A neurotoxicity screening battery for use in safety evaluation: Effects of acrylamide and 3′,3′-iminodipropionitrile

Abstract

The effects of two known neurotoxicants, acrylamide (ACR) and 3′,3′-iminodipropionitrile (IDPN), were assessed using a functional observational battery (FOB), a measurement of motor activity (MA), and neuropathology (NP) in the context of a safety evaluation study. One hundred Sprague-Dawley rats (10/sex/group) were tested initially and then doses with vehicle, ACR (10 or 30 mg/kg/day), or IDPN (50 or 125 mg/kg/day) by oral gavage 7 days/week for 5 weeks (except where otherwise indicated). Neurobehavioral assessments were conducted prior to initiating treatment at 1, 6, and 24 hr after the first dose, and weekly thereafter. Body weight and food consumption were determined weekly, and animals were observed twice daily for signs of toxicity. Blood samples were obtained at termination for routine clinical pathology studies. At termination three animals/sex/group were perfused in situ for neuropathology evaluations and the remaining animals were necropsied for standard histological evaluations. Prominent neurological signs were observed in high-dose animals after 2 weeks, and significant mortality occurred in high-dose ACR animals during Week 3. A 7- or 10-day recovery period was initiated after 20 or 22 daily doses for high-dose IDPN and ACR animals, respectively. ACR and IDPN affected body weight, body-weight gain, food consumption, general activity (horizontal and vertical), urination, muscle tone (grip strength), motor reflexes, gait, and posture. Significant sex effects were seen in animals exposed to IDPN, with males being more severely affected. Microscopic examination of nervous system tissue and selected organs revealed minimal to moderately severe axonal swelling characterized by the presence of enlarged balloon-like axons in the brainstem and the cervical and lumbar cord of IDPN-treated animals. This change was most prominent in males and most severe in the lumbar spinal cord. An increased incidence of chronic progressive nephropathy was also noted in IDPN-treated rats. ACR-treated animals exhibited minimal to moderate degeneration in the cervical and lumbar spinal cord, the gasserian and dorsal root ganglia, and the tibial, sciatic, and sural nerves which were characterized by changes in axonal diameter, increased argyrophilia of axons, and disruption, fragmentation, and distortion of axons and the myelin sheath. Granulomatous inflammation in the lungs of high-dose ACR animals resulted from inhalation of feed, most probably due to partial paralysis or incoordination during feeding.