Overview of the Final MEIC Results: II. The In Vitro-- In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans

Abstract

In MEIC, all 50 reference chemicals were tested in 61 in vitro assays. To provide a background to the in vitro/in vivo evaluation, mouse LD 50 values were compared with human lethal doses, resulting in a good correlation (R 2 0.65). To study the relevance of in vitro results, IC 50 values were compared with human lethal blood concentrations (LCs) by linear regression. An average IC 50 for the ten 24-hour human cell line tests predicted peak LCs better (R 2 0.74) than other groups of tests. When IC 50 values for 32 chemicals which rapidly enter brain were divided by a factor of 3.2 and 48-hour IC 50 values were compared with 48-hour human LCs for 10 slow-acting chemicals, the prediction improved considerably. Human toxicity was clearly underpredicted for only four chemicals, namely digoxin, malathion, nicotine and atropine, indicating a high relevance of the human cell line toxicity. All chemicals entering the brain induced a CNS depression, explaining this syndrome as a cytotoxic effect. Multivariate analysis was used to select an optimal combination of assays, resulting in a battery of three 24-hour human cell line tests (endpoints: protein, ATP and morphology/pH) with good direct prediction of human peak LCs (R 2 0.77).