Theoretical consideration on the prediction of in vivo toxicity from in vitro toxicity: Effect of bio-uptake equilibrium, kinetics and mode of action

Abstract Although in vitro assay is an ideal alternative method for the in vivo toxicity prediction, different in vivo-in vitro correlations have been observed for the toxicity endpoints obtained from different levels of species. In this paper, theoretical in vivo-in vitro toxicity correlations have been developed for cytotoxicity versus human, mammalian and fish toxicity, respectively. These theoretical models were then used to investigate the correlations and the influencing factors between in vivo and in vitro toxicity. Bio-uptake equilibrium theory can well explain why there is a significant correlation between fish and cell toxicity (R 2  = 0.70); why human toxicity is very close to fish toxicity; and why hydrophobic compounds exhibit relatively greater toxicity than reactive or specifically-acting compounds to human and fish as compared to cells. The kinetic theory can well explain why there is a very poor relationship between mammal and cell toxicity (R 2  = 0.44). This paper reveals that polar and ionized compounds can more easily pass through cell membrane and have greater bioconcentration potential. Increasing of hydrophobicity and ionization can increase the cytotoxicity. Inclusion of descriptors representing hydrophobicity, ionization, acidity and absorption into the correlation equations can significantly improve the correlations of cytotoxicity with human and fish toxicity (R 2  > 0.8), but not with mammal toxicity (R 2  = 0.49). These descriptors reflect the differences of the toxicodynamics and toxicokinetics between cells and organisms.