Estimation of human blood LC50 values for use in modeling of in vitro–in vivo data of the ACuteTox project

Abstract

The main aim of the ACuteTox project, under EU 6th Framework programme, is to investigate whether animal toxicity tests for acute systemic toxicity could be replaced by a combination of alternative assays. Data for 97 reference chemicals was collected in the ACuteTox database (Acutoxbase), designed to handle invitro and invivo (human and animal) lodged data. The principal basis for demonstration of the applicability of invitro tests is the invitro-invivo modeling, by using statistical correlation between invitro IC50 molar values (the 50% inhibitory concentration for the endpoints measured) and human blood molar concentrations LC50 (50% lethal concentrations). The LC50 values were calculated from time-related sub-lethal and lethal blood concentrations determined from human acute poisoning cases. The 3T3 standard NRU assay (3T3 NRU) was chosen, among the various basal cytotoxicity assays, applied in the ACuteTox project, to demonstrate the applicability of the IC50/LC50 values for invitro-invivo modeling. Linear regression analysis between IC50 (x) and LC50 (y) gave an explained variance R2=0.56 for the 67 reference chemicals, for which both sets of data were available. The results demonstrated usefulness of human LC50 values for invitro-invivo evaluation of the predictability of basal cytotoxicity assays for human acute systemic toxicity. The R2 value of 0.56 shows, as in the MEIC study, that additional organ-specific and biokinetic tests are needed in order to improve the predictability.