This is a combined experimental and clinical study of the occupational neuropathy induced by repetitive overexposure to acrylamide monomer. The experimental portion (90% of workload) continues from previous studies which suggest the neuropathic potency of acrylamide is linked to toxic inhibition of certain glycolytic enzymes which are required for the maintenance of axonal transport and nerve-fiber integrity. Proposed studies are designed to test this hypothesis. A tissue-culture model of acrylamide neuropathy will be developed and used to study acrylamide-induced degeneraion of living nerve fibers in vitro. Selected drugs (e.g. substrates and inhibitors of glycolysis and Krebs cycle) will be tested for their ability to modify the neurotoxic response to acrylamide in vitro. Agents which protect by delaying or preventing the onset of nerve-fiber degeneration in culture will be tested for their effects on mice repeatedly treated with acrylamide. Initial studies will employ dietary supplementation with sodium pyruvate, an effective therapeutic regimen in rats treated with acrylamide. Treated and control animals will be assayed for neuropathy by quantitative functional, morphological and biochemical assays. The relationship between molecular and cellular mechanisms of acrylamide neurotoxicity will be examined by determining the effects of single and multiple doses on energy-dependent axonal transport. Dose dependent decrements in fast retrograde axonal transport will be examined in sensory and motor axons and their relationship to changes in fast anterograde transport and distal axonal degeneration determined. The fate of vulnerable glycolytic enzymes transported slowly from neuronal perikaryon to nerve terminal will be examined in the optic nerves of rabbits with advanced acrylamide neuropathy. Finally, studies in rats will examine the current hypothesis that acrylamide induces damages to axons by direct toxic action on nerve fibers. Rates of binding of acrylamide to proteins in peripheral nerves will be determined with the aid of radiolabeled toxin. The clinical portion (10% of workload) will explore the efficacy of the newly developed Optecon Tactile Tester to monitor worker populations at risk for acrylamide and related neuropathies. The major goals of these studies are to develop experimentally proven methods to diagnose, prevent and treat individuals with acrylamide and related occupational neuropathies. These studies respond to some of the research needs specified in the National Institute of Occupational Safety and Health Criterion Document for Acrylamide (1976).
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