Cholinesterase inhibition in young-adult and preweanling Wistar rats treated by gavage for eleven days with ethoprophos

Document Number: M-252722-01-1
Report Number: 201317
Date: 2005-06-14




Technical-grade Ethoprophos was administered daily by gavage on 11 consecutive days to young-adult and preweanling (treated on postnatal days 11 through 21) male and female Wistar rats to evaluate relative sensitivity based on inhibition of acetylcholinesterase (AChE) activity. The test substance was administered as a solution in corn oil, at a dose volume of 5 ml/kg, at nominal dosages (mg/kg/day) of 0, 0.50, 1.0 and 2.0 in adults and 0, 0.25, 0.50 and 1.0 in preweanling animals. Blood and brain samples were collected at the time of peak effect following the administration of the last dose to measure plasma ChE and erythrocyte and brain AChE activities.

Based on analytical results, the confirmed dosages of test substance were as follows: 

Adult: 0.48, 1.03, and 2.04 mg/kg/day;
Preweanling: 0.25, 0.50 and 1.02 mg/kg/day.

Plasma ChE activity. In adults, the lowest dosage of 0.50 mg/kg/day had no effect in adult males and 44% inhibition of activity in females. Statistically-significant inhibition was evident in males and females at the mid- (23% and 57%, respectively) and highest (23% and 66%, respectively) dosage levels. In preweanlings, there was gender-based differences in sensitivity and inhibition was statistically significant at all dosage levels. There were minimal differences from control (17-24%) at the lowest dosage of 0.25 mg/kg/day, with a dose- related increase in inhibition at the mid- (34-39%) and highest (47-49%) levels for males and females.

Brain AChE activity was not affected by treatment in adult males at any dosage level. For adult females, there was no effect at 0.50 or 1.0 mg/kg/day and only slight inhibition (12%) at the highest dosage. In preweanlings, statistically-significant inhibition was evident at all dosage levels in both sexes, with comparable effects in males and females at 0.25 (10- 15% ), 0.50 (24-27%) and 1.0 (42-43%) mg/kg/day.

Erythrocyte AChE activity. In adults, there was no effect on activity in males or females at the 0.50 mg/kg/day dosage. Statistically-significant inhibition was evident in adult males and females at the mid- (53% and 28%, respectively) and highest (73% and 61%, respectively) dosage levels. In preweanlings, statistically significant inhibition was apparent in males at the mid- and high dosage (39% and 65%, respectively) and in females at the highest dosage (54%). Females dosed at 0.50 mg/kg/day dosage level were unaffected by treatment.

A benchmark dose analysis was performed with these data to determine dosages associated with 10% (BMD10) and 20% (BMD20) inhibition of AChE activity. For adult males and females, the BMD10 and BMD20 for erythrocyte AChE activity is 0.26-0.36 and 0.52-0.72, respectively, and the BMD10 and BMD20 for brain AChE activity is 2.62-1.79 and 3.71-2.54, respectively. By comparison, for preweanling males and females, the BMD10 and BMD20 for erythrocyte AChE activity is 0.15-0.22 and 0.31-0.42, respectively, and the BMD10 and BMD20 for brain AChE activity is 0.23-0.24 and 0.46-0.48, respectively.

These results indicate that brain AChE activity is affected to a much greater extent in preweanling rats than in adults but there is very little difference in sensitivity to erythrocyte AChE activity, which is the more sensitive measure of an effect at both ages (BMD10 = 0.15 mg/kg/day in the young and 0.26 mg/kg/day in the adult).

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