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Time-course, dose-response, and age comparative sensitivity of N-methyl carbamates in rats
Citation:
MOSER, V. C., K. MCDANIEL, P. PHILLIPS, AND A. LOWIT. Time-course, dose-response, and age comparative sensitivity of N-methyl carbamates in rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 114(1):113-123, (2010).
Impact/Purpose:
To study potential age-related differences, we evaluated seven carbamates (carbaryl, carbofuran, formetanate, methiocarb, methomyl, oxamyl, and propoxur) in preweanling (17 days old, or PND 17) male rats.
Description:
N-Methyl carbamate insecticides are reversible inhibitors of central and peripheral acetylcholinesterease (ChE). Despite their widespread use, there are few studies of neurotoxicity in young animals. To study potential age-related differences, we evaluated seven carbamates (carbaryl, carbofuran, formetanate, methiocarb, methomyl, oxamyl, and propoxur) in preweanling (17 days old, or PND 17) male rats. Motor activity was monitored, and ChE inhibition was measured in brain and red blood cells (RBC) using a radiometric assay that minimized reactivation ofChE. First, we conducted time-course studies in PND17 Long-Evans (LE) male rats, using a single oral dose of each carbamate. Almost all carbamates showed maximal ChE inhibition at a 45-min time point; only methomyl showed an earlier peak effect (15 min). At 24 hr, most inhibition had recovered. The time-course of recovery of enzyme inhibition was similar for RBC and brain for all carbamates. Next, dose-response data were collected for each carbamate, using four doses and control, with motor activity testing beginning 15 min after dosing, and tissue collection at 40-45 min. RBC ChE was inhibited to a greater degree than brain in all studies. Motor activity was not as sensitive a measure for some ofthe carbamates, with some differences across carbamates in the shapes ofthe dose-response curves. Additional studies documented age-related differences by comparing ChE inhibition in PNDll, PND 17, and adult rats following administration of carbaryl or carbofuran. Only the youngest (PNDll) rats were more sensitive than adults to carbaryl, but both younger ages showed more effects than adults with carbofuran. In addition, compared to previous work with some ofthese carbamates in adult LE male rats, the preweanling rats appeared somewhat more sensitive to acute ChE inhibition. Thus, these data show the time-course and dose-response characteristics for each chemical and document greater sensitivity ofthe young for carbofuran and carbaryl.
