CORRELATION OF ACUTE LETHAL POTENCY WITH INVITRO CYTOTOXICITY

The in vitro cytotoxicity (measured as ID50 value) of 27 compounds believed to act by interference with cell basal functions/structures has been determined and compared with their acute lethal toxicity (measured as oral and ip LD50 values) using a previously described approach to the choice of the most appropriate LD50 value from the Registry of Toxic Effects of Chemical Substances database. A weak, but significant, positive correlation of log oral LD50 value with log ID50 value was obtained (r = 0.49; 0.02 < P < 0.05) for 21 compounds for which oral and ip LD50 values were obtainable. A better correlation between LD50 and ID50 was obtained when the log ip LD50 value was used (r = 0.68; P < 0.001). Three compounds, for which metabolism is a major determinant of toxicity in vivo, yielded anomalous results in the ip LD50/ID50 comparison. A further improvement in the correlation of log ip LD50 with log ID50 was obtained when data from these compounds were excluded (r = 0.82; P < 0.001). Close correlations of log ip LD50/log ID50 were obtained with groups of six anti-metabolites and six alkylating agents (r = 0.94 and 0.96, respectively; P < 0.001 in each case). The locations of the regression lines for these two groups were significantly different (P < 0.01). It is concluded that the in vitro cytotoxicity of compounds that exert their toxicity by interference with cell basal functions/structures is correlated with their intrinsic lethal potency, but that information on absorption, metabolism and disposition are required before the cytotoxicity data can be used to assess apparent potency. The data provide evidence that the precise relation of LD50/ID50 values is determined by the mode of toxicity. © 1990.