Correlation between cytotoxicity in vitro and LD50‐values.

Abstract Previous studies of the correlation between cytotoxicity in vitro and LD50 in rodents have shown a good correspondence for small groups of substances, such as antibiotics, metals, and solvents, but a poor correspondence for other small groups of substances, such as drugs and pesticides, as well as for larger groups of heterogeneous chemicals. The generally poor correlation may be the result of the joint operation of three factors: 1. The existence of organ‐specific toxicity. 2. The pharmacokinetics in whole animals. 3. Methodological problems disturbing a basically equivalent in vitro/in vivo toxicity. We have made further studies of the correlation for altogether 95 drugs. The type of human and mouse systemic lethal poisoning was compared with the cytotoxicity divided by the i.v. LD50 in the mouse and approximate i.v. LD in man, called Specific Indices (SI1d). A minority of the drugs had an organ‐specific lethal action which was corresponding to high SI1d of 100 or more for all drugs. A majority of the drugs (80%) had a known or possible lethal interference with basal functions of animal and human tissues correlated to low SI1d of 1–10. At lethal dosage most of the latter drugs induce a non‐specific CNS depression, which was interpreted as the systemic reaction to basal cytotoxicity of chemicals reaching brain cells. Tissue culture tests of cytotoxicity seem to be relevant for the lethal action of most chemicals in man. Comparisons of in vitro/in vivo toxic dosage (SI1d) and concentrations might be used to screen the selectivity of lethal action of chemicals, and to select chemicals interfering with basal cell functions for further studies in vitro. It will be difficult to replace animal testing by cell tests in toxicity evaluation because of the organ‐specific toxicity and characteristic pharmacokinetics of many substances. However, initial standard in vitro cytotoxicity tests combined with subsequent approximative LD50 tests coupled to pharmacokinetic studies in the animals could produce data discriminating organ‐specific from basal cell toxicity. The toxic mechanisms of the probable majority of common chemicals with a basal cytotoxicity at lethal dosage could then be analysed in tissue culture, which would increase the precision of analysis, as well as saving animal lives.