Incorporating cell proliferation kinetics into models for cancer risk assessment

Some general principles in incorporating cell proliferation kinetics into dose-response models for cancer risk assessment are discussed. Two examples are presented in which a biologically-based dose-response model explicitly incorporating cell proliferation kinetics was used for the analysis of toxicologic data. In the first example, analysis of an initiation-promotion experiment in the rat liver, with diethylnitrosamine (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 promoters, is presented. The results of the analysis indicate that, in addition to its promoting activity, TCDD has weak initiating activity. In the second example, multiple doses of N-nitrosomorpholine (NNM) were administered to rats in their drinking water and quantitative information on ATPase deficient foci in the liver recorded at various times. Additionally, a separate group of animals, administered the same doses, was 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 construct a dose-response curve for the probability of malignant tumors. Few malignant tumors were observed at the lower doses; however, the information on ATPase deficient foci can be used in the model to extend the range of the dose-response curve below the doses at which malignant tumors are observed.