Dose-response and time-course of neurobehavioral changes following oral chlorpyrifos in rats of different ages

Young rats have been shown in several laboratories to be more sensitive to the neurotoxic effects of acute exposure to chlorpyrifos. To examine the ne urobehavioral effects of chlorpyrifos as a function of age and dose, we con ducted dose-response and time-course assessments in rats of three different ages (postnatal day, or PND, 17, 27, and adults). Doses were selected to s pan the effective dose range in each age group: PND17-4, 10, 20 mg/kg; PND2 7-10, 25, 50 mg/kg; adult-10, 50, 100 mg/kg. Rats were tested at the time o f peak effect on the day of dosing, and again at 1 and 3 days, and at 1 and 2 weeks after a single oral dose. There were age- and sex-related differen ces in the recovery of these behavioral effects; the adult males recovered from the behavioral effects more quickly than the other age groups, and the adult females showed the slowest recovery (up to at least 3 days). Althoug h these doses had been shown previously to produce a similar degree of chol inesterase inhibition, the neurobehavioral alterations fell into the follow ing three patterns of effect as a function of age. (1) Some endpoints (e.g. , gait abnormalities, tremor) showed a dose-response curve that was shifted to the right in the older animals. Calculated ED50 values indicated that t he PND17 rats were three- to five-fold more sensitive than the adults. (2) Some measures showed less effect in the youngest rats; for example, maximal motor activity decreases were half as great as with adults. (3) A few effe cts that were typically observed in adults, e.g., salivation, were not seen at all in the PND17 rats. Thus, differential responses on these neurobehav ioral endpoints were observed as a function of age. These data suggest that , for some endpoints, young rats are more sensitive to a range of chlorpyri fos doses; however, the magnitude of age-related differences depends on the specific endpoint and time of assessment, as well as age and sex of the te st subject. (C) 2000 Elsevier Science Inc. All rights reserved.