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Evaluating age-related sensitivity to carbaryl-induced behavorial changes by PBPK/PD modeling
Citation:
Billings, D., M. Yoon, V. C. Moser, R. Macphail, AND H. Clewell. Evaluating age-related sensitivity to carbaryl-induced behavorial changes by PBPK/PD modeling. Presented at Society of Toxicology meeting, March 10 - 14, 2013.
Impact/Purpose:
This abstract will be presented at the Society of Toxicology meeting March 10-14, 2013, San antonio, TX
Description:
Due to its reversible inhibition of cholinesterases (ChEs), acute neurotoxicity is the primary effect of concern for carbaryl. Sensitivity to acute behavioral neurotoxicity of carbaryl was observed to be greater in aged rats, which was not fully attributable to differences in ChE inhibition. We used a PBPK/PD model to evaluate appropriate dose metrics to describe the observed age-related sensitivity to carbaryl in Brown Norway rats, using the change in horizontal motor activity as a marker of biological effect. The current model extends our previous PBPK/PD model in adult SpragueDawley rats that describes carbaryl disposition and inhibition of ChE in brain and blood. Age-appropriate physiological parameters were incorporated in the model in conjunction with age-specific metabolism parameters determined in primary hepatocytes isolated from young adult and aged rats (4, 12 and 24 month old). The model-simulated values compared well with the data both for peak and time-dependent changes in carbaryl concentration in the brain, liver and plasma as well as inhibition of ChE in brain and erythrocytes after a single oral exposure of carbaryl (3, 7.5, 15, or 22.5 mg/kg). While changes in motor activity were correlated with the degree of ChE inhibition at the time of peak effect (40 mm), the model did not reproduce the recovery of activity in the older rats up to 240 mm. The age-related difference was not explained by kinetics of reaction with ChE by carbaryl, but suggested differences in recovery dynamics in aged rats. The current study demonstrated the use of a PBPK/PD model to describe age-dependent acute effects and recovery from carbaryl, and provided a novel explanation for prolonged recovery in old animals. This is an abstract of a proposed presentation and does not reflect EPA policy (supported by EPA STAR grant R833452 and ACC-LRI).