Resultsindicate that acute organophosphate exposure through inhalationcan lead to skeletal muscle fiber damage in humans, similarto results obtained by ingestion. Furthermore, the pathologyis comparable to the histological alterations observed in ratsfollowing acute injection of organophosphates.     

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.     

Alterations of High-Energy Phosphate Compounds in the Skeletal Muscles of Rats Intoxicated with Diisopropylphosphorofluoridate (DFP) and Soman

Alterations of High-Energy Phosphate Compounds in the SkeletalMuscles of Rats Intoxicated with Diisopropylphosphorofluoridate(DFP) and Soman. GUPTA, R. C, and DETTBARN, W.-D. Fundam. Appl.Toxicol. 8, 400–407. The purpose of the present investigationwas to determine the changes in high-energy phosphate compoundsand to establish their relationship with organophosphate-inducednecrotic lesions in skeletal muscles of rats. Following an acutetoxicity signs-producing dose of either diisopropylphosphorofluoridate(DFP) (1.5 mg/kg, sc) or soman (0.1 mg/kg, sc), a significantdecline in phosphocreatine (PC) was seen as early as within1 hr, coinciding with the appearance of necrotic lesions, asreported earlier. The maximum decrease in PC was measured after6 hr. At this time, among the muscles studied, the hemi-diaphragm(the muscle which is known to show the greatest number of necroticlesions with both of the organophosphorus compounds) showedmaximum decrease in PC (57%) with soman treatment. A detailedanalysis of adenine nucleotides indicated a significant decreaseof adenosine triphosphate (ATP) in all three skeletal muscles,with a marked increase in adenosine monophosphate (AMP) andadenosine diphosphate (except in extensor digitorum longus (EDL)).The levels of creatine in all three skeletal muscles remainedunaltered throughout the time-course of study. The observedchanges in PC, ATP, and AMP were reversed toward control baselinevalues after 72 hr. Daily administration of DFP (0.5 mg/kg,sc/day) for 14 days caused only a significant decrease of PCin EDL and soleus during the toxic phase (Day 5), with recoverytoward the normal value during the tolerance phase (Day 14).It is concluded that both DFP and soman reduced the PC in skeletalmuscles, and the time-course for PC reduction correlates wellwith the previously reported time-course for muscle fiber necrosis.It is suggested that the reduction in PC is caused through anincreased demand to meet ATP requirements during severe muscularfasciculations.