TRIPHENYL PHOSPHITE AND DIISOPROPYLPHOSPHOROFLUORIDATE PRODUCE SEPARATE AND DISTINCT AXONAL DEGENERATION PATTERNS IN THE CENTRAL-NERVOUS-SYSTEM OF THE RAT

This study compared the neurotoxic effects of triphenyl phosphite (TPP ) in the rat with those seen after exposure to diisopropylphosphoroflu oridate (DFP), a compound known to produce organophosphorus-induced de layed neurotoxicity (OPIDN). Animals received either three subcutaneou s injections of TPP (1184 mg/kg body wt each dose) administered at 3-d ay intervals or a single subcutaneous injection of DFP (4 mg/kg body w t). TPP-induced clinical signs were initially observed 2 to 18 days af ter the last injection and included ataxia, flaccid paresis, stereotyp ed alternating side-to-side movements, and circling behavior. Axonal a nd terminal degeneration were present in the cerebellum, vestibular nu clear complex, cochlear nuclei, and superior and inferior colliculi. T he subthalamic nucleus, substantia nigra, septal region, hypothalamus, thalamus, hippocampus, and cerebral cortex also contained degeneratin g axons and terminals. Degeneration was particularly evident in the se nsorimotor cerebral cortex, mediodorsal, ventromedial, and medial geni culate thalamic nuclei and in the magnocellular preoptic and medial ma mmillary nuclei of the hypothalamus. Very light degeneration was prese nt in the gracile fasciculus and nucleus. In contrast, rats injected w ith DFP showed moderate degeneration in the gracile fasciculus and nuc leus but did not display degeneration in any other brain region. Injec tions of DFP did not produce delayed onset clinical signs. The results indicate that in the rat, different central nervous system cell group s are affected by these two organophosphorus compounds and that TPP af fects nuclei and tracts at all levels of the neuraxis, including those associated with higher-order processing and cognitive functions. In a ddition, the distinct degeneration patterns produced by these two comp ounds support the view that TPP-induced neurotoxicity should not be co nsidered as a type of OPIDN, but rather as a separate category of orga nophosphorus-induced neurotoxicity. (C) 1996 Society of Toxicology