Rodent carcinogenicity and toxicity, in vitro mutagenicity, and their physical chemical determinants

In this paper, we considered rodent carcinogenicity and toxicity, and four in vitro mutagenicity systems, and we made a global comparison between their different response profiles to a common set of 297 chemicals. This analysis is complemented with a study of the physical chemical properties of active and inactive compounds in the different systems.

A clearcut separation between the different classes of toxicological end-points (carcinogenicity, in vivo toxicity, in vitro carcinogenicity) was evident. The observed lack of association between carcinogenicity and toxicity supports the validity of the rodent bioassays; this is contrary to the position that the positive results obtained are due mainly to the use of excessive doses that exert cytotoxic effects. We found substantial consistency in the responses of the in vivo toxicity systems (maximum tolerated dose and LD₅₀), but we also found that remarkable differences exist between the in vitro mutagenicity assay systems. The study of the structure-activity relationships showed that: (a) the hydrophobic-electronic properties of the chemicals influence rodent carcinogenicity, with the tendency of carcinogens to be more electrophilic and more hydrophobic than non-carcinogens; (b) steric effects are implied in in vitro mutagenicity, bulkier molecules being less mutagenic than smaller molecules; (c) no clear association between in vivo toxicity and physical chemical properties was apparent. The differences between carcinogenicity and in vitro mutagenicity may hypothetically be related to their different experimental procedures. The relatively short treatment of in vitro mutagenicity requires that chemicals penetrate easily into the cells, and are well dissolved into the aqueous medium, size and hydrophilicity thus being critical for the action of the chemicals. The size of the molecules is not critical in the long-term rodent carcinogenicity experiments, where other factors, like bioaccumulation (hydrophobicity) and electronic reactivity, become essential.