INCORPORATING CELL-PROLIFERATION KINETICS INTO MODELS FOR CANCER RISKASSESSMENT

Some general principles in incorporating cell proliferation kinetics i nto dose-response models for cancer risk assessment are discussed. Two examples are presented in which a biologically-based dose-response mo del explicitly incorporating cell proliferation kinetics was used for the: analysis of toxicologic data. In the first example, analysis of a n initiation-promotion experiment in the rat liver, with diethylnitros amine (DEN) as initiator and with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HCDD) as promote rs, is presented. The results of the analysis indicate that, in additi on to its promoting activity, TCDD has weak initiating activity. In th e second example, multiple doses of N-nitrosomorpholine (NNM) were adm inistered to rats in their drinking water and quantitative information on ATPase deficient foci in the liver recorded at various times. Addi tionally, a separate group of animals, administered the same doses, wa s followed until death and the presence or absence of malignant liver tumors recorded. The parameters of the model were estimated by fitting the model to these data and the estimated parameters were used to con struct a dose-response curve for the probability of malignant tumors. Few malignant tumors were observed at the lower doses; however, the in formation on ATPase deficient foci can be used in the model to extend the range of the dose-response curve below the doses at which malignan t tumors are observed.