Structural relationships between mutagenicity, maximum tolerated dose, and carcinogenicity in rodents.
The CASE structure-activity relational system was applied to a study of the structural bases of toxicity as expressed in the maximum tolerated dose (MTD) of a group of chemicals for which rodent carcinogenicity and mutagenicity data were also available. All of the results were obtained under the aegis of the U.S. National Toxicology Program. The analyses revealed that there was a structural basis for the MTD in mice and in rats and that these overlapped considerably. There was also some overlap between structural determinants of the MTD and of carcinogenicity in rodents but there was also a significant "antagonism" between such fragments; i.e., fragments associated with high toxicity (low MTD) were associated with lack of carcinogenicity and vice versa. The highest overlaps observed were between the structural determinant for a low MTD (i.e., high toxicity) and mutagenicity in Salmonella.
Rosenkranz
H S
HS
Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15238.
Klopman
G
G
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship
D002273:Carcinogens; D009153:Mutagens