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EVALUATING TOOLS AND MODELS USED FOR QUANTITATIVE EXTRAPOLATION OF IN VITRO TO IN VIVO DATA FOR NEUROTOXICANTS*
Citation:
Chan, M. P., M. J. DeVito, T. J. SHAFER, R. Tornero-Velez, AND M. F. HUGHES. EVALUATING TOOLS AND MODELS USED FOR QUANTITATIVE EXTRAPOLATION OF IN VITRO TO IN VIVO DATA FOR NEUROTOXICANTS*. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
This abstract describes the quantative extrapolation of in vitro to in vivo data for the pyrethroids bifenthrin and deltamethrin. Reverse dosimetry/toxicokinetic modeling estimated administered in vivo dose within a factor of 22 for deltamethrin and a factor of 2-3 for bifenthrin
Description:
There are a number of risk management decisions, which range from prioritization for testing to quantitative risk assessments. The utility of in vitro studies in these decisions depends on how well the results of such data can be qualitatively and quantitatively extrapolated to in vivo responses. Extrapolation of in vitro data to in vivo responses includes both pharmacodynamic and pharmacokinetic ccnslderatlons, and often assumes that media concentrations are equivalent to steady-state blood concentrations. For this assumption to be correct, the partitioning of the chemical between media and cells must be equivalent to the partitioning of the chemical between blood and tissue. The relationship between in vitro effects and in vivo responses was evaluated using deltamethrin and bifenthrin as test chemicals. In vitro data on chemical-induced decreases in cell firing in rat primary cortical cell cultures were compared to decreases in motor activity in vivo. Reverse dosimetry/toxicokinetic modeling using media concentrations estimated the administered in vivo dose within a factor of 22 for deltamethrin and factor of 2-3 for bifenthrin. However, when the data are compared on a cell or tissue concentration, reverse dosimetry/toxicokinetic modeling using cellular concentrations estimated the administered in vivo dose within a factor of 2 for deltamethrin and factor of 6-20 for bifenthrin. Accounting for cell:media partitioning reconciled in vitro/ in vivo comparison for deltamethrin but not for bifenthrin suggesting that for bifenthrin the in vitro effect model is mis-specified or that cellular concentrations are not accurately estimated by these procedures. Successful comparisons with deltamethrin but not bifenthrin indicate the need to examine these approaches for a wider set of pyrethroids. (This abstract does not reflect NIEHS or EPA policy).