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ANALYSIS OF THE MOTOR NEUROTOXICITY INDUCED BY ACUTE ORAL EXPOSURE TO MULTIPLE PYRETHROID COMPOUNDS IN THE RAT USING AN ADDITIVITY MODEL.
Citation:
WOLANSKY, M., C. GENNING, AND K. M. CROFTON. ANALYSIS OF THE MOTOR NEUROTOXICITY INDUCED BY ACUTE ORAL EXPOSURE TO MULTIPLE PYRETHROID COMPOUNDS IN THE RAT USING AN ADDITIVITY MODEL. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Description:
Use of pyrethroids has increased in the last decade, and co-exposure to multiple pyrethroids has been reported in humans. Pyrethroids produce neurotoxicity in mammals at dosages far below those producing lethality. The Food Quality Protection Act requires the EPA to consider cumulative risk for pesticides having a common mechanism-of-action (MOA). A common MOA proposed for pyrethroids is based on altered neuronal sodium channel dynamics, consequent changes in membrane polarization and abnormal discharge of targeted neurons. We recently characterized dose-responses for in vivo motor neurotoxicity (figure-8 maze activity) in adult male Long Evans rats for 11 commonly used pyrethroids (5 Type I, 5 Type II, and one Type I/II pyrethroids, po, corn oil as vehicle). A threshold additivity model was used to estimate: ED30s, threshold doses, and relative potency factors (RPFs; deltamethrin as index compound). This model was also used to predict the effects of a pyrethroid mixture containing all 11 pyrethroids. All pyrethroids produced dosage-dependent drops in activity. RPFs ranged from 0.009 to 2.09. Threshold doses ranged from 0.48 (esfenvalerate) to 116.6 (resmethrin) mg/kg. A mixture dose-response was characterized in rats dosed 2 hr prior to motor activity testing. A stock mixture solution was made with concentrations of the individual pyrethroids based on the ratio of threshold doses. Seven dilutions (100, 66, 50, 33, 10, 4, and 1%) of the mixture were tested (n=11-12/group). The mixture produced a concentration-dependent decrease in motor activity, with significant effects at 33% and higher. Data analysis revealed two important outcomes: 1) the empirical effects of the mixture were predicted by dose-addition theory, and 2) that a mixture containing only sub-threshold concentrations of individual pyrethroids will significantly alter behavioral function. Future work will test the assumption of additivity using mixture exposure scenarios derived from environmental samples. (This abstract does not reflect U.S. EPA policy.)