Comparisons of human-cell-based and submitochondrial particle bioassay responses to the MEIC compounds in reference to human toxicity data

Abstract

Toxicity results from submitochondrial particle (SMP) bioassays were compared to results from multiple human-cell-based assays to evaluate the SMP tests’ ability to indicate cellular toxicity. Correlation analyses between cell-based and SMP responses were conducted on a series of diverse chemicals of human toxicologic interest chosen in the Multicentre Evaluation of In vitro Cytotoxicity (MEIC) study and suggest a high degree of ordering. The r 2 correlation coefficient obtained when comparing the log-transformed SMP results to the average cellular response for all compounds was 0.75 ( n=42). When specific mitochondrial inhibitors (to which SMP arc extremely sensitive) and toxic metals (which SMP modeled poorly) were removed, the correlation improved to 0.91 ( n=34). When the SMP assay of each individual cell-based assay was compared to the average toxic response of all the cell-based assays for these 34 compounds, the SMP r 2 was greater than the median r 2 of the cell-based assays, indicating its ability to predict cell-based toxic responses with a high degree of accuracy. Comparisons of the SMP data to the human toxicity data are similar to the cell line assays, where removal of the specific mitochondrial toxicants and metals greatly improves the relationship.