Prediction of carcinogenicity based on structure, chemical reactivity and possible metabolic pathways

The carcinogenicity and chemical structure-reactivity relationships of alkylating and acylating agents have been examined for approximately one hundred compounds in these classes. The alkylating compound types of interest included epoxides, lactones, halo-ethers and 1,4-dichlorobutene-2. The acylating agents examined were dimethyl- and diethyl-carbamyl chloride. The biologically active compounds in this series are direct-acting carcinogens, i.e. they do not need to be metabolized to activated intermediates. Of the compounds examined, three industrial chemicals are now classified as human carcinogens based on epidemiologic studies. They are: chloromethyl methyl ether, bis(chloromethyl)ether, and the widely used compound epichlorohydrin. Two other industrial chemicals which have been shown to be potent carcinogens by several routes of administration in mice and rats, including inhalation exposure in rats, are potential human occupational carcinogens. They are: 1,4-dichlorobutene-2 and dimethyl-carbamyl chloride. The studies show that this approach of structure-activity studies can lead to prediction of human carcinogenicity before epidemiologic studies are carried out. This work has been extended to indirect-acting carcinogens such as halo-olefins by an examination of possible metabolic pathways and from the latter, the prediction of carcinogenicity. These extensive studies have led to the capability of selecting and pinpointing potential animal carcinogens and in some instances also human carcinogens, as exemplified by the three occupational carcinogens cited above. Similar studies have been extended to co-carcinogens and tumor promoters.