DOSE-RESPONSE RELATIONSHIP IN MULTISTAGE CARCINOGENESIS - PROMOTERS

Published dose-response curves of promoters of multistage carcinogenes is were selected that met the combined criteria of long study times, m ultiple doses, and low doses. In rat liver, 12 dose-response studies o f 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-d ioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta- , and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected . These promoters were studied for 7-86 weeks and either altered hepat ic foci or hepatic cancer were determined. The doses ranged from 1 ng (TCDD) to 400 mg (chloroform). In mouse skin, 10 dose-response studies of 4 promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], anthralin , chrysarobin, and -di-tert-butyl-4-hydroperoxyl-2,5-cyclohexadienone [BHTOOH]) were selected. In these mouse skin studies the doses ranged from 0.425 nmole (TPA) to 20,000 mnole (BHTOOH) per mouse. The length of time promoters were applied to the skin varied between 15 and 60 we eks. Either skin papillomas or carcinomas were determined. The dose-re sponse relationships are presented on the basis of moles of promoter, percentage of the fully effective promoting dose, of percentage of the acute oral rat LD(50). The degree of concavity of the dose-response c urves was determined. The available dose-response data are critiqued a nd discussed on the basis of future research needs for biologically ba sed cancer risk assessment models.