THE SAME CHEMICALS INDUCE DIFFERENT NEUROTOXICITY WHEN ADMINISTERED IN HIGH-DOSES FOR SHORT-TERM OF LOW-DOSES FOR LONG-TERM TO RATS AND DOGS

Dose- and term-dependent differences in the location and nature of brain lesions induced in rats and dogs by 2,5-hexanedione (2,5-HD), misonidazole, clioquinol, and acrylamide are reported. Subchronic neuropathies ("distal axonopathy") were induced by low-dose administration of these neurotoxicants and at high doses, lesions caused by acute or subacute neurotoxicity were found in the central nervous, system (CNS). In rats, 2,5-HD induced extracellular edema, nerve cell degeneration, and axonal degeneration in the cerebellar and vestibular nuclei. Similar lesions were observed in misonidazole-treated dogs and clioquinol induced nerve cell degeneration in the hippocampus and malacia in the piriform lobes of these animals. In rats, acrylamide induced degeneration of Purkinje cells. Although the mechanism(s) underlying the differential neurotoxicity of high and low doses of these neurotoxicants remains unclear, we suggest certain biochemical mechanisms, cytotoxic edema and excitotoxicity, as factors in the production of such lesions after high-dose treatment.