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CHOLINESTERASE INHIBITION AND HYPOTHERMIA FOLLOWING EXPOSURE TO BINARY MIXTURES OF ANTICHOLINESTERASE AGENTS: LACK OF EVIDENCE FOR CAUSE-AND-EFFECT
Citation:
Gordon, C J., D W. Herr, C. Gennings, AND C M. Mack. CHOLINESTERASE INHIBITION AND HYPOTHERMIA FOLLOWING EXPOSURE TO BINARY MIXTURES OF ANTICHOLINESTERASE AGENTS: LACK OF EVIDENCE FOR CAUSE-AND-EFFECT. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Dose-additivity has been the default assumption in risk assessments of pesticides with a common mechanism of action but it has been suspected that there could be non-additive effects. Inhibition of plasma cholinesterase (ChE) activity and hypothermia were used as benchmarks of exposure to anticholinesterase insecticides to test the assumption of additivity of binary mixtures of chlorpyrifos (CHP) and carbaryl (CAR) in the Long-Evans rat. Male rats were dosed orally with mixtures of CHP and CAR in 2:1 and 1:1 ratios while core temperature (Tc) was monitored continuously by radiotelemetry. Plasma ChE activity was measured at 4 hr after dosing, a time associated with the peak hypothermic effect, in duplicate sets of rats dosed with 2:1 and 1:1 CHP:CAR mixtures. Doses were selected that coincided with a predicted threshold or maximal decrease in Tc. An additivity model was developed and predicted a threshold total mixture dose for hypothermia of 12 mg/kg for the 2:1 ratio and 14 mg/kg for the 1:1 ratio. The hypothermic response of the 2:1 ratio was antagonistic with significant hypothermia not observed until the dose equaled 35 mg/kg. However, the hypothermic response of the 1:1 ratio was additive at all doses tested. CHP and CAR reference doses of 30 and 70 mg/kg led to 84 and 37% reductions in plasma ChE activity at 4 hours post-dosing, respectively. Plasma ChE activity was inhibited by 60 and 50% for total doses of 14 and 35 mg/kg for the 2:1 CHP:CAR ratio; for the 1:1 ratio, ChE was inhibited by 54 and 64% for total doses of 12 and 42 mg/kg. The inhibition in ChE activity was not correlated with the magnitude of the thermoregulatory response. The inhibition in plasma ChE activity was not proportional to mixture dose. Overall, binary mixtures of CHP and CAR were either additive or antagonistic, depending on their ratio in a mixture, in terms of their effects on temperature regulation. These effects on Tc are not reflected in the inhibition in plasma ChE activity. Hence, the physiological response (i.e., decrease in Tc) is not necessarily correlated with the inhibition in plasma ChE activity for binary mixtures of CHP and CAR. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.