TOXICOLOGY OF DITHIOBIURET AND ENVIRONMENTAL AGENTS

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The 2, 4-Dithiobiuret (DTB), has a wide range of speciality uses in the chemical industry. In rats and cats DTB produces a delayed onset muscle weakness that appears to be due to a central-peripheral distal axonopathy. The long range objectives are to describe the neuropathology of DTB in rats and cats and determine it's nervous system sites and mechanisms of action. First, to establish conditions for producing neurotoxicity the specific aims are to: develop a treadmill method for assessing degrees of weakness, describe dosage regimens for the production of weakness, conduct structure-activity studies with DTB congeners and DTB metabolites, and conduct a complete morphologic study of the evolution of the neuropathy. Second, to determine the role of DTB metabolism and disposition in neurotoxicity the aims are to: develop a HPLC system for separating DTB and DTB metabolites, identify urinary DTB metabolites, measure DTB plasma clearance and urinary excretion, and identify enzyme systems involved in DTB metabolism. Third, to determine the mechanism of DTB neurotoxicity in rats the aims are to: see if axoplasmic flow is depressed, determine if neuronal energy-producing pathways are depressed, see if choline acetyltransferase activity is diminished, determine if weakness is secondary to hypoxemia or hyperglycemia, and develop DTB antagonists to pharmacologically dissect DTB's mechanism of action. Fourth, to determine nervous system sites, and mechanisms of action the specific aims are to: determine if electrophysiologic changes in somatic afferent fibers exist which can be linked to the weakness, see if monosynaptic spinal reflexes and primary afferent reflexes are depressed (suggestive of interneuron and/or motoneuron damage), identify effects of DTB on frequency dependent reflexes and transmitter turnover, evaluate electrophysiological properties of the motoneuron soma, assess DTB effects on motor axons and their terminals, and determine if nicotinic receptor properties or the mechanism which links receptor activation to muscle membrane conductance changes are altered. The application of these studies to human health is that DTB neuropathy may be a model for certain neuropathic diseases in man and DTB antagonists may ultimately be used in the treatment of these diseases.