Incorporating additional biological phenomena into two-stage cancer models.

Several difficulties arise in the implementation of the Armitage-Doll-type carcinogenesis model. Some of these difficulties have been briefly discussed herein, with particular attention to the recent finding that the magnitude of current animal-based bounds on human cancer potency is influenced by animal background transition rates. Although the ideal method of accounting for the background transition rates necessitates more direct biological information, this paper offers risk assessors some alternatives for improving current quantitative cancer potency assessment. Computer software has been developed to facilitate the use of not only the multistage model but also other dose-response models, including the following: 1) tolerance models (probit, logit, multihit, and Weibull), which assume that a distribution of tolerances exists in the population and that when a tolerance is exceeded, a carcinogenic response occurs; 2) multihit models, which assume that a carcinogenic response occurs when a tissue receives more than a specified number of hits; 3) Armitage-Doll multistage models, which explicitly model the time and/or dose dependence of each transition stage; 4) time-to-response extensions of the multistage model; and 5) extensions of the multistage model including cell proliferation (Lu and Sielken 1991, Holland and Sielken 1993). In any of the dose-response models, the dose scale is not restricted to the administered dose scale. Computer software that facilitates the use of more biologically relevant dose scales (such as delivered and biologically effective dose scales) is now available. Furthermore, the differences between species and routes of exposure in the amount of delivered or biologically effective dose corresponding to a particular administered dose can be incorporated. The dependence of an individual's dose on not only the individual's administered dose but also the individual's background dose and susceptibility can be incorporated as well. Hence, interindividual variability in dose levels and probabilities of a carcinogenic response can be considered (Holland and Sielken 1993). The possibility also exists of incorporating more cell biology into carcinogenesis theory using the MVK two-stage model. In this model, cell proliferation parameters are included, in contrast to models of the Armitage-Doll family. The MVK model offers increased potential for obtaining estimates of low-dose behavior that reflect more of the available biological data, including microdosimetry data. A Monte Carlo simulator for this model can be used in cases in which more complex biological mechanisms are included, information other than the means of population distributions is desired, and information on subpopulations is desired.(ABSTRACT TRUNCATED AT 400 WORDS)