The neurotoxic effects of concurrent exposure to triethyllead- chloride (1067147) (TELC) and 2,5-hexanedione (110134) (2,5H) were investigated by examining time course of neurotoxicity, histopathological lesion severity, neurologic deficit, and the effect on drug metabolism. Groups of ten male Fischer-344-rats were treated for 6 weeks with TELC (0.7mg/kg/week by gavage), 2,5H (0.5 percent in drinking water 7 days/wk), TELC and 2,5H, or water only (controls). A significant decrease in body weight was observed with repeated exposure to 2,5H or TELC and the combination of the two resulted in even greater loss in body weight. Combined treatment also resulted in mortality not evident in other groups (three died by week five). Body weight increased after TELC and 2,5H treatments were discontinued, and by 4 weeks after cessation of dosing, treated rats weighed significantly more than controls. Both fore and hind limb grip strength was reduced by 2,5H treatment while TELC had no significant effect. Rats receiving combined treatment had significantly lower scores than animals receiving 2,5H alone. Hot plate latencies were significantly increased with TELC, while 2,5H responses showed no statistical significance; combined treatment did not differ from TELC alone. Repeated treatment with 2,5H decreased horizontal motor activity significantly while TELC treatments and combined treatments showed no differences. No treatment resulted in any significant differences in cytochrome-P-450 content or cytochrome-C-reductase activity. No overt damage to the brain or spinal cord was seen in any treated animals. The sciatic nerves of three animals in the combined treatment group exhibited some histological damage which also showed a greater severity of damage than either treatment alone. The authors conclude that TELC and 2,5H produce neurotoxic effects through two separate and independent mechanisms.