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.
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).
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