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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines
consequences after acute administration. Two-way shuttle box avoidance learning, open-field behavior, and complex coordinated movements in rats were interrupted by PB at doses of about 0.27 mg/kg, which neither produced overt symptoms nor affected running speed and coordinated locomotion (Wolthius and Vanwersch, 1984). Shih and colleagues (1991) examined a wider range of PB doses on lever pressing of rats maintained under a multiple fixed-ratio (FR 20) time-out schedule of reinforcement for water reward. They noted that doses greater than 6 mg/kg disrupted responding but there were no overt signs of peripheral neurotoxicity until doses in excess of 12 mg/kg were administered. Liu (1991) confirmed that doses of 3–12 mg/kg interfered with responding but did not cause overt toxicity.
PB has been tested in primates (Macaca mulatta) for its effects on the ability of subjects to perform compensatory tracking on an equilibrium platform (Blick et al., 1994). Of the doses of PB tested, only the highest dose interfered with performance of the task (Murphy et al., 1989). Plasma ChE inhibition at this dose was 83 percent. Thus, it appears that PB, particularly at higher doses, is capable of modifying experimentally measured behavioral end points. This might suggest some degree of entry of PB into the CNS.
Many aspects of gastrointestinal function are mediated or influenced by ACh, and PB would be predicted to cause gastrointestinal disturbance, especially if administered orally. Thus, the most common complaints of troops taking the prescribed dosage of PB (3 × 30 mg per day—the equivalent of 0.4 mg/kg every 8 hours) included nausea, vomiting, diarrhea, abdominal cramping, increased salivation, bronchial secretions, miosis, and diaphoresis—symptoms referable to a parasympathetic (and peripheral) predominance. Human symptoms are in accord with observations made in laboratory animals. In beagles, the threshold dosage for gastrointestinal effects of PB is as low as 0.05 mg/kg; this dose causes significant inhibition of both plasma butyrylcholinesterase and RBC AChE (Kluwe et al., 1990). Higher doses of PB result in proportionally greater effects. Species differences in responsiveness to toxicities of PB have been noted (Levine et al., 1991).
One 180-day subchronic oral toxicity study of PB has been reported (Morgan et al., 1990). Rats were administered 0–10 mg PB/kg, 5–7 days per week, for 180 days. During the dosing phase of the study, ChE inhibition was up to 63 percent in plasma and 49 percent in erythrocytes. An extensive battery of tests (including hematological and serum analyses) were performed 30 days after the last dose of PB, at which time ChE levels had returned to control values. Although serum chemistry revealed elevations in lactate dehydrogenase,