Comparison of Developmental Toxicity of Methylmercury in Vitro and in Vivo: Potential Value of in Vitro-Derived Data for Dose-Response Assessment. T. A. Lewandowski, R. A. Ponce, S. M. Bartell, and E. M. Faustman, University of Washington
The use of in vitro data in human health risk assessment holds great promise for increasing the rate at which we gain information about potentially hazardous chemicals but it also involves considerable uncertainty. While in vitro studies can provide qualitative and mechanistic data on chemical toxicity, the dose-response data derived using a cell culture system are difficult to relate quantitatively to the in vivo situation. In studying the developmental toxicity of methylmercury (MeHg) on the developing rat brain, we have acquired considerable in vitro and in vivo data for this compound. In vitro data was collected using primary midbrain cell cultures while in vivo data were collected using the same cell type and same gestational timepoints. The in vitro data indicates that MeHg inhibits cell cycle progression at concentrations of 1-2 uM (4 to 7 ug Hg/g in the cells). A similar brain cell concentration appears to be required for cell cycle inhibition in our in vivo studies. These results are also consistent with the study of Fuyuta et al (1978) which examined MeHg induced malformations. We have used a toxicokinetic model for MeHg to convert Fuyuta’s maternal doses to estimated embryonic brain concentrations. The threshold for effects in that study appears to be in the range of 5 to 9 ug Hg/g brain, consistent with our own findings. Taken together, these data suggest that a carefully chosen in vitro system can provide dose-response data which are quantitatively similar to those observed in vivo. Such an approach also provides a framework by which in vitro data can be included in dose/response assessment.
Supported by NIEHS T32ESO-7032, USEPA CR825173, USEPA R825358 and USEPA/NIEHS R826886.
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