The neurotoxic effects of long term, low-level exposure to the commercially available insecticide, Fenthion, were examined in the present study. Young adult, male long-Evans rats were dermally exposed to Fenthion (25 mg/kg, 3X wk.) and sampled after 2 and 10 month exposure to assess neurotoxic damage in the hippocampus using morphological and biochemical endpoints. Cytopathology, consisting of gliosis and swollen and necrotic neurons, occurred in the dentate gyrus (DG) and hilus (CA4) as early as 2 mo. exposure. Acetylcholinesterase (AChE) staining of brain tissues taken at the time was severely reduced in the septal nuclei, the DG molecular layer, the hilus, and the hippocampus proper. After 10 mo. exposure to Fenthion, cellular necrosis and gliosis progressed to the CA3 regions and occasionally involved the CA2. Radiometric assays of AChE activity in the hippocampus indicated a 65% and 85% depression after 2 and 10 mo. exposure, respectively. Quinuclidinyl benzilate (QNB) binding for the hippocampal muscarinic receptor was reduced by 6% and 15% after 2 and 10 mo. exposure. A separate group of older (12 mo.) rats were exposed to the same dosing regimen of Fenthion and examined for neuropathic damage after 2 mo. and 10 mo. exposure. Aged animals exposed for only 2 mo. expressed severe hippocampal degeneration in a pattern similar to that seen in the young adult after 10 mo. exposure (viz., DG, CA4, CA3). (Copyright (c) 1990 by Academic Press, Inc.).