The committee recommends studies in experimental animals to investigate the long-term effects of acute, short-term sarin exposure at doses that do not cause overt cholinergic effects and cause only minimal acetylcholinesterase inhibition.

Massive acute doses of sarin, through inhibition of neuropathy target esterase (NTE), can induce delayed neurotoxicity in some, but not all, animal species. Lower doses over long periods may also exert this effect, but more research is needed to substantiate this finding. Long-term alterations in the EEG of nonhuman primates occur after sarin administration at high doses, as well as at doses that do not produce acute signs of toxicity. The clinical and long-term significance of these EEG changes is unclear. Studies should describe concomitant changes at the behavioral, electrophysiological, and biochemical levels. Studies should test the hypothesis that repeated exposure to sarin—alone and in combination with other organophosphate (OP) pesticides or nerve agents—at doses that do not cause overt cholinergic toxicity can produce delayed polyneuropathy.

The committee recommends research on genetic factors that may alter susceptibility to sarin toxicity.

The enzyme paraoxonase inactivates sarin by hydrolysis. The human PON1 gene has various polymorphisms. The corresponding genotypes determine the catalytic properties of an enzyme that hydrolyzes certain organophosphates at two different rates depending on which polymorphism is present. Studies have suggested a relationship between these genetic polymorphisms and neurological impairment in Gulf War veterans. However, because of their small size the findings require confirmation in a larger population. Studies on genetic polymorphisms, particularly of PON1, may elucidate the nature of human susceptibility to sarin toxicity.

PYRIDOSTIGMINE BROMIDE

The committee recommends studies on chemical interactions between pyridostigmine bromide (PB) and other agents, such as stress, and insecticides.

Studies have suggested the possibility that combinations of chemicals (particularly insecticides) and stress result in greater toxic consequences than when each of these exposures is present alone. Possible synergistic interactions of PB with chemicals and stressors (environmental and psychological) require replication and confirmation, particularly studies exploring the possibility of toxic interactions resulting from exposure to chemicals at low doses and over long periods of time. Such studies may also shed light on whether or not PB (which is unlikely to initiate organophosphate-induced delayed neuropathy [OPIDN]) may promote other chemically induced neuropathies.



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