though AChE activity was still significantly inhibited. In the cat, an infused dose of 0.56 LD50 caused respiratory arrest, while neuromuscular blockade required a dose in excess of five times the LD50 (Rickett et al., 1986). The diaphragm was still responsive to electrical stimulation at doses that inhibited respiratory nerve activity. The cells first affected were respiratory-related neurons in the medulla, and their inhibition preceded phrenic nerve inhibition. Therefore, the cause of death after sarin exposure is rapid inhibition of respiratory centers in the medulla followed by inhibition of phrenic nerve activity, which causes respiration to cease. The diaphragm muscle is paralyzed last.

Neurotoxicity

Short- and long-term neurobehavioral toxicity. Sarin’s short-term behavioral effects are dose dependent. In several studies of rodents, behavior was assessed by flavor aversion, spontaneous motor activity, and motor coordination. Following subcutaneous administration of 61–115 μg/kg, sarin led to conditioned flavor aversion at doses greater than 70 μg/kg. Motor coordination, as measured by rotarod performance, was decreased at 98 μg/kg, but not at lower doses (Landauer and Romano, 1984). This study also found an increase in spontaneous locomotion at 61 μg/kg and a decrease at higher doses (measured only within 10 minutes of sarin administration). Nieminen and colleagues (1990) studied rats given intraperitoneal doses of 12.5 and 50 μg/kg, neither of which was sufficient to produce acute toxicity. By monitoring locomotor activity up to 72 hours, they found a decrease in rodent locomotion only with the highest dose until 6 hours of administration, after which time there was no difference from controls. In separate behavioral tests, they also found the highest dose of sarin to decrease certain behaviors (e.g., grooming) at 40–50 minutes after injection (Nieminen et al., 1990).

Short-term behavioral effects also have been examined in marmosets, a nonhuman primate. Doses at 33 to 55 percent of the LD50 disrupted the performance of animals’ food-reinforced visually guided reaching response. Performance returned to normal by 24 hours after sarin administration (D’Mello and Duffy, 1985). The only other studies of short-term behavioral consequences of low-dose exposures in nonhuman primates were carried out with soman, an organophosphate nerve agent that also inhibits AChE. Hartgraves and Murphy (1992) studied the effects of different dosing regimens—which did not produce signs of acute toxicity—on equilibrium performance, as measured on the primate equilibrium platform (PEP). This device requires the animal to manipulate a joystick in order to keep a rotating platform as level as possible. After administration, doses of soman, less than 2.0 μg/kg did not induce decrements in PEP performance, while doses greater than 2.75 μg/kg did induce decrements. Decrements were measured for 5 days after soman administration but later returned to normal. These findings, although not from sarin, are reported here because vestibular dysfunction has been reported as a long-term effect in humans after sarin exposure (see next section).



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